SNPMiner Trials by Shray Alag


SNPMiner Trials: Mutation Report


Report for Mutation L858R

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

There are 263 clinical trials

Clinical Trials


1 Gefitinib Versus Combination of Gefitinib With Chemotherapy or Anti-angiogenesis as 1st Line Treatment in Advanced NSCLC Patients Detected With Bim Deletion or Low EGFR Activating Mutation Abundance:A Randomized, Multicentre, Phase II Study

This is an open-label, multicenter, randomized, phase II clinical trial, which aims to evaluate the effectiveness and safety of gefitinib versus combination of gefitinib and doublet chemotherapy or apatinib in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) activating mutation (exon 19 deletion or exon 21 L858R point mutation), accompanied with Bim deletion or low activating EGFR mutation abundance.

NCT03267654 Non-small-cell Lung Cancer Drug: gefitinib combined with chemotherapy Drug: gefitinib combined with apatinib Drug: gefitinib single agent
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

Gefitinib With Chemotherapy or Anti-angiogenesis in NSCLC Patients With Bim Deletion or Low EGFR Mutation Abundance This is an open-label, multicenter, randomized, phase II clinical trial, which aims to evaluate the effectiveness and safety of gefitinib versus combination of gefitinib and doublet chemotherapy or apatinib in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) activating mutation (exon 19 deletion or exon 21 L858R point mutation), accompanied with Bim deletion or low activating EGFR mutation abundance. --- L858R ---

3. EGFR mutation (exon 19 deletion or exon 21 L858R) with Bim deletion or low abundance for EGFR mutation. --- L858R ---

Primary Outcomes

Description: From start of anti-cancer therapy until progression or death

Measure: Progression free survival

Time: 8 weeks

Secondary Outcomes

Description: evaluated in the 36th since treatment begain

Measure: overall survival

Time: 36 months

Description: Evaluated the rate of complete response and partial response in the 8 weeks since treatment began

Measure: objective response rate

Time: 8 weeks

Description: Evaluated the rate of complete response,partial response and stable disease in the 8 weeks since anti-cancer therapy

Measure: disease control rate

Time: 8 weeks

Description: interval between the time which complete response or partial response happened and progressive disease or death

Measure: duration of response

Time: 8 weeks

Description: Safety observation indexes were listed as following: adverse events and serious adverse events (according to CommonTerminology Criteria Adverse Events Version 4.03), physical exam, vital signs(blood pressure, heart rate, respiratory rate,body temperature), weight variation, laboratory examination(hematology, blood biochemistry, urinalysis and so on), electrocardiograph(ECG),ultrasonic cardiogram(UCG), ect.

Measure: safety evaluation

Time: 8 weeks

Description: Quality of Life Questionnaire(including QLQ-C30 and QLQ-LC13) evaluated since treatment began.At the end of the trial, the differences between the two indicators were compared with Mixed-effects model repeated measures (MMRM), where the baseline was scored as a covariant and the treatment group as a fixed variable. In addition, the baseline values of the two scores, the value of each visit, and the change value of the baseline were statistically described.

Measure: compare quality of life

Time: 24 months

2 A Multicenter, Open-Label Phase 1 Study of U3-1402 in Subjects With Metastatic or Unresectable Non-small Cell Lung Cancer

This study has two parts: dose escalation and dose expansion. The primary objectives are: - For Dose Escalation, to assess the safety and tolerability of U3-1402 in the study population and to determine the recommended dose for expansion of U3-1402 in the study population - For Dose Expansion, to investigate the antitumor activity of U3-1402 The number of treatment cycles is not fixed in this study. Participants will continue study treatment (for approximately 36 months) until they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity) or other stopping reasons have been met.

NCT03260491 Non-Small Cell Lung Cancer (NSCLC) Drug: U3-1402
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria for both Dose Escalation and Dose Expansion: 1. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 2. Has at least one measurable lesion per RECIST version 1.1 3. Has Eastern Cooperative Oncology Group performance status of 0 or 1, with no deterioration over the previous 2 weeks Inclusion Criteria for Dose Escalation only: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011) 1. Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 3. Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib 4. Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of Screening 5. Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib 6. --- L858R ---

3. Has documentation of EGFR-activating mutation(s) detected from tumor tissue: G719X, exon deletion 19, L858R, or L861Q. --- L858R ---

Has clinically significant corneal disease Additional Exclusion Criteria for Dose Expansion Cohort 2: 1. Has documentation of one or more of the following EGFR activating mutations: G719X, exon 19 deletion, L858R, or L861Q Inclusion Criteria for both Dose Escalation and Dose Expansion: 1. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 2. Has at least one measurable lesion per RECIST version 1.1 3. Has Eastern Cooperative Oncology Group performance status of 0 or 1, with no deterioration over the previous 2 weeks Inclusion Criteria for Dose Escalation only: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011) 1. Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 3. Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib 4. Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of Screening 5. Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib 6. --- L858R ---

Has clinically significant corneal disease Additional Exclusion Criteria for Dose Expansion Cohort 2: 1. Has documentation of one or more of the following EGFR activating mutations: G719X, exon 19 deletion, L858R, or L861Q Inclusion Criteria for both Dose Escalation and Dose Expansion: 1. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 2. Has at least one measurable lesion per RECIST version 1.1 3. Has Eastern Cooperative Oncology Group performance status of 0 or 1, with no deterioration over the previous 2 weeks Inclusion Criteria for Dose Escalation only: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011) 1. Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 3. Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib 4. Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of Screening 5. Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib 6. --- L858R --- --- L861Q --- --- L858R ---

Has clinically significant corneal disease Additional Exclusion Criteria for Dose Expansion Cohort 2: 1. Has documentation of one or more of the following EGFR activating mutations: G719X, exon 19 deletion, L858R, or L861Q Non-Small Cell Lung Cancer (NSCLC) Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R ---

Primary Outcomes

Measure: Dose-limiting toxicities (DLTs) in the dose escalation period

Time: 21 days of Cycle 1

Measure: Summary of adverse events in the dose escalation period

Time: By the global end of trial date, approximately within 36 months

Description: Evaluated using RECIST 1.1

Measure: Overall response rate (ORR) assessed by Independent Central Review Committee (Central Review) in the dose expansion period

Time: Approximately within 36 months

Secondary Outcomes

Measure: Maximum plasma concentration (Cmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Time of maximum concentration (Tmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Area under the serum concentration-time curve from time 0 to 8 hours (AUC[0-8]) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Area under the serum concentration-time curve up to the last quantifiable time (AUC[last]) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Terminal elimination rate constant (Kel) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Elimination half-life (t1/2) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Total body clearance (CL) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Volume of distribution after a single-dose (Vz) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Volume of distribution at steady-state after multiple doses (Vss) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Description: Evaluated using RECIST 1.1

Measure: Overall response rate (ORR) in the dose escalation period

Time: Approximately within 36 months

Measure: Disease control rate (DCR) in the dose escalation period

Time: Approximately within 36 months

Measure: Duration of response (DOR) in the dose escalation period

Time: Approximately within 36 months

Measure: Time to response (TTR) in the dose escalation period

Time: Approximately within 36 months

Measure: Progression free survival (PFS) in the dose escalation period

Time: Approximately within 36 months

Measure: Overall Survival (OS) in the dose escalation period

Time: Approximately within 36 months

Measure: Summary of adverse events in the dose expansion period

Time: By the global end of trial date, approximately within 36 months

Measure: Maximum plasma concentration (Cmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Time of maximum concentration (Tmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Area under the serum concentration-time curve from time 0 to 8 hours (AUC[0-8]) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Area under the serum concentration-time curve up to the last quantifiable time (AUC[last]) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Terminal elimination rate constant (Kel) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Elimination half-life (t1/2) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Total body clearance (CL) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Volume of distribution after a single-dose (Vz) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Volume of distribution at steady-state after multiple doses (Vss) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Description: Evaluated using RECIST 1.1

Measure: Overall response rate (ORR) in the dose expansion period

Time: Approximately within 36 months

Measure: Disease control rate (DCR) in the dose expansion period

Time: Approximately within 36 months

Measure: Duration of response (DOR) in the dose expansion period

Time: Approximately within 36 months

Measure: Time to response (TTR) in the dose expansion period

Time: Approximately within 36 months

Measure: Progression free survival (PFS) in the dose expansion period

Time: Approximately within 36 months

Measure: Overall Survival (OS) in the dose expansion period

Time: Approximately within 36 months

3 Evaluation of the Efficacy of Domestic Gefitinib Tablets in the Treatment of Locally Advanced or Metastatic Non-small Cell Lung Cancer Patients Using a Multicenter, Randomized, Positive Drug Gefitinib Pharmacodynamics and Pharmacodynamics

1. Gefitinib CTTQ production gefitinib and erlotinib sheet AstraZeneca imatinib sheet (trade name: Iressa ®) comparison, human pharmacokinetics and relative bioavailability of comparative studies which examine people in vivo pharmacokinetic behavior, provide the basis for clinical use. 2. Evaluation CTTQ gefitinib imatinib sheet production efficacy and safety of Chinese patients with locally advanced or metastatic non-small cell lung cancer.

NCT03264794 Non-small Cell Lung Cancer Drug: Gefitinib Tab (CTTQ),First medication;Gefitinib Tab (CTTQ),From the 8th day of trial Drug: Gefitinib tablets (Yi Ruisha),First medication Drug: Gefitinib Tab 250 MG(CTTQ),From the 8th day of trial.
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: 1. Patients volunteered to participate in this study, signed informed consent; 2. ≥18 years old; ECOG PS score: 0 ~ 1; expected survival period of more than 3 months; 3. patients with locally advanced or metastatic non-small cell lung cancer diagnosed by histology or cytology, who can not receive radical surgery or radiotherapy; patients with measurable lesions(according to RECIST criteria); 4. Detection of EGFR-positive exon 19 deletion or exon 21 (L858R) mutation was performed by providing a detectable specimen (tissue or cancerous pleural effusion) prior to enrollment; 5. --- L858R ---

Primary Outcomes

Description: After the use of gefitinib to reach the highest plasma concentration

Measure: Gefitinib plasma concentration

Time: 0hour before administration and 1, 2, 3, 4, 5, 6, 7, 8,9,13,24,48,72,120,168 16 hour time points after administration

Description: Taking the time required for the concentration of gefitinib to reach the peak

Measure: Tmax time

Time: 0hour before administration and 1, 2, 3, 4, 5, 6, 7, 8,9,13,24,48,72,120,168 16 hour time points after administration

Description: The area between the axis of the coordinate and the time drug concentration curve

Measure: AUC0-t

Time: 0hour before administration and 1, 2, 3, 4, 5, 6, 7, 8,9,13,24,48,72,120,168 16 hour time points after administration

Description: The time required for gefitinib to decrease by half the highest concentration in plasma

Measure: t 1/2

Time: 0hour before administration and 1, 2, 3, 4, 5, 6, 7, 8,9,13,24,48,72,120,168 16 hour time points after administration

Description: Gefitinib absorbs the relative amount of blood into the cycle

Measure: F

Time: 0hour before administration and 1, 2, 3, 4, 5, 6, 7, 8,9,13,24,48,72,120,168 16 hour time points after administration

4 A Randomized, Open-label, Multi-center Phase III Study of Erlotinib Versus Gemcitabine/Carboplatin in Chemo-naive Stage IIIB/IV Non-Small Cell Lung Cancer Patients With EGFR Exon 19 or 21 Mutation (Optimal)

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) such as erlotinib have proved effective in second or third line therapy for advanced non-small cell lung cancer(NSCLC).It is well tolerated without the side effects usually associated with chemotherapy. The mutations in EGFR exons 19 or 21 have been reported to be associated with efficacy of EGFR TKIs.Based on the encouraging preliminary results from the Spanish lung cancer group' prospective study reported that the efficacy of Tarceva as first line treatment for metastatic NSCLC patients with EGFR mutation would delay disease progression,prolong overall survival and be well tolerated, medium Progression-free survival(PFS) was around 12 months and OS reach 24 months,our study is designed to compare PFS between the patients with mutant EGFR treated by gemcitabine/carboplatin and those by erlotinib in the first-line setting. We assumed 11 months of PFS on Tarceva arm versus 6 months on chemotherapy arm with a=0.025(alpha-spend for an interim analysis), 80% power and 12 months enrolment period, 12 months FU duration to calculate the sample size. The sample size is 69 pairs. Considering about 10% drop-out rate, the final sample size is 152 patients.So, chemo-naive staged IIIb/IV patients with EGFR mutations in exon 19 or 21 will be enrolled into this open-label, randomized,multicenter phase III study.

NCT00874419 Non-small Cell Lung Cancer Drug: erlotinib Drug: gemcitabine/carboplatin
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

2. EGFR exon19 deletions or exon 21 L858R mutation by the DNA direct PCR sequencing using fresh tumor sample or paraffin embed tumor sample. --- L858R ---

Primary Outcomes

Measure: Progression free survival

Time: 12 months

Secondary Outcomes

Measure: OS

Time: 24 months

Measure: ORR

Time: 24 months

Measure: Time to Progression

Time: 24 months

Measure: lung cancer symptoms and health-related quality of life (HRQoL)

Time: 24 months

Measure: explore the biological markers (tumor tissue)

Time: 24 months

5 Sequential Phase I/II Trial of Oral Vorinostat in Combination With Erlotinib in Non-small-cell Lung Cancer Patients With Mutations at Epidermal Growth Factor Receptor With Disease Progression After Erlotinib Treatment

This is an open label, non-randomized, sequential, phase I/II trial in patients with stage IIIB or IV non-small cell lung cancer (NSCLC) with EGFR mutations after progression to Erlotinib. The study will have two parts. The first part (phase I) will be a dose finding (MTD) study to be implemented at three hospitals. The second part of the study (phase II) will asses the safety and efficacy of the combination. In this second part (phase II) patients will be treated with oral Erlotinib 150 mg P.O daily plus oral Vorinostat administered according to the results of the phase I. The study endpoints to be evaluated will include safety and response rate (RR) as primary endpoints and clinical benefit rate (CBR), time to progression, time to response, response duration and progression free survival as secondary endpoints. All the patients (phase I and II) will be treated until progression disease, unacceptable toxicity or withdrawal of the consent, and will be treated at the discretion of the principal investigator.

NCT00503971 Non-small Cell Lung Cancer Drug: Vorinostat plus Erlotinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

4. Have demonstrated mutations at epidermal growth factor receptor (EGFR) at Exon 19 or Exon 21 (Exon 19 mutations characterized by in-frame deletions (747-750), and Exon 21 mutations resulting in L858R substitutions). --- L858R ---

Primary Outcomes

Measure: MTD (Maximum Tolerated Dose)defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.

Time: First cycle

Secondary Outcomes

Measure: Efficacy: Objective response rate; Time to progression; Time to response Response duration;Progression free survival;Clinical Benefict Rate

Time: Along the study

Measure: Exploratory Endpoints: Molecular analysis (EGFR mutations; thioredoxin; Hsp70; methylation of 14-3-3 sigma and CHFR, EGFR mutation at serum (in blood samples from patients)

Time: baseline, after cycle 3 and at the end of treatment

6 An Open-Label Phase 1/2 Study of Itacitinib in Combination With Osimertinib in Subjects With Locally Advanced or Metastatic Non-Small Cell Lung Cancer

The purpose of this study is to evaluate the safety and tolerability of itacitinib in combination with osimertinib in subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC).

NCT02917993 Lung Cancer Drug: Itacitinib Drug: Osimertinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

- Documented evidence of somatic activating mutation in EGFR (eg, G719X, exon 19 deletion, L858R, L861Q) in a tumor tissue sample. --- L858R ---

Primary Outcomes

Measure: Phase 1: Frequency, severity, and duration of adverse events (AEs)

Time: From screening through 30-35 days after end of treatment, approximately 2 years.

Measure: Phase 1: Number of subjects with dose-limiting toxicities (DLTs)

Time: Day 1 through Day 28

Description: ORR defined as the percentage of subjects who have a confirmed best overall response of complete response (CR) or partial response (PR).

Measure: Phase 2: Objective response rate (ORR) based on RECIST v1.1

Time: Screening and 8-week intervals throughout the study, approximately 2 years.

Secondary Outcomes

Measure: Phase 1 and Phase 2: Maximum plasma concentration (Cmax) of itacitinib and osimertinib when administered in combination

Time: Measured at protocol-defined study visits from Cycle 1 Day 1 through Cycle 1 Day 28.

Measure: Phase 1 and Phase 2: Area under the plasma concentration-time curve (AUC) of Itacitinib and osimertinib when administered in combination

Time: Measured at protocol-defined study visits from Cycle 1 Day 1 through Cycle 1 Day 28.

Description: Defined as the percentage of maximal tumor shrinkage observed at the lowest point (nadir) compared with baseline.

Measure: Phase 2: Depth of response (DpR) based on RECIST v1.1

Time: Screening and 8-week intervals throughout the study, approximately 2 years.

Measure: Phase 2: Progression-free survival (PFS)

Time: Interval from the first day of study treatment until disease progression or death due to any cause, approximately 3 years.

Measure: Phase 2: Overall survival (OS)

Time: Interval from the first day of study treatment until death due to any cause, approximately 3 years.

Measure: Phase 2: Frequency, severity, and duration of AEs

Time: From screening through 30-35 days after end of treatment, approximately 2 years.

7 A Phase 1 Study of BPI-15086 in Patients With Epidermal Growth Factor Receptor T790M Mutation-positive Non-Small Cell Lung Cancer Who Have Progressed on Previous EGFR Tyrosine Kinase Inhibitor Therapy

The main objective of this study is to evaluate the safety and tolerability of BPI-15086.

NCT02914990 Non-Small Cell Lung Cancer Drug: BPI-15086
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

icotinib, gefitinib, afatinib, neratinib, dacomitnib, or erlotinib) treatment - Patients must fulfil one of the following: - Confirmation that the tumour harbours EGFR sensitivity mutation (exon 19 deletion, L858R and L861R, G719X) - Must have experienced clinical benefit from EGFR TKIs, according to the Jackman criteria - Confirmation of T790M mutation positive after disease progression on EGFR TKIs - Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and estimated life expectancy of at least 12 weeks - Measurable lesion per Response Evaluation Criteria in Solid Tumors(RECIST1.1) --- L858R ---

Primary Outcomes

Description: Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03

Measure: Adverse events

Time: 18 months

Secondary Outcomes

Measure: Cmax

Time: 4 weeks

Measure: Half life

Time: 4 weeks

Measure: AUC

Time: 4 weeks

Measure: Objective Response Rate

Time: 12 weeks

Measure: Progression-Free Survival

Time: 18 months

8 APPLE Trial: Feasibility and Activity of AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR Mutant NSCLC Patients

The phase II APPLE trial gives the opportunity to prospectively validate liquid biopsies as a new standard for testing tumor progression compared with conventional radiological procedure in EGFR mutant advanced NSCLC patients. Moreover based on the sequential T790M test during treatment the investigators will assess the predictive value of liquid biopsies. APPLE trial will examine the best strategy for delivering osimertinib (upfront versus sequential treatment after 1st generation EGFR TKI) in EGFR mutant NSCLC patients. Finally, the trial will also explore the mechanisms of acquired resistance to Osimertinib based on the results of an optional biopsy upon progression.

NCT02856893 NSCLC Drug: Osimertinib Drug: Gefitinib

Adverse events, serious adverse events and adverse reactions will be monitored.. Inclusion: Registration: - Pathological diagnosis of adenocarcinoma of the lung carrying common EGFR activating mutations associated with EGFR-TKI sensitivity (Del19 or L858R); performed locally; no other EGFR mutations will be allowed. --- L858R ---

Inclusion: Registration: - Pathological diagnosis of adenocarcinoma of the lung carrying common EGFR activating mutations associated with EGFR-TKI sensitivity (Del19 or L858R); performed locally; no other EGFR mutations will be allowed. --- L858R ---

Primary Outcomes

Measure: PFS Rate at 18 months

Time: 24 months after first patient in

Secondary Outcomes

Measure: PFS measured from switching to Osimertinib by RECIST criteria 1.1

Time: 24 months after first patient in

Measure: Proportion of patients receiving Osimertinib based on the determination of cfDNA T790M mutation positive

Time: 24 months after first patient in

Measure: Time to progression on Osimertinib

Time: through study completion

Measure: Time to symptomatic brain metastases in patients with presence of brain metastases at study entry

Time: 24 months after first patient in

Measure: Overall Response Rate (ORR) to Osimertinib

Time: 24 months after first patient in

Measure: Treatment duration

Time: 24 months after first patient in

Measure: Overall Survival (OS)

Time: 24 months after first patient in

Measure: Time to brain progression (TTBP)

Time: 24 months after first patient in

Description: Number of participants with treatment-related adverse events by CTCAE version 4.0. Adverse events, serious adverse events and adverse reactions will be monitored.

Measure: Safety

Time: 24 months after first patient in

9 A Phase 1B Study of AZD9291 in Combination With Navitoclax in EGFR-Mutant Non-Small Cell Lung Cancer Following Resistance to Initial EGFR Kinase Inhibitor

This phase Ib trial studies the side effects and best dose of osimertinib and navitoclax when given together and to see how well they work in treating patients with previously treated epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer that has spread to other places in the body or has not responded to previous treatment with initial EGFR kinase inhibitor. Osimertinib and navitoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02520778 Advanced Lung Non-Squamous Non-Small Cell Carcinoma EGFR Activating Mutation EGFR Exon 19 Deletion Mutation EGFR NP_005219.2:p.G719X EGFR NP_005219.2:p.L858R EGFR NP_005219.2:p.L861Q EGFR NP_005219.2:p.T790M Metastatic Lung Non-Squamous Non-Small Cell Carcinoma Stage III Lung Non-Small Cell Cancer AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Stage IIIB Lung Non-Small Cell Cancer AJCC v7 Stage IV Lung Non-Small Cell Cancer AJCC v7 Drug: Navitoclax Drug: Osimertinib
MeSH: Carcinoma Carcinoma, Non-Small-Cell Lung
HPO: Carcinoma Non-small cell lung carcinoma

Biomarkers of apoptosis such as BCL-XL and BIM levels will be measured in tumor tissue and correlated with response in an exploratory fashion, under the hypothesis that navitoclax will have greater activity in cancers with high BCL-XL levels and inadequate apoptotic response.. Inclusion Criteria: - Histologically confirmed non-squamous NSCLC, with incurable advanced or metastatic disease - Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q) - Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR TKI; or willing to undergo a new tumor biopsy prior to registration (for the dose escalation portion only this requirement can be waived if T790M status has already been determined using a local assay) - For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. --- L858R ---

AZD9291, rociletinib, etc); T790M testing may be done locally or centrally on study, but if done locally, tissue must be available for central confirmation - Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) - Any number of prior therapies are allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Patients must have the ability to swallow oral dosage forms - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Hemoglobin >= 8.0 g/dL - Platelets >= 100,000/mcL - Activated partial thromboplastin time (aPTT), prothrombin time (PT) =< 1.2 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (patients with Gilbert's syndrome may have serum bilirubin > 1.5 x ULN) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN - Creatinine =< 2.0 mg/dL - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and navitoclax on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or navitoclax: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration) - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) for at least 3 months prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion - Intrauterine device (IUD) - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the study and 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post-menopausal (amenorrheic for at least 12 months) - Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment - Patients who are receiving any other investigational agents - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use at least 1 week prior to receiving the 1st dose of AZD9291) medications or herbal supplements known to be potent inhibitors of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) and potent inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; patients are eligible if they stop use of these compounds at least 1 week prior to receiving any treatment on this protocol - Patients receiving anticoagulation or anti-platelet therapy are excluded due to the risk of thrombocytopenia with navitoclax; excluded agents include heparin or low molecular weight heparin, warfarin, clopidogrel, ibuprofen and other nonsteroidal anti-inflammatory drug (NSAIDS), tirofiban, and other anticoagulants, drugs, or herbal supplements that affect platelet function; administration of heparin to keep subject's infusion lines patent is allowed; low-dose anticoagulation medications that are used to maintain the patency of a central intravenous catheter are allowed; aspirin will not be allowed within 7 days prior to the first dose of navitoclax or during navitoclax administration; however, subjects who have previously received aspirin therapy for thrombosis prevention, may resume a low dose (i.e., maximum 100 mg QD) of aspirin if platelet counts are stable (>= 50,000/mm^3) through 6 weeks of navitoclax administration; all decisions regarding treatment with aspirin therapy will be determined by the investigator in conjunction with the medical monitor - Patients with an underlying condition predisposing them to bleeding or currently exhibiting signs of clinically significant bleeding - Patients with a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug - Patients with a significant history of cardiovascular disease (e.g., myocardial infarction [MI], thrombotic or thromboembolic event in the last 6 months) - Any of the following cardiac criteria: - Mean resting corrected QT interval (QTc using Frederica's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Congenital long QT syndrome or family history of long QT syndrome - Patients with active malignancies other than NSCLC or patients with prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study because AZD9291 and navitoclax have the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD9291 and navitoclax, breastfeeding should be discontinued if the mother is treated with AZD9291 and navitoclax - History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or class to AZD9291) or any excipients of these agents - Patients with human immunodeficiency virus (HIV) on antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Histologically confirmed non-squamous NSCLC, with incurable advanced or metastatic disease - Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q) - Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR TKI; or willing to undergo a new tumor biopsy prior to registration (for the dose escalation portion only this requirement can be waived if T790M status has already been determined using a local assay) - For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. --- T790M --- --- L858R ---

Primary Outcomes

Description: Incidence of toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

Measure: Incidence of toxicity (dose escalation)

Time: Up to 2 years

Description: Will be measured as at least 50% of patients achieving the expected dose duration and intensity. The proportion of patients completing 3 courses of therapy with > 75% of total dose of each drug will be quantified. The combination dosing will be considered potentially feasible if at least 50% of patients achieve the expected dose duration and intensity (95% confidence interval 30%-70%).

Measure: Feasibility of the combination therapy in T790M+ lung cancer (dose expansion)

Time: Up to 12 weeks (3 cycles of treatment)

Secondary Outcomes

Description: Pharmacokinetic calculations will incorporate consideration of the dosing change in navitoclax between the two measurement days.

Measure: Pharmacokinetics parameters (maximum observed plasma drug concentration, area-under-the concentration-time-curve, trough drug concentration at steady state, and half-life) of osimertinib in combination with navitoclax

Time: Pre-dose, 1, 2, 4, 6, and 8 hours after navitoclax administration (day 3 of cycle 1 and day 1 of cycle 2)

Description: Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Calculated in the 20 patient expansion cohort and compared to the expected response rate of 61% in T790M+ lung cancer.

Measure: Objective response rate

Time: Baseline up to 30 days after completion of study drug

Description: Change in plasma concentration of EGFR T790M and other EGFR mutations will be studied in an exploratory fashion and compared to tumor response on imaging.

Measure: Change in plasma concentration of EGFR T790M and other EGFR mutations

Time: Baseline to up to 2 years

Description: Biomarkers of apoptosis such as BCL-XL and BIM levels will be measured in tumor tissue and correlated with response in an exploratory fashion, under the hypothesis that navitoclax will have greater activity in cancers with high BCL-XL levels and inadequate apoptotic response.

Measure: Biomarkers of apoptosis such as BCL2-like 1 (BCL-XL) and BCL2-like 11 (apoptosis facilitator) (BIM) levels in tumor tissue

Time: Baseline

10 Phase I, Open-Label, Two Parts Study in Chinese Patients With Advanced NSCLC Who Have Progressed Following Prior Therapy With an EGFR Tyrosine Kinase Inhibitor Agent

A Phase I, Open-Label, Two Parts Study to Assess the Safety, Tolerability,Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9291 in Chinese Patients with Advanced Non-Small Cell Lung Cancer who have Progressed Following Prior Therapy with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent Study Objective: 1, Primary Objective To characterise the pharmacokinetics (PK) of AZD9291 and its metabolites (AZ5104 and AZ7550) after single then multiple doses of AZD9291 administered orally once daily in Chinese patients with locally advanced or metastatic non small cell lung Cancer (NSCLC) who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) agent. 2, Secondary objective(s) To investigate the safety and tolerability of AZD9291 when given orally to Chinese patients with locally advanced or metastatic NSCLC who have progressed following prior therapy with an approved EGFR TKI agent. To obtain a preliminary assessment of the anti-tumour activity of AZD9291 by evaluation of tumour response using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.

NCT02529995 Carcinoma, Non-Small-Cell Lung With EGFR Mutation Positive Drug: AZD9291 40 mg Drug: AZD9291 80 mg
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

In addition other lines of therapy may have been given - Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 6. World Health Organisation (WHO) performance status 0-1 7. --- L858R ---

Primary Outcomes

Description: Pharmacokinetics of AZD9291 after single dosing by assessment of maximum plasma AZD9291 concentration

Measure: Cmax of AZD9291 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after single dosing by assessment of maximum plasma concentration

Measure: Cmax of AZ5104 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after single dosing by assessment of maximum plasma concentration

Measure: Cmax of AZ7550 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after single dosing by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZD9291 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after single dosing by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZ5104 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after single dosing by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZ7550 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Rate and extent of absorption of single dose AZD9291 by assessment of apparent clearance following oral administration

Measure: CL/F of AZD9291 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of maximum plasma concentration at steady state

Measure: C(ss, Max) of AZD9291 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after multiple dosing by assessment of maximum plasma concentration at steady state

Measure: C(ss, Max) of AZ5104 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after multiple dosing by assessment of maximum plasma concentration at steady state

Measure: C(ss, Max) of AZ7550 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval

Measure: AUC(ss) of AZD9291 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval

Measure: AUC(ss) of AZ5104 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval

Measure: AUC(ss) of AZ7550 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of apparent plasma clearance at steady state

Measure: CL(ss)/F of AZD9291 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR)

Time: Treatment discontinuation plus 28 days or 12 months after last subject first dose (LSFD). Results are based on data cut off of 2 Nov 2016.

11 The Postoperative Adjuvant Therapy of Gefitinib for High Risk Stage Ib NSCLC Patients With EGFR Sensitive Mutation, an Open, Paired, Non-interventional, Multi-center Clinical Study

Currently, whether adjuvant therapy should be applied to Stage Ib non-small cell lung cancer (NSCLC) patients who received radical resection remains controversial. There is still no clear evidence that the postoperative adjuvant chemotherapy or other treatments can improve the survival rate for patients with stage Ib NSCLC. Tyrosine Kinase Inhibitors (TKIs) such as Gefitinib and Erlotinib are widely accepted as the first-line therapy for Epidermal growth factor receptor (EGFR) gene mutation late stage NSCLC patients. However the effect is largely uncertain for early stage patients who received surgery. The investigators aim to evaluate the effect of postoperative adjuvant use of Gefitinib for high risk stage Ib EGFR sensitive mutation NSCLC patients.

NCT02526537 NSCLC

2. Patients with pathology confirmed Ib stage NSCLC 3. Patients with deletion of exon 19 or mutation of L858R at exon 21 in EGFR gene 4. ECOG score of 0-1 5. Life expectancy over 12 weeks 6. --- L858R ---

Primary Outcomes

Measure: Relapse Free Survival in 2 years

Time: Treatment period: 2 years (24 months)

Secondary Outcomes

Measure: Relapse Free Survival in 3 years

Time: Follow-up: 3 years

Measure: 5 year Overall Survival

Time: Follow-up: 5 years

Measure: Relapse Free Survival in 5 years

Time: Follow-up: 5 years

12 A Phase Ib/II, Open-label, Multicenter Trial With Oral cMET Inhibitor INC280 Alone and in Combination With Erlotinib Versus Platinum With Pemetrexed in Adult Patients With EGFR Mutated, cMET-amplified, Locally Advanced/Metastatic Non-small Cell Lung Cancer (NSCLC) With Acquired Resistance to Prior EGFR Tyrosine Kinase Inhibitor (EGFR TKI)

The purpose of this study is to determine the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of INC280 in combination with erlotinib in the Phase Ib of this study, and to assess the anti-tumor activity and safety of INC280 alone, and in combination with erlotinib, versus platinum with pemetrexed in the Phase II of this study, in adult patients with EGFR mutated, cMET amplified, advanced/metastatic non-small cell lung cancer with acquired resistance to prior EGFR TKI.

NCT02468661 Non-Small Cell Lung Cancer Drug: INC280 single agent Drug: INC280 in combination with erlotinib Drug: Platinum/pemetrexed
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Safety and tolerability of INC280 in combination with erlotinib assessed by change in vital signs, laboratory results and electrocardiogram (ECG).. Inclusion Criteria: - Locally advanced or metastatic NSCLC - EGFR mutation (L858R and /or ex19del) - cMET amplification by FISH (GCN ≥ 6), - Acquired resistance to EGFR TKI (1st or 2nd génération) - ECOG performance status (PS) ≤ 1. Exclusion Criteria: - Prior treatment with 3rd generation TKI - PhaseII : Prior treatment with any of the following agents: - Crizotinib, or any other cMET inhibitor or HGF-targeting inhibitor. --- L858R ---

- Platinum-based chemotherapy as first line treatment Inclusion Criteria: - Locally advanced or metastatic NSCLC - EGFR mutation (L858R and /or ex19del) - cMET amplification by FISH (GCN ≥ 6), - Acquired resistance to EGFR TKI (1st or 2nd génération) - ECOG performance status (PS) ≤ 1. Exclusion Criteria: - Prior treatment with 3rd generation TKI - PhaseII : Prior treatment with any of the following agents: - Crizotinib, or any other cMET inhibitor or HGF-targeting inhibitor. --- L858R ---

Primary Outcomes

Measure: Phase Ib: Frequency and characteristics of Dose Limiting Toxicity (DLTs) to the INC280 and erlotinib combination

Time: First 28 days of dosing

Secondary Outcomes

Description: Correlation between IHC determined expression level and PFS

Measure: Phase Ib: Progression Free Survival (PFS)

Time: Every 6 weeks, up to 2 years

Description: OS, defined as time from the first dose of study treatment to death due to any cause

Measure: Phase Ib: Overall Survival (OS)

Time: Every 3 weeks, up to 5 years

Description: Safety and tolerability of INC280 in combination with erlotinib assessed by change in vital signs, laboratory results and electrocardiogram (ECG).

Measure: Phase Ib: Number of patients with adverse events (AEs) as a measure of safety and tolerability

Time: Every 3 weeks, up to 2 years

Description: Composite pharmacokinetics of INC280 in the presence of erlotinib.

Measure: Phase Ib: Plasma concentration-time profiles of INC280 and pharmacokinetic parameters

Time: 6 weeks

Description: Composite pharmacokinetics of erlotinib in the presence of INC280.

Measure: Phase Ib: Plasma concentration-time profiles of erlotinib in the presence of INC280

Time: 6 weeks

Description: DCR, proportion of patients with best overall response of CR, PR or SD

Measure: Phase Ib: Disease Control Rate (DCR)

Time: Every 6 weeks, up to 2 years

Description: DOR, defined as time from the first documented CR or PR to first documented progression or death due to any cause

Measure: Phase Ib: Duration of Response (DOR)

Time: Every 6 weeks, up to 2 years

Description: PFS, defined as time from the first dose of study treatment to disease progression or death due to any cause

Measure: Phase Ib: Progression-free Survival (PFS)

Time: Every 6 weeks, up to 2 years

Description: Safety and tolerability of INC280 in combination with erlotinib assessed by change in vital signs, laboratory results and electrocardiogram (ECG).

Measure: Phase Ib: Number of patients with serious adverse events as a measure of safety and tolerability

Time: Every 3 weeks, up to 2 years

13 A Phase 1/2 Trial of Erlotinib and Onalespib Lactate in EGFR-Mutant Non-Small Cell Lung Cancer

This phase I/II trial studies the side effects and best dose of onalespib lactate when given together with erlotinib hydrochloride and to see how well they work in treating patients with EGFR-mutant non-small cell lung cancer that has come back (recurrent) or has spread to other places in the body (metastatic). Erlotinib hydrochloride and onalespib lactate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02535338 EGFR Activating Mutation EGFR Exon 20 Insertion Mutation Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Drug: Erlotinib Hydrochloride Other: Laboratory Biomarker Analysis Drug: Onalespib Lactate Other: Pharmacological Study
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

Progression-free survival will be summarized for both cohorts as time from first protocol treatment, using the product-limit, Kaplan-Meier, estimator.. Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R ---

Progression-free survival will be summarized for both cohorts as time from first protocol treatment, using the product-limit, Kaplan-Meier, estimator.. Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R --- --- L861Q --- --- L858R ---

m^2 for patients with creatinine levels above institutional normal - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.3 upper limit of normal (ULN) - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of erlotinib and/or onalespib administration - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients who are receiving any other investigational agents - History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib and/or onalespib - History of pneumonitis attributed to an EGFR inhibitor; history of radiation pneumonitis is allowed provided steroid administration for pneumonitis was not required - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Left ventricular ejection fraction =< 50% as demonstrated by echocardiogram or multigated acquisition scan (MUGA) - Drugs that are known to increase torsades de pointes should be avoided; patients must discontinue these medications prior to enrollment on study; selection of alternate concomitant medications with no or minimal torsades de pointes potential is recommended - Strong CYP3A4 inducers and inhibitors should be avoided; selection of alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is recommended; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with erlotinib and onalespib - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - Prior treatment with a Hsp90 inhibitor - Treatment with proton pump inhibitors within 3 days prior to study entry; if treatment with an histamine (H2)-receptor antagonist such as ranitidine is required, erlotinib must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist; although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the erlotinib dose should be separated by several hours, if an antacid is necessary - Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R ---

m^2 for patients with creatinine levels above institutional normal - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.3 upper limit of normal (ULN) - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of erlotinib and/or onalespib administration - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients who are receiving any other investigational agents - History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib and/or onalespib - History of pneumonitis attributed to an EGFR inhibitor; history of radiation pneumonitis is allowed provided steroid administration for pneumonitis was not required - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Left ventricular ejection fraction =< 50% as demonstrated by echocardiogram or multigated acquisition scan (MUGA) - Drugs that are known to increase torsades de pointes should be avoided; patients must discontinue these medications prior to enrollment on study; selection of alternate concomitant medications with no or minimal torsades de pointes potential is recommended - Strong CYP3A4 inducers and inhibitors should be avoided; selection of alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is recommended; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with erlotinib and onalespib - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - Prior treatment with a Hsp90 inhibitor - Treatment with proton pump inhibitors within 3 days prior to study entry; if treatment with an histamine (H2)-receptor antagonist such as ranitidine is required, erlotinib must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist; although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the erlotinib dose should be separated by several hours, if an antacid is necessary - Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R --- --- L861Q --- --- L858R ---

Primary Outcomes

Description: Will be graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0

Measure: Incidence of dose-limiting toxicities from onalespib lactate in combination with erlotinib hydrochloride (Phase I)

Time: Up to 28 days

Description: Each cohort will be independently governed by Simon's two-stage minimax design, implemented to distinguish a 25% response rate from an assumed background rate of 5%, with 10% type I and type II error rates.

Measure: Tumor response by Response Evaluation Criteria in Solid Tumors version 1.1 (Phase II)

Time: Up to at least 1 year

Secondary Outcomes

Description: Each cohort will be independently governed by Simon's two-stage minimax design, implemented to distinguish a 25% response rate from an assumed background rate of 5%, with 10% type I and type II error rates.

Measure: Tumor response by Response Evaluation Criteria in Solid Tumors version 1.1 (Phase I)

Time: Up to at least 1 year

Description: Progression-free survival will be summarized for both cohorts as time from first protocol treatment, using the product-limit, Kaplan-Meier, estimator.

Measure: Progression-free survival

Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to at least 1 year

14 A Phase IIa Clinical Trial to Evaluate the Safety and Efficacy of Osimertinib (AZD9291) in First-line Patients With EGFR Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer and Concomitant EGFR T790M Mutation at Time of Diagnosis

The primary goal is to evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M mutation at diagnosis as defined by RECIST 1.1 criteria. Safety and efficacy will also be measured.

NCT02841579 Non-Small Cell Lung Cancer Drug: Osimertinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

- Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 (G719X) and concomitant T790M mutation before treatment confirmed centrally. --- L858R ---

- Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 (G719X) and concomitant T790M mutation before treatment that have not been confirmed centrally. --- L858R ---

Primary Outcomes

Description: Defined as the rate of complete responses [CR] or partial responses [PR] to treatment in accordance to the guidelines of RECIST version 1.1 criteria

Measure: Objective response rate

Time: Baseline up to 78 weeks after patient entry

Secondary Outcomes

Description: Patient safety and adverse events will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) of the U.S. National Cancer Institute (NCI), version 4

Measure: Grade 3 or 4 adverse events and SAEs

Time: Baseline up to 78 weeks after patient entry

Description: Time from treatment start to the time of death due to any cause

Measure: Overall survival

Time: Baseline up to 78 weeks after patient entry

Description: Time from treatment start to the time at which the patient discontinues treatment due to any cause

Measure: Time to treatment failure

Time: Baseline up to 78 weeks after patient entry

Description: Time from the first documented response to documented disease progression or death

Measure: Duration of response

Time: Baseline up to 78 weeks after patient entry

Description: Percentage of patients with complete response, partial response or stable disease for a minimum of 24 weeks, assessed in accordance with the modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, during all study period from baseline up to 78 weeks after patient entry

Measure: Disease control rate

Time: Baseline up to 78 weeks after patient entry

Measure: Tumor shrinkage

Time: Baseline up to 78 weeks after patient entry

Description: Correlation ratio of mutational status and documented clinical response

Measure: Correlation ratio between mutational status and clinical response

Time: Baseline up to 78 weeks after patient entry

Measure: Tumour EGFR mutation status by histology

Time: Baseline up to 78 weeks after patient entry

Description: Measured by Percentage of patients with a positive EGFR mutation in plasma

Measure: Overall plasma EGFR mutation status

Time: Baseline up to 78 weeks after patient entry

Measure: BIM mRNA levels

Time: Baseline up to 78 weeks after patient entry

Description: Percentage of patients who develop anti-drug mutations in tumour tissue

Measure: Acquired resistance to osimertinib (AZD9291) by histology

Time: Baseline up to 78 weeks after patient entry

Description: Percentage of patients who develop anti-drug mutations in plasma

Measure: Overall plasma acquired resistance to osimertinib (AZD9291)

Time: Baseline up to 78 weeks after patient entry

15 Exploratory Phase 0/1 of Positron Emission Tomography (PET) Imaging Agent [18F]-ODS2004436 as a Marker of EGFR Mutation in Subjects With NSCLC

The development of biomarkers will lead the dynamic of personalized medicine and fill the unsatisfied needs in oncology for prediction of therapeutic response. Molecular imaging enables non invasive quantification of biomarkers. The development of molecular imaging biomarkers is closely related to the development of therapeutic molecules. Among the potential targets, kinases offer a lot of advantages: (i) they play a central role in cellular regulation, (ii) numerous kinase-specific small molecule libraries exist in biotech and pharma industry, (iii) several kinase-targeted therapies are used in clinic (imatinib, sorafenib, sunitinib…) with application across a variety of therapeutic indications. Among the imaging technologies, the Positron Emission Tomography (PET) is the most sensitive and dedicated to evaluate small molecules. However few radiotracers are available and their specificity limits their clinical use. The IMAkinib® approach is an innovative method proposed to develop new PET radiotracers adapted to current medical and economical challenges. The epidermal growth factor receptor (EGFR) is an established target for the treatment of advanced non-small cell lung cancer (NSCLC). The EGFR tyrosine kinase inhibitors (TKIs) Gefitinib (Iressa®), erlotinib (Tarceva®) and afatinib (Giotrif®) have already been approved for treatment of NSCLC harboring EGFR activating mutations (L858R or del exon 19). Unfortunately the majority of patients will develop a resistance to the TKI in the long term (6-12 months). If the mechanism of resistance is not yet fully characterized, most patients (50%) will acquire an additional T790M mutation of EGFR. TKI PET-imaging can provide a tool to determine and predict responsiveness to EGFR TKI in vivo. That is why, the investigators have selected and radiolabeled (18-Fluor) a compound targeting specifically EGFR mutated ([18F]-ODS2004436) which was further evaluated in a preclinical imaging study to determine the feasibility of TKI-PET. The investigators proved in vivo that [18F]-ODS2004436 a compound is a good candidate to evaluate the EGFR activity in human lung tumours using PET imaging.

NCT02847377 Carcinoma, Non-Small-Cell Lung Other: Injection of [18F]-ODS2004436 radiotracer
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

The EGFR tyrosine kinase inhibitors (TKIs) Gefitinib (Iressa®), erlotinib (Tarceva®) and afatinib (Giotrif®) have already been approved for treatment of NSCLC harboring EGFR activating mutations (L858R or del exon 19). --- L858R ---

Primary Outcomes

Description: Sensibility will be evaluated by positron emission tomography (PET) performed on EGFR mutant patient

Measure: Evaluation of sensibility of [18F] ODS2004436

Time: 1 day

Description: Specificity will be evaluated by positron emission tomography (PET) performed on EGFR wild type patient

Measure: Evaluation of specificity of [18F] ODS2004436

Time: 1 day

Other Outcomes

Description: A follow up visit will be performed 3 days after each PET has been performed in order to register adverse events

Measure: Security

Time: 10 days

16 A Phase II Trial of Gefitinib Monotherapy in Pretreated Patients With Advanced Non-small Cell Lung Cancer Not Harboring Active EGFR Mutations

The investigators will examine efficacy and toxicity of gefitinib in Korean patients with EGFR wild tumors diagnosed with direct sequence test.

NCT01312337 Nonsmall Cell Lung Cancer Drug: salvage iressa
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Pathologically proven NSCLC - Ineligibile for curative treatment (namely, stage IIIb or IV) - History of one to three prior systemic chemotherapy tumors without active EGFR mutations (exon 19 deletion, L858R mutation in exon 21) - At least one lesion that was unidimensionally measurable by computed tomography (by RECIST 1.1) - 18 years old or older - Performance status ECOG 0-2 - Adequate organ function as evidenced by the following: - Absolute neutrophil count > 1.0 x 109/L - Platelets > 75 x 109/L - Total bilirubin ≤ 1.5 UNL - AST and/or ALT < 5 UNL - Creatinine clearance ≥ 45mL/min Exclusion Criteria: - Previous EGFR TKI therapy history - Systemic anticancer therapy within the previous 3 weeks - Other invasive malignancy within the past 2 years except non-melanoma skin cancer, in situ cervix cancer, or papillary thyroid cancer - Other concurrent illness that would preclude study participation (severe heart disease) - Other concurrent physical condition (e.g., infectious disease) that would preclude study participation - Pregnant or nursing Inclusion Criteria: - Pathologically proven NSCLC - Ineligibile for curative treatment (namely, stage IIIb or IV) - History of one to three prior systemic chemotherapy tumors without active EGFR mutations (exon 19 deletion, L858R mutation in exon 21) - At least one lesion that was unidimensionally measurable by computed tomography (by RECIST 1.1) - 18 years old or older - Performance status ECOG 0-2 - Adequate organ function as evidenced by the following: - Absolute neutrophil count > 1.0 x 109/L - Platelets > 75 x 109/L - Total bilirubin ≤ 1.5 UNL - AST and/or ALT < 5 UNL - Creatinine clearance ≥ 45mL/min Exclusion Criteria: - Previous EGFR TKI therapy history - Systemic anticancer therapy within the previous 3 weeks - Other invasive malignancy within the past 2 years except non-melanoma skin cancer, in situ cervix cancer, or papillary thyroid cancer - Other concurrent illness that would preclude study participation (severe heart disease) - Other concurrent physical condition (e.g., infectious disease) that would preclude study participation - Pregnant or nursing Nonsmall Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R ---

Inclusion Criteria: - Pathologically proven NSCLC - Ineligibile for curative treatment (namely, stage IIIb or IV) - History of one to three prior systemic chemotherapy tumors without active EGFR mutations (exon 19 deletion, L858R mutation in exon 21) - At least one lesion that was unidimensionally measurable by computed tomography (by RECIST 1.1) - 18 years old or older - Performance status ECOG 0-2 - Adequate organ function as evidenced by the following: - Absolute neutrophil count > 1.0 x 109/L - Platelets > 75 x 109/L - Total bilirubin ≤ 1.5 UNL - AST and/or ALT < 5 UNL - Creatinine clearance ≥ 45mL/min Exclusion Criteria: - Previous EGFR TKI therapy history - Systemic anticancer therapy within the previous 3 weeks - Other invasive malignancy within the past 2 years except non-melanoma skin cancer, in situ cervix cancer, or papillary thyroid cancer - Other concurrent illness that would preclude study participation (severe heart disease) - Other concurrent physical condition (e.g., infectious disease) that would preclude study participation - Pregnant or nursing Inclusion Criteria: - Pathologically proven NSCLC - Ineligibile for curative treatment (namely, stage IIIb or IV) - History of one to three prior systemic chemotherapy tumors without active EGFR mutations (exon 19 deletion, L858R mutation in exon 21) - At least one lesion that was unidimensionally measurable by computed tomography (by RECIST 1.1) - 18 years old or older - Performance status ECOG 0-2 - Adequate organ function as evidenced by the following: - Absolute neutrophil count > 1.0 x 109/L - Platelets > 75 x 109/L - Total bilirubin ≤ 1.5 UNL - AST and/or ALT < 5 UNL - Creatinine clearance ≥ 45mL/min Exclusion Criteria: - Previous EGFR TKI therapy history - Systemic anticancer therapy within the previous 3 weeks - Other invasive malignancy within the past 2 years except non-melanoma skin cancer, in situ cervix cancer, or papillary thyroid cancer - Other concurrent illness that would preclude study participation (severe heart disease) - Other concurrent physical condition (e.g., infectious disease) that would preclude study participation - Pregnant or nursing Nonsmall Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L858R ---

Primary Outcomes

Measure: To determine disease control rate at 8 weeks will be 35% or higher in the the study group

Time: 6 months after the enrollment of the last patients

Secondary Outcomes

Measure: The number of patients who live longer than 6 months after enrollment

Time: 6 months after the enrollment of the last patients

17 An Open-Label Multicenter Study of Erlotinib (Tarceva®) as First Line Therapy Until and Beyond RECIST Progression in NSCLC Patients Who Harbour EGFR Mutations

This open-label, single arm study will evaluate the safety and efficacy of Tarceva (erlotinib) as first-line therapy in participants with stage IV or recurrent non-small cell lung cancer who harbour epidermal growth factor receptor (EGFR) mutations. All participants will receive Tarceva 150 mg daily orally until disease progression or unacceptable toxicity occurs. At the investigator's discretion, participants may receive Tarceva beyond disease progression.

NCT01310036 Non-Squamous Non-Small Cell Lung Cancer Drug: Erlotinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

PFS2 was defined as time from first study dose to off-erlotinib progressive disease (PD), assessed by the investigator based on overall clinical evaluation.. Objective Response Rate (ORR) for All Participants and Participants With EGFR Mutation E19del or L858R. --- L858R ---

PR was defined as least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.. Disease Control Rate (DCR) for All Participants and Participants With EGFR Mutation E19del or L858R. --- L858R ---

PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.. Progression-free Survival for Participants With EGFR Mutation E19del or L858R Per RECIST, v. 1.1 (PFS1). --- L858R ---

PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.. Overall Survival (OS) for All Participants and Participants With EGFR Mutation E19del or L858R. --- L858R ---

Primary Outcomes

Description: PFS1 was defined as time from first dose until documented progressive disease (PD), assessed per Response Evaluation Criteria in Solid Tumors RECIST, v. 1.1, or death from any cause, whichever occurred first. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.

Measure: Progression-free Survival Per RECIST, v. 1.1 (PFS1)

Time: Approximately 68 months

Secondary Outcomes

Description: PFS2 was defined as time from first study dose to off-erlotinib progressive disease (PD), assessed by the investigator based on overall clinical evaluation.

Measure: Progression-free Survival Per Investigator (PFS2)

Time: Approximately 68 months

Description: ORR was defined as the occurrence of either a confirmed complete (CR) or a partial response (PR, as a best overall response), as determined by RECIST, v. 1.1 criteria. CR was defined as disappearance of all target lesions. PR was defined as least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

Measure: Objective Response Rate (ORR) for All Participants and Participants With EGFR Mutation E19del or L858R

Time: Approximately 68 months

Description: DCR was defined as CR + PR + Stable disease (SD). CR was defined as disappearance of all target lesions. PR was defined as least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.

Measure: Disease Control Rate (DCR) for All Participants and Participants With EGFR Mutation E19del or L858R

Time: Approximately 68 months

Description: PFS1 was defined as time from first dose until documented progressive disease (PD), assessed per Response Evaluation Criteria in Solid Tumors RECIST, v. 1.1, or death from any cause, whichever occurred first. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.

Measure: Progression-free Survival for Participants With EGFR Mutation E19del or L858R Per RECIST, v. 1.1 (PFS1)

Time: Approximately 68 months

Description: OS was defined as the time from baseline to the date of death from any cause.

Measure: Overall Survival (OS) for All Participants and Participants With EGFR Mutation E19del or L858R

Time: Approximately 68 months

Description: An adverse event is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not considered related to the study drug.

Measure: Number of Participants With Adverse Events

Time: Approximately 68 months

Description: This outcome measure was not assessed.

Measure: Correlation Between EGFR Mutations in Plasma and Clinical Outcome (ORR/PFS/OS)

Time: Approximately 68 months

18 A Phase I/II Trial of Hsp 90 Inhibitor AUY-922 in Patients With Lung Adenocarcinoma With "Acquired Resistance" to EGFR Tyrosine Kinase Inhibitors

Hsp90 inhibitor AUY922 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This phase I/II trial is studying the side effects and best dose of Hsp90 inhibitor AUY922 when given together with erlotinib hydrochloride and to see how well it works in treating patients with stage IIIB-IV non-small cell lung cancer.

NCT01259089 Adenocarcinoma of the Lung Non-small Cell Lung Cancer Drug: erlotinib hydrochloride Drug: Hsp90 inhibitor AUY922 Other: laboratory biomarker analysis Procedure: needle biopsy Genetic: mutation analysis Other: pharmacological study
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung Adenocarcinoma Adenocarcinoma of Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Overall Survival (OS) will be measured from treatment initiation until death due to any cause for patients with acquired resistance with T790M mutations in the phase II portion of the study.. Inclusion Criteria: - All patients must have pathologic evidence of advanced lung adenocarcinoma (stage IIIB or stage IV) confirmed histologically/cytologically at NU, MSKCC, or DFCI and EITHER previous RECIST-defined response (CR or PR) to an EGFR-TKI (erlotinib or gefitinib) or an investigational EGFR TK inhibitor OR a documented mutation in the EGFR gene (G719X, exon 19 deletion, L858R, L861Q) - Radiographic progression by RECIST during treatment with erlotinib/gefitinib - Received treatment with erlotinib/gefitinib throughout the one month prior to enrollment and at least six months at any time - Measurable (RECIST) indicator lesion not previously irradiated - Must have undergone a biopsy after the development of acquired resistance - Karnofsky Performance Status >= 70% OR ECOG/WHO Performance Status 0-1 - Signed informed consent - Effective contraception and negative serum pregnancy test obtained within two weeks prior to the first administration of AUY922 in all pre-menopausal women (ie., last menstrual period =< 24 months ago) and women < 2 years after onset of menopause; menopause is defined as the time at which fertility ceases, where a woman has had no menstruation for > 24 months - Total bilirubin =< 1.5 x Upper Limit of Normal (ULN) - AST/SGOT and ALT/SGPT =< 3.0 x ULN, or =< 5.0 x ULN if liver metastasis present - Absolute neutrophil count (ANC) >= 1.5 x10^9/L - Hemoglobin (Hgb) >= 9g/dL - Platelets (plts) >= 100 x 10^9/L - Serum creatinine =< 1.5 x ULN or 24 hour clearance >= 50 mL/min Exclusion Criteria: - Symptomatic CNS metastases which are symptomatic and /or requiring escalating doses of steroids - Prior treatment with any HSP90 inhibitor compounds - Conventional chemotherapy, radiation or monoclonal antibodies within 4 weeks (erlotinib/gefitinib therapy within the past 4 weeks IS allowed) - Palliative radiation within 2 weeks - Unresolved diarrhea >= CTCAE grade 2 - Pregnant or lactating women - Women of childbearing potential (WCBP) (i.e. --- T790M --- --- L858R ---

Gilbert's syndrome) Inclusion Criteria: - All patients must have pathologic evidence of advanced lung adenocarcinoma (stage IIIB or stage IV) confirmed histologically/cytologically at NU, MSKCC, or DFCI and EITHER previous RECIST-defined response (CR or PR) to an EGFR-TKI (erlotinib or gefitinib) or an investigational EGFR TK inhibitor OR a documented mutation in the EGFR gene (G719X, exon 19 deletion, L858R, L861Q) - Radiographic progression by RECIST during treatment with erlotinib/gefitinib - Received treatment with erlotinib/gefitinib throughout the one month prior to enrollment and at least six months at any time - Measurable (RECIST) indicator lesion not previously irradiated - Must have undergone a biopsy after the development of acquired resistance - Karnofsky Performance Status >= 70% OR ECOG/WHO Performance Status 0-1 - Signed informed consent - Effective contraception and negative serum pregnancy test obtained within two weeks prior to the first administration of AUY922 in all pre-menopausal women (ie., last menstrual period =< 24 months ago) and women < 2 years after onset of menopause; menopause is defined as the time at which fertility ceases, where a woman has had no menstruation for > 24 months - Total bilirubin =< 1.5 x Upper Limit of Normal (ULN) - AST/SGOT and ALT/SGPT =< 3.0 x ULN, or =< 5.0 x ULN if liver metastasis present - Absolute neutrophil count (ANC) >= 1.5 x10^9/L - Hemoglobin (Hgb) >= 9g/dL - Platelets (plts) >= 100 x 10^9/L - Serum creatinine =< 1.5 x ULN or 24 hour clearance >= 50 mL/min Exclusion Criteria: - Symptomatic CNS metastases which are symptomatic and /or requiring escalating doses of steroids - Prior treatment with any HSP90 inhibitor compounds - Conventional chemotherapy, radiation or monoclonal antibodies within 4 weeks (erlotinib/gefitinib therapy within the past 4 weeks IS allowed) - Palliative radiation within 2 weeks - Unresolved diarrhea >= CTCAE grade 2 - Pregnant or lactating women - Women of childbearing potential (WCBP) (i.e. --- L858R ---

Primary Outcomes

Description: To determine the maximally tolerated dose (MTD), and recommended phase II dose of AUY922 when given in combination with erlotinib for patients with acquired resistance to erlotinib. (Phase I) Escalation of dose will be in a 3+3 design. If no dose limiting toxicities (DLTs) are seen in 3 patients enrolled at that dose level, then dose will be escalated to the next dose level and the next 3 patients will be enrolled at that dose. Alternatively, if 1 DLT is seen in 3 patients at that dose level, 3 more patients will be added at that same dose level. If 1 DLT is seen in 6 patients at that dose level, MTD will be determined to be at that dose. If more than 1 DLT is seen at that dose level, then the prior lower dose level will be the considered the MTD. DLT is defined as any of the following related to the investigational agent: Death and grade 3 and 4 specific hematological and non-hematological toxicities defined in the protocol.

Measure: Maximally Tolerated Dose (MTD) of AUY922 and Erlotinib Treatment Combination (Phase I)

Time: During the first 4 weeks of treatment for each patient.

Description: Overall response rate (ORR) will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT scan or MRI: Complete response (CR) defined as disappearance of all target lesions. Partial Response (PR), defined as >=30% decrease in the sum of the longest diameter of target lesions. Stable Disease (SD) defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. Progressive Disease (PD) defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions

Measure: Overall Response Rate (ORR), Defined as Complete Response(CR) + Partial Response (PR) Using the Modified RECIST 1.1 Criteria for All Patients Treated at Dose of 70mg/m2 AUG922

Time: At 8 weeks from treatment initiation

Description: To characterize the toxicity profile for the combination of erlotinib and AUY922. Toxicity data will be collected every week for the first 28 day cycle and then every two weeks during treatment and up to 28 days after the last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (CTCAE v4.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

Measure: Toxicity as Assessed by NCI CTCAE Version 4.00 When AUG922 Administered at Its MTD (Phase I and II)

Time: At weeks 1 through 4 and then every 2 weeks during treatment and 30 days post last treatment for up to 2 years and half years

Secondary Outcomes

Description: Adverse events will be collected weekly for the first 28 day cycle and then every two weeks during treatment and up to 28 days after the last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (CTCAE v4.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

Measure: Incidence of Reported Adverse Events in Phase I

Time: At weeks 1 through 4 and then every 2 weeks during treatment and 30 days post last treatment, for up to 2 years and half years

Description: Median Progression Free Survival (PFS) will be calculated from time of treatment initiation until the first documentation of progressive disease. Patients will be considered to have progressive disease when CT scan or MRI show at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Measure: Progression-free Survival (Phase II)

Time: From the time of first treatment with AUY922 to disease progression for up to 2 years post treatment

Description: Overall survival (OS) is defined as the time from treatment initiation until death due to any cause.

Measure: Overall Survival (Phase II)

Time: From the time of first treatment with AUY922 to death, followed up to 2 years post treatment

Description: Overall Survival (OS) will be measured from treatment initiation until death due to any cause for patients with acquired resistance with T790M mutations in the phase II portion of the study.

Measure: Overall Survival Among Patients With Acquired Resistance With T790M Mutations (Phase II)

Time: From the time of first treatment with AUY922 to death, followed for up to 2 years

19 Development of Circulating Tumour Cell Molecular Diagnostics Using a Novel Microfluidic Device

1. To compare EGFR mutations between primary non-small cell lung cancer (NSCLC) tumours and corresponding CTCs isolated by a label-free microfluidic device-based system 2. To characterize the association between clinical response in NSCLC patients treated with gefitinib and serial changes in CTC EGFR mutations detected by a label-free microfluidic device-based system The investigators recently developed a label-free, microfluidic device for capturing circulating tumour cells (CTCs) and acquired a Fluidigm Biomark digital PCR instrument for reliable low-level DNA quantification. The overall aim of this study is to test the feasibility of using these state-of-the-art devices to reliably detect clinically relevant EGFR mutations in CTCs.

NCT01193829 Patients With Non-small Cell Lung Cancer
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

DNA will be extracted from the retrieved CTCs and tumour samples, and analyzed exon 19 deletion, L858R and T790M mutations by digital PCR on the Fluidigm Biomark according to methods described previously.23 --- L858R ---


20 A Phase Ib, Open Label, Multi-center Study to Characterize the Safety, Tolerability and Preliminary Efficacy of EGF816 in Combination With Selected Targeted Agents in EGFR Mutant NSCLC

The study purpose is to evaluate the safety, tolerability, and preliminary efficacy of the addition of INC280, trametinib, ribociclib, gefitinib, or LXH254 to EGF816 in adult patients with advanced EGFR-mutant NSCLC.

NCT03333343 EGFR-mutant Non-small Cell Lung Cancer Drug: EGF816 Drug: trametinib Drug: ribociclib Drug: LXH254 Drug: INC280 Drug: gefitinib
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

Inclusion Criteria: - Patients must have histologically or cytologically confirmed locally advanced (stage IIIB) or metastatic (stage IV) EGFR mutant (ex19del, L858R) NSCLC. --- L858R ---

- Requirements of EGFR mutation status and prior lines of treatment: - Treatment naive patients, who have locally advanced or metastatic NSCLC with EGFR sensitizing mutation (e.g., L858R and/or ex19del), have not received any systemic antineoplastic therapy for advanced NSCLC and are eligible to receive EGFR TKI treatment. --- L858R ---

- Patients who have locally advanced or metastatic NSCLC with EGFR sensitizing mutation AND an acquired T790M mutation (e.g., L858R and/or ex19del, T790M+) following progression on prior treatment with a 1st-generation EGFR TKI or 2nd-generation EGFR TKI. --- T790M --- --- L858R ---

- Patients who have been treated with systemic anti-neoplastic therapy within: - 2 weeks for fluoropyrimidine monotherapy - 6 weeks for nitrosoureas and mitomycin - 4 weeks or ≤ 5 half-lives (whichever is shorter) for biological therapy (including monoclonal antibodies) and continuous or intermittent small molecule therapeutics or any other investigational agent Inclusion Criteria: - Patients must have histologically or cytologically confirmed locally advanced (stage IIIB) or metastatic (stage IV) EGFR mutant (ex19del, L858R) NSCLC. --- L858R ---

Primary Outcomes

Description: Assess safety and tolerability including incidence of dose limiting toxicities, adverse events, and serious adverse events.

Measure: Number of patients with adverse events and serious adverse events

Time: Every day until study end, approximately 4 years

Description: Modified objective response rate (ORR2) per RECIST v1.1 (taking as baseline the most recent assessment prior to initiating combination)

Measure: ORR2

Time: Every 8-12 weeks until study ends, approximately 4 years

Secondary Outcomes

Description: Overall response rate (ORR) per RECIST v1.1

Measure: ORR

Time: Every 8-12 weeks until study ends, approximately 4 years

Description: Time from the date of first dose of study treatment to the date of first documented disease progression (per RECIST v1.1) or death due to any cause

Measure: PFS

Time: Every 8-12 weeks until study ends, approximately 4 years

Description: Proportion of patients with best overall response of CR, PR, or SD

Measure: DCR

Time: Every 8-12 weeks until study ends, approximately 4 years

Description: Time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause

Measure: DOR

Time: Every 8-12 weeks until study ends, approximately 4 years

Measure: Time to response

Time: Every 8-12 weeks until study ends, approximately 4 years

21 Comprehensive Stereotactic Body Radiotherapy (SBRT) to All Sites of Oligometastatic Non-small Cell Lung Cancer (NSCLC) Combined With Durvalumab (MEDI4736) and Tremelimumab Dual Immune Checkpoint Inhibition.

This is a phase Ib study to evaluate safety and tolerability of dual checkpoint inhibition (DCI) of durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) with SBRT in the treatment of oligometastatic NSCLC. This study will examine the sequential delivery of SBRT to all disease sites followed by combination of durvalumab and tremelimumab for patients for whom the goal is ablating all known sites of disease. We anticipate that for many patients this will be the first line-therapy. Patients who have received prior-platinum-based chemotherapy and/or any line of prior chemotherapy are eligible. Prior immunotherapy treatment is not allowed.

NCT03275597 Non-small Cell Lung Cancer Non-small Cell Lung Cancer Stage IV Drug: Durvalumab Drug: Tremelimumab Radiation: Stereotactic Body Radiotherapy
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

exon 19 deletion or exon 21 L858R) or ALK rearrangement. --- L858R ---

Primary Outcomes

Description: Toxicities will be summarized by type and severity in tabular format. Toxicity rates (grade 2, grade 3, grade 4, grade ≥ 2, grade ≥ 3, etc.) will be calculated and reported along the corresponding 95% confidence intervals. The 95% confidence intervals will be constructed using the Wilson score method.

Measure: Safety and tolerability of SBRT followed by combined durvalumab and tremelimumab, assessed by CTCAE v4.03

Time: Up to 3 years

Secondary Outcomes

Description: Progression-free survival (PFS) will be defined as the difference (in months) between the date of study enrollment and the date of disease progression or death due to any cause. PFS will be analyzed using the Kaplan-Meier method, and the Brookmeyer-Crowley method will be used to construct the 95% confidence interval for the median PFS. PFS assessed with RECIST 1.1 tumor assessments. The effect of DCI with durvalumab and tremelimumab will be compared against historical controls for a 95% CI and p-value.

Measure: Progression Free Survival assessed with RECIST 1.1 tumor assessments

Time: Up to 4 years

Description: Overall survival (OS) will be defined as the difference (in months) between the date of study enrollment to the date death due to any cause. OS will be analyzed using the Kaplan-Meier method, and the Brookmeyer-Crowley method will be used to construct the 95% confidence interval for the median OS. The effect of DCI with durvalumab tremelimumab will be compared against historical controls for a 95% CI and p-value.

Measure: Overall Survival assessed with RECIST 1.1 tumor assessments

Time: Up to 4 years

Other Outcomes

Description: Determine whether immune response on biopsy sections or circulating tumor cells is increased following SBRT. The paired McNemar's test will be used to compare with subjects with an immune response between assessment time point.

Measure: Evaluate immune response

Time: Up to 4 years

Description: Determine whether PD-L1 expression on biopsy sections or circulating tumor cells is increased following SBRT. PD-L1 expression will be summarized in terms of means, standard deviation, median and range. Absolute and percentage changes in PD-L1 expression levels between the pre-SBRT versus post-SBRT assessment will be calculated and evaluated using a paired t-test.

Measure: Evaluate PD-L1 expression

Time: Up to 4 years

22 A Phase III, Open-Label, Multicenter, Randomized Study to Investigate the Efficacy and Safety of Atezolizumab Compared With Chemotherapy in Patients With Treatment Naïve Advanced or Recurrent (Stage IIIb Not Amenable for Multimodality Treatment) or Metastatic (Stage IV) Non-Small Cell Lung Cancer Who Are Deemed Unsuitable for Platinum-Containing Therapy

This Phase III, global, multicenter, open-label, randomized, controlled study will evaluate the efficacy and safety of atezolizumab (an anti-programmed death-ligand 1 [anti-PD-L1] antibody) compared with a single agent chemotherapy regimen by investigator choice (vinorelbine or gemcitabine) in treatment-naïve participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) who are deemed unsuitable for any platinum-doublet chemotherapy due to poor performance status (Eastern Cooperative Oncology Group [ECOG] performance status of 2-3).

NCT03191786 Non-Small Cell Lung Cancer Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody Drug: Vinorelbine Drug: Gemcitabine
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC as per the American Joint Committee on Cancer (AJCC) 7th edition - No sensitizing epidermal growth factor receptor (EGFR) mutation (L858R or exon 19 deletions) or anaplastic lymphoma kinase (ALK) fusion oncogene detected - No prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC as per the AJCC 7th edition - Life expectancy greater than or equal to (>/=) 8 weeks - Deemed unsuitable by the investigator for any platinum-doublet chemotherapy due to poor performance status (ECOG performance status of 2-3). --- L858R ---

Grade 3 or higher toxicities due to any prior therapy (example [e.g.], radiotherapy) (excluding alopecia), which have not shown improvement and are strictly considered to interfere with current study medication - Participants who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, or chemoradiotherapy with curative intent for non-metastatic disease must have experienced a treatment-free interval of at least 6 months from randomization since the last chemotherapy, radiotherapy, or chemoradiotherapy General Medical Exclusion Criteria: - History of autoimmune disease except autoimmune-related hypothyroidism and controlled Type I diabetes mellitus - History of idiopathic pulmonary fibrosis (IPF), organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis - Known positivity for human immunodeficiency virus (HIV) - Known active hepatitis B or hepatitis C - Active tuberculosis - Severe infections within 4 weeks prior to randomization - Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina - Major surgical procedure other than for diagnosis within 4 weeks prior to randomization or anticipation of need for a major surgical procedure during the course of the study - Prior allogeneic bone marrow transplantation or solid organ transplant - Participants with an illness or condition that may interfere with capacity or compliance with the study protocol, as per investigator's judgment - Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 28 days prior to randomization Exclusion Criteria Related to Atezolizumab: - History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins - Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation - Oral or IV antibiotic treatment - Administration of a live, attenuated vaccine within 4 weeks before randomization or anticipation that such a live attenuated vaccine will be required during the study - Prior treatment with cluster of differentiation 137 (CD137) agonists or immune checkpoint blockade therapies, anti-programmed death-1 (anti-PD-1), and anti-PD-L1 therapeutic antibodies - Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to randomization - Treatment with systemic corticosteroids or other immunosuppressive medications - Participants not willing to stop treatment with traditional herbal medicines Exclusion Criteria Related to Chemotherapy: - Known sensitivity and contraindications to the 2 comparative chemotherapy agents (that is [i.e.] vinorelbine, oral or intravenous, and gemcitabine, intravenous) Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC as per the American Joint Committee on Cancer (AJCC) 7th edition - No sensitizing epidermal growth factor receptor (EGFR) mutation (L858R or exon 19 deletions) or anaplastic lymphoma kinase (ALK) fusion oncogene detected - No prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC as per the AJCC 7th edition - Life expectancy greater than or equal to (>/=) 8 weeks - Deemed unsuitable by the investigator for any platinum-doublet chemotherapy due to poor performance status (ECOG performance status of 2-3). --- L858R ---

Primary Outcomes

Measure: Overall Survival

Time: From randomization up to death from any cause (up to approximately 3.5 years)

Secondary Outcomes

Measure: Percentage of Participants Who Are Alive at Specified Timepoints

Time: 6, 12, 18 and 24 months

Description: Objective response is defined as partial response (PR) plus complete response (CR).

Measure: Percentage of Participants With Objective Response, as Determined by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 (v1.1)

Time: From randomization to the first occurence of disease progression or death from any cause, whichever occurs first (up to approximately 3.5 years)

Measure: Progression-Free Survival (PFS), as Determined by the Investigator Using RECIST v1.1

Time: From randomization to the first occurence of disease progression or death from any cause, whichever occurs first (up to approximately 3.5 years)

Measure: Duration of Response, as Determined by the Investigator Using RECIST v1.1

Time: Time from the first occurrence of a documented objective response to the time of disease progression or death from any cause, whichever occurs first (up to approximately 3.5 years)

Measure: Percentage of Participants With Adverse Events (AEs)

Time: From randomization up to approximately 3.5 years

Measure: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC-QLQ-C30) Score

Time: Baseline, Day 1 of each treatment cycle up to 30 days after last dose (up to approximately 3.5 years) (Cycle length = 21 days)

Measure: Change From Baseline in EORTC QLQ Supplementary Lung Cancer Module 13 (EORTC QLQ-LC13) Score

Time: Baseline, Day 1 of each treatment cycle up to 30 days after last dose (up to approximately 3.5 years) (Cycle length = 21 days)

Measure: Time to Deterioration in Patient-Reported Lung Cancer Symptoms as Assessed by EORTC QLQ-C30 Score

Time: From baseline up to approximately 3.5 years

Measure: Time to Deterioration in Patient-Reported Lung Cancer Symptoms As Assessed by EORTC QLQ-LC13 Score

Time: From baseline up to approximately 3.5 years

23 A Multicenter, Open-Label Phase 1 Study of DS-1205c in Combination With Osimertinib in Subjects With Metastatic or Unresectable EGFR-Mutant Non-Small Cell Lung Cancer

This study has two parts: dose escalation and dose expansion. The primary objectives are: - For Dose Escalation, to assess the safety and tolerability of DS-1205c when combined with osimertinib in the study population and to determine the recommended dose for expansion of DS-1205c when combined with osimertinib in the study population - For Dose Expansion, to assess the safety and tolerability of DS-1205c when combined with osimertinib in the study population In Dose Escalation, after a 7-day run in period (Cycle 0), there will be 21-day cycles (Cycle 1 onward). In Dose Expansion, there will be 21-day cycles. The number of treatment cycles is not fixed in this study. Participants will continue study treatment for 36 months unless they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity).

NCT03255083 Non-small Cell Lung Cancer (NSCLC) Drug: DS-1205c Drug: Osimertinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

3. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011): 1. Historical confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) or 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression (Response Evaluation Criteria in Solid Tumors [RECIST version 1.1] or World Health Organization [WHO]) while on continuous treatment with an EGFR TKI. 4. Is currently receiving, and is able to discontinue erlotinib, gefinitib, or afatinib; or is currently receiving osimertinib at the prescribed 80 mg dose and is able to interrupt osimertinib. --- L858R ---

Primary Outcomes

Measure: Number of participants with dose-limiting toxicities (DLTs) when taking DS-1205c in combination with osimertinib during dose escalation

Time: within 28 days

Description: Categories: during dose escalation, during dose expansion

Measure: Number of participants with clinically significant safety measures when taking DS-1205c in combination with osimertinib

Time: within 36 months

Secondary Outcomes

Description: DS-1205a is the free form of DS-1205c when DS-1205c is administered alone

Measure: Area under the plasma concentration time curve (AUC) for DS-1205a

Time: during Cycle 0 of the dose escalation period (within 28 days)

Measure: Maximum observed analyte concentration (Cmax) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Measure: Actual sampling time to reach Cmax (Tmax) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Measure: Area under the analyte concentration versus time curve during a dosing interval (AUCtau) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Measure: Minimum observed analyte concentration prior to the beginning, or at the end, of a dosing interval (Ctrough) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Cmax during a dosing interval (Tau) at steady state (Cmax,ss)

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Plasma concentration of DS-1205a versus time

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Tmax

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Ctrough

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites

Measure: AUCtau

Time: during the dose expansion period, within 36 months

Description: Objective response rate is calculated as the number of participants with best objective response [complete response (CR) or partial response (PR) determined by Investigator assessment based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1], divided by the number of participants in the analysis population.

Measure: Objective response rate (ORR), graded according to RECIST version 1.1

Time: within 36 months

Measure: Change from baseline in size of target lesion(s)

Time: within 36 months

Description: DOR is defined as the time from documentation of tumor response [either CR or PR] to disease progression

Measure: Duration of response (DOR)

Time: within 36 months

Description: DCR is defined as the sum of CR rate, PR rate, and stable disease (SD) rate

Measure: Disease control rate (DCR)

Time: first dose to 36 months

Description: PFS is defined as the time from the date of the first dose to the earlier of the dates of the first objective documentation of radiographic PD, or death due to any cause

Measure: Progression-free survival (PFS)

Time: baseline to objective disease progression or death from any cause (within 36 months)

Measure: Overall survival (OS)

Time: baseline to death from any cause (within 36 months)

24 A Phase II Study of Nivolumab in Combination With Carboplatin and Pemetrexed, or Nivolumab in Combination With Ipilimumab, in Patients With Advanced, EGFR-mutant or ALK-rearranged, Non-Small Cell Lung Cancer

This research study is studying a drug intervention as a possible treatment for lung cancer. The drugs involved in this study are: - Nivolumab - Carboplatin - Pemetrexed - Ipilimumab

NCT03256136 Lung Cancer Drug: Carboplatin Drug: Nivolumab Drug: pemetrexed Drug: Ipilimumab
MeSH: Lung Neoplasms
HPO: Neoplasm of the lung

- EGFR-mutant NSCLC: EGFR activating gene mutation (e.g., L858R, exon 19 deletion) as well as a T790M mutation per local testing. --- L858R ---

Primary Outcomes

Description: Complete response (CR) or partial response (PR) per RECIST version 1.1

Measure: Objective Response Rate (ORR)

Time: 2 years

Secondary Outcomes

Description: Complete response (CR), partial response (PR), or stable disease (SD) per RECIST version 1.1

Measure: Disease Control Rate (DCR)

Time: 2 years

Description: Time from initiation of the study drugs to progression or death, whichever occurs first

Measure: Progression Free Survival (PFS)

Time: 2 years

Description: Time from initiation of the study drugs to date of death due to any cause

Measure: Overall Survival (OS)

Time: 2 years

Description: Time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective tumor progression or death due to any cause, whichever occurs first

Measure: Duration Of Response

Time: 2 years

25 Tailored Second Line Treatment by EGFR Mutation in Patients With Advanced Lung Adenocarcinoma

Currently the investigators have two different classes of second-line treatment options in recurrent non-small Cell Lung Cancer (NSCLC). In chemotherapy, docetaxel and pemetrexed produced similar treatment efficacy outcomes, while pemetrexed had a better tolerability. In recent analysis of pemetrexed clinical studies, a strong treatment-by-histology interaction in overall survival and progression free survival that indicated better efficacy for non-squamous patients treated with pemetrexed. These data supports that pemetrexed could be a preferable chemotherapy drug especially in adenocarcinoma NSCLC patients.

NCT00903292 Non-Small Cell Lung Cancer Drug: erlotinib (Tarceva) Drug: pemetrexed (Alimta)
MeSH: Carcinoma, Non-Small-Cell Lung Adenocarcinoma Adenocarcinoma of Lung
HPO: Non-small cell lung carcinoma

Since typical EGFR gene mutations (i.e., the deletion of typically five amino acids at codons 746-750 (ELREA) in exon 19 and a leucine-to-arginine mutation at codon 858 (L858R)) are a good predictor for tumor response to tyrosine kinase inhibitor, this present study is to tailor the patient's treatment according to his/her EGFR gene mutation status. --- L858R ---

Primary Outcomes

Measure: The primary analysis will be the overall best response rate, including a 95% confidence interval (Leemis and Trivedi 1996).

Time: 02/2009 - 04/2010

26 Adjuvant Erlotinib Intercalating Chemotherapy or Adjuvant Chemotherapy Alone in NSCLC With Common EGFR Mutation

This study will be performed as a local multicenter, randomized, phase III clinical study. It will compare the adjuvant chemotherapy in Stage IB-IIIA NSCLC with common EGFR mutation (Exon 19 deletion or L858R) who underwent total resection and the Erlotinib-Intercalation adjuvant chemotherapy with the chemotherapy alone. The patients will be randomly assigned to the Intercalation combination chemotherapy regimen and the chemotherapy alone regimen at the ratio of 1:1. The treatment regimen of each arm is as follows.

NCT02795884 NSCLC Drug: intercalation therapy using pemetrexed, cisplatin and erlotinib Drug: Vinorelbine, cisplatin

It will compare the adjuvant chemotherapy in Stage IB-IIIA NSCLC with common EGFR mutation (Exon 19 deletion or L858R) who underwent total resection and the Erlotinib-Intercalation adjuvant chemotherapy with the chemotherapy alone. --- L858R ---

- Stage IB-IIIA Non-squamous NSCLC (Based on AJCC Version 7 TNM Disease Stages) - Surgically complete resection - Confirmed with Exon 19 deletion or L858R EGFR mutation - Complete recovery from the surgery. --- L858R ---

Primary Outcomes

Description: Time from randomization to disease recurrence or death of any cause

Measure: Disease-free survival (DFS)

Time: 3 years

Secondary Outcomes

Measure: Overall survival (OS)

Time: 3 years

Measure: Treatment-related adverse events assessed by CTCAE v4.0

Time: 3 years

27 Pilot Study of Local Therapies for Oligometastatic Non-Small Cell Lung Cancer Harboring Sensitizing EGFR Mutations

This study will test if local therapies in addition to erlotinib can improve responses and delay the time until new treatment is required. This study will also collect blood samples for research blood tests.

NCT02450591 Oligometastatic Lung Adenocarcinoma Drug: Erlotinib Other: Local Therapies
MeSH: Carcinoma, Non-Small-Cell Lung Adenocarcinoma Adenocarcinoma of Lung
HPO: Non-small cell lung carcinoma

At least five patients will need to complete local therapy within 2 years of the study being open to accrual for the primary endpoint to be met.. Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma (recurrent or de novo) harboring sensitizing EGFR mutations (L858R, exon 19 deletion, G719A, L861Q, S768I, exon 19 insertions) with oligometastatic disease (≤5 discrete lesions of disease irrespective of location, inclusive of the primary lesion): - all sites of disease must be amenable to definitive treatment with a local therapy (surgical resection, stereotactic radiosurgery, ablation and conventional radiation therapy) as determined by surgery, interventional radiology and radiation oncology - all intrathoracic lymph nodes (including hilar, mediastinal, and supraclavicular nodal disease) are considered 1 discrete lesion. --- L858R ---

- Any medical co-morbidities that would preclude surgery or radiation therapy Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma (recurrent or de novo) harboring sensitizing EGFR mutations (L858R, exon 19 deletion, G719A, L861Q, S768I, exon 19 insertions) with oligometastatic disease (≤5 discrete lesions of disease irrespective of location, inclusive of the primary lesion): - all sites of disease must be amenable to definitive treatment with a local therapy (surgical resection, stereotactic radiosurgery, ablation and conventional radiation therapy) as determined by surgery, interventional radiology and radiation oncology - all intrathoracic lymph nodes (including hilar, mediastinal, and supraclavicular nodal disease) are considered 1 discrete lesion. --- L858R ---

Primary Outcomes

Description: At least five patients will need to complete local therapy within 2 years of the study being open to accrual for the primary endpoint to be met.

Measure: Feasibility as Measured by at Least Five Patients Will Need to Complete Local Therapy.

Time: 2 years

28 Pemetrexed Disodium and Cisplatin Chemotherapy Combined With Synchronous Gefitinib vs Chemotherapy Alone as Adjuvent Therapy in Patient With Stage II-IIIA, Epidermal Growth Factor Receptor Mutant Expressing Lung Adenocarcinoma

This randomized phase III trial is studying gefitinib and synchronous pemetrexed/cisplatin chenmotherapy to see how well it works compared to pemetrexed/cisplatin chenmotherapy alone in treating patients who have undergone surgery for stage II-IIIA(N1-N2) lung adenocarcinoma with EGFR activating mutation in Asian population.

NCT02518802 Lung Neoplasms Drug: Gefitinib Drug: Pemetrexed
MeSH: Adenocarcinoma Lung Neoplasms Adenocarcinoma of Lung
HPO: Neoplasm of the lung

- Target population is completely resected pathological stage II-IIIA(N1-N2) NSCLC with EGFR exon 19 deletions and exon 21 L858R activating mutation. --- L858R ---

Primary Outcomes

Description: To evaluate the disease free survival of synchronous therapy versus combination of Pemetrexed plus Cisplatin as adjuvant treatment for pathological stage II-IIIA(N1-N2) lung adenocarcinoma with EGFR mutation.Disease free survival (DFS)- defined as the time from randomization to the first documented disease progression or death, whichever occurs first.

Measure: Disease free survival

Time: From date of randomization to the first documented disease progression or death, whichever occurs first, assessed up to 3 and 5 years.

Secondary Outcomes

Description: To evaluate the overall survival of synchronous therapy versus combination of Pemetrexed plus Cisplatin as adjuvant treatment for stage II-IIIA(N1-N2) lung adenocarcinoma with EGFR mutation.

Measure: Overall survival

Time: From date of randomization to the first documented death, assessed up to 5 years.

Description: The safety and tolerability profile of gefitinib at a 250 mg daily dose relative to that of Chemotherapy.

Measure: Number of Participants with Adverse Events

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months. Pemetrexed 500 mg/m2 intravenous infusion on day 1, Cisplatin 75 mg/m2 on day 1 for 4 cycles.

Description: Quality of life as measured by the total score and Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy - Lung Cancer (FACT-L) questionnaire.

Measure: Quality of life

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months. Pemetrexed 500 mg/m2 intravenous infusion on day 1, Cisplatin 75 mg/m2 on day 1 for 4 cycles.

29 A Phase III, Double-blind, Randomized, Placebo-controlled Multi-centre, Study to Assess the Efficacy and Safety of AZD9291 Versus Placebo, in Patients With Epidermal Growth Factor Receptor Mutation Positive Stage IB-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy (ADAURA).

To assess the efficacy and safety of AZD9291 versus Placebo, in patients with Epidermal Growth Factor Receptor Mutation Positive stage IB-IIIA non-small cell lung carcinoma, following complete tumour resection with or without adjuvant chemotherapy

NCT02511106 Stage IB-IIIA Non-small Cell Lung Carcinoma Drug: AZD9291 80 mg/40 mg Drug: Placebo AZD9291 80 mg/40 mg
MeSH: Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

5. Confirmation by the central laboratory that the tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations including T790M. --- L858R ---

Stage IB-IIIA Non-small Cell Lung Carcinoma Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a phase 3 double-blind, randomized, placebo-controlled, study to assess the efficacy and safety of AZD9291 versus placebo in patients with stage IB-IIIA non-small cell lung cancer (NSCLC) with centrally confirmed, most common sensitising EGFR mutations (Ex19Del and L858R) either alone or in combination with other EGFR mutations as confirmed by a central test, who have had complete tumour resection, with or without postoperative adjuvant chemotherapy. --- L858R ---

Primary Outcomes

Description: Defined as the time from the date of randomization until the date of disease recurrence or death (by any cause in the absence of recurrence)

Measure: Disease free survival (DFS)

Time: From date of randomization until date of disease recurrence or death (by any cause in the absence of recurrence). Estimated median time to event of 46 and 66 months for those on placebo and AZD9291, respectively.

Secondary Outcomes

Description: Defined as the proportion of patients alive and disease free at 2, 3 and 5 years, respectively, estimated from Kaplan Meier plots of the primary endpoint of DFS at the time of the primary analysis

Measure: Disease free survival (DFS) rate at 2, 3 and 5 years

Time: From date of randomization until date of disease recurrence or death (by any cause in the absence of recurrence). Estimated median time to event of 46 and 66 months for those on placebo and AZD9291, respectively.

Description: Defined as the time from the date of randomization until date of death due to any cause

Measure: Overall Survival (OS)

Time: From date of randomization until date of death due to any cause (estimated median 96 months for those on placebo)

Description: Defined as the proportion of patients alive at 5 years, estimated from a Kaplan Meier plot of OS at the time of the primary analysis

Measure: Overall Survival rate at 5 years

Time: From date of randomization until date of death due to any cause (estimated median 96 months for those on placebo)

Description: Measured by SF-36 Questionnaire consisting in 36 items that is an instrument for assessing a person's general health status over the past 28 days. The scores for each of the 8 health domain scores and for each of the physical and mental component summary measures from the SF-36 v2 will be summarized in terms of mean changes from baseline at each post-baseline assessment.

Measure: Patient health-related quality of life and symptoms (HRQoL) by SF-36v2 Health Survey

Time: From date of randomization until treatment completion or discontinuation (max. 36 months)

Description: The pharmacokinetics exposure parameters derived from plasma concentrations of AZD9291

Measure: Plasma concentrations of AZD9291

Time: From date of dosing to month 24 (approximately 24 months)

Description: The pharmacokinetics exposure parameters derived from plasma concentrations of AZ5104 and AZ7550 metabolites

Measure: Plasma concentrations of AZ5104 and AZ7550 metabolites and ratio of metabolite to AZD9291

Time: From date of dosing to month 24 (approximately 24 months)

Other Outcomes

Description: AEs graded by CTCAE version 4.0

Measure: Incidence of Adverse Events (AEs)

Time: From date of randomization until 28 days after treatment completion (max. 37 months)

30 A Single Arm Phase IV Study of Afatinib in Elderly Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer Whose Tumors Have Epidermal Growth Factor Receptor (EGFR) Exon 19 Deletions or Exon 21(L858R) Substitution Mutations

Continuous treatment until progression or occurence of intolerable Adverse Event (AE) or end of trial. The end of trial is one year after the last patient has entered the study.

NCT02514174 Carcinoma, Non-Small-Cell Lung ErbB Receptors Drug: Afatinib
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

A Single Arm Phase IV Study of Afatinib in Elderly Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer Whose Tumors Have Epidermal Growth Factor Receptor (EGFR) Exon 19 Deletions or Exon 21(L858R) Substitution Mutations. --- L858R ---

Staging is based on American Joint Committee on Cancer (AJCC) Staging for NSCLC 7th edition (R12-4710) - Evidence of common EGFR mutation (Del 19 and/or L858R) - Age >= 70 years - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (R01-0787) - Further inclusion criteria apply. --- L858R ---

Primary Outcomes

Measure: Occurrence of AEs leading to dose reduction of afatinib

Time: One year after LPE

Secondary Outcomes

Measure: Occurrence of CTCAE grade 3 or higher diarrhoea

Time: One year after LPE

Measure: Occurrence of CTCAE grade 3 or higher rash/acne+ (+ represents grouped term)

Time: One year after LPE

Measure: Occurence of CTCAE grade 3 or higher stomatitis+ (+ represents grouped term)

Time: One year after LPE

Measure: Occurence of CTCAE grade 3 or higher paronychia+ (+ represents grouped term)

Time: One year after LPE

Measure: Time to first dose reduction of afatinib caused by AE's, defined as time from the date of the first administration of afatinib to the first dose reduction of afatinib caused by AE's.

Time: One year after LPE

31 A Phase 1 Trial of MLN0128 (TAK-228) in Combination With Osimertinib (AZD9291) in Advanced EGFR Mutation Positive Non-Small Cell Lung Cancer (NSCLC) After Progression on a Previous EGFR Tyrosine Kinase Inhibitor

This phase I trial studies the side effects and best dose of sapanisertib when given together with osimertinib in treating patients with stage IV EGFR mutation positive non-small cell lung cancer that has progressed after treatment with an EGFR tyrosine kinase inhibitor. Sapanisertib and osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02503722 EGFR Activating Mutation EGFR Exon 19 Deletion Mutation EGFR NP_005219.2:p.G719X EGFR NP_005219.2:p.L858R EGFR NP_005219.2:p.L861Q EGFR T790M Mutation Negative Recurrent Lung Non-Small Cell Carcinoma Stage III Lung Non-Small Cell Cancer AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Stage IIIB Lung Non-Small Cell Cancer AJCC v7 Stage IV Lung Non-Small Cell Cancer AJCC v7 Other: Laboratory Biomarker Analysis Drug: Osimertinib Other: Pharmacological Study Drug: Sapanisertib
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

Descriptive statistics and plotting of data will also be used to better understand potential relationships.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically or cytologically confirmed non-squamous NSCLC - NSCLC must harbor an EGFR activating mutation (Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q) - Progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including osimertinib [AZD9291] allowed for dose escalation only) - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent to a fresh tumor biopsy (mandatory for dose expansion cohort only; optional for dose escalation) - For the dose expansion portion ONLY, patient must: 1) have progression of disease with erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) tumors must be EGFR T790M negative confirmed by central testing prior to treatment (If EGFR-T790M status is unknown, patient may consent for trial for biopsy and testing for EGFR T790M will be performed as part of the initial biopsy for the trial: patients who test positive for EGFR T790M by central testing will be ineligible for the dose expansion), 3) be treatment naive for 3rd generation EGFR-TKI (CO-1686 and osimertinib [AZD9291]) and mTOR inhibitors - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 28 days prior to start of protocol therapy; the CT from a combined positron emission tomography (PET)/CT may be used if it is of diagnostic quality; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies are allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Hemoglobin >= 90 g/L (or >= 9 g/dL) - Platelets >= 100 x 10^9/L - Calculated creatinine clearance of > 50 mL/min using Cockcroft Gault equation equation or 24-hour urine sampling - Total bilirubin =< 1.5 institutional upper limit of normal - Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Fasting plasma glucose =< 130 mg/dL (or 7.2 mmol/L) - Glycosylated hemoglobin (Hb A1c) =< 7% - Fasting triglycerides =< 300 mg/dL (3.42 mmol/L) - Cholesterol =< 300 mg/dL (7.75 mmol/L) - Fridericia's correction formula (QTcF) =< 470 msec - Patients must have had sufficient time between a prior therapy and resolution of toxicities from the prior therapies prior to registration as follows: - Prior EGFR inhibitor: A minimum of 7 days must have elapsed from the last dose of the prior EGFR inhibitor and resolution of any drug-related toxicity to =< grade 1 except for alopecia - Chemotherapy: A minimum of 21 days must have elapsed from the last dose and resolution of toxicity to =< grade 1 excluding =< grade 2 peripheral neuropathy or alopecia - Surgery: A minimum of 21 days must have elapsed following major surgery and resolution of toxicity to < grade 1 and complete wound healing must have occurred - Radiation: A minimum of 14 days must have elapsed following radiation therapy and resolution of all radiation induced toxicity excluding alopecia - Treatment with an investigational drug: A minimum of 3 months or five half-lives of the compound, whichever is greater, must have elapsed from last treatment date - Ability to understand and the willingness to sign a written informed consent document - Available for follow-up of their disease after treatment until progressive disease is documented and resolution of related adverse events until < grade 2 Exclusion Criteria: - Any serious intercurrent or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol including but not limited to: - Uncontrolled diabetes mellitus (fasting plasma glucose > 130 mg/dL or 7.2 mmol/L) - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease - Active infections - Gastrointestinal disease limiting the ability to swallow oral medications or absorb oral medications including refractory nausea and vomiting, chronic gastrointestinal diseases, inflammatory bowel disease; malabsorption syndromes - Patients with enteric stomata or significant bowel resection - Prior history of corneal ulceration - Patients with any evidence of severe or uncontrolled systemic liver disease including those with known hepatitis B and hepatitis C (excluding treated hepatitis C that has been cured) - Active bleeding diatheses - Significant active cardiovascular or pulmonary disease including: - Uncontrolled hypertension (i.e., systolic blood pressure > 180 mmHg, diastolic blood pressure > 95 mmHg); use of anti-hypertensive agents to control hypertension before cycle 1 day 1 is allowed - Pulmonary hypertension - Uncontrolled asthma or oxygen (O2) saturation < 90% by arterial blood gas analysis or pulse oximetry on room air - Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement - History of arrhythmia requiring an implantable cardiac defibrillator - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) e.g. --- L858R ---

medically significant (symptomatic) bradycardia, complete left bundle branch block, third degree heart block and second-degree heart block or history of arrhythmia requiring an implantable cardiac defibrillator; or within the last 6 months before administration of the first dose of drug: - Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia) - Placement of a pacemaker for control of rhythm - Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures - Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures - New York Heart Association (NYHA) class III or IV heart failure - Pulmonary embolism - Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTcF >= 470 msec (mean value) obtained from 3 ECGs, using the screening clinic ECG machine derived QTc value, or history of congenital long QT syndrome, or torsades de pointes); any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval - Left ventricular ejection fraction (LVEF) by either multigated acquisition (MUGA) or echocardiography (ECHO) less than lower limit of normal - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Concurrent anti-cancer therapy - History of hypersensitivity attributed to compounds of similar chemical or biologic composition to MLN0128 (TAK-228) or osimertinib (AZD9291) - Pregnant women or women who are breast feeding are not eligible for the study; the effects of MLN0128 (TAK-228) and osimertinib (AZD9291) on the developing human fetus are unknown - Women of non-child bearing potential must be: - Women more than 50 years must be post-menopausal for at least 12 months following the end of all exogenous hormonal treatments OR - Women under 50 years must be postmenopausal for at least 12 months following the end of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution OR - Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation - Women of child bearing potential must have a negative serum or urine pregnancy test within 7 days of registration and must agree to: - Practice 1 highly effective method of contraception and 1 additional effective (barrier) method, at the same time, from the time of signing the informed consent through 120 days (or longer, as mandated by local labeling [e.g., United Surgical Partners International (USPI), Summary of Product Characteristics (SmPC), etc.;]) after the last dose of study drug, OR - Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient; NOTE: Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception; female and male condoms should not be used together - Male patients, even if surgically sterilized (i.e., status postvasectomy) must agree to: - Practice highly effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, OR - Practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient; NOTE: Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception; female and male condoms should not be used together - Not to donate sperm during the course of this study or within 120 days after receiving their last dose of study drug - Inability to discontinue drugs that are strong cytochrome P450 3A4 (CYP3A4) or P450 3A5 (CYP3A5), cytochrome P450 2C19 (CYP2C19), and cytochrome P450 2C9 (CYP 2C9) inhibitors and/or inducers; and substrates of CYP 3A4/5 or CYP1A2 that are sensitive or have a narrow therapeutic window at least three weeks prior to study registration - Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug - Consumption of grapefruit or grapefruit juice is not permitted during the study; patients should not consume food or beverages containing the fruit or juice of grapefruits or Seville oranges within 7 days before the first dose of study drug and throughout the study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - No concomitant use of proton pump inhibitors (PPI) is allowed; any prior PPI must be discontinued at least one week before receiving MLN0128 (TAK-228) Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically or cytologically confirmed non-squamous NSCLC - NSCLC must harbor an EGFR activating mutation (Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q) - Progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including osimertinib [AZD9291] allowed for dose escalation only) - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent to a fresh tumor biopsy (mandatory for dose expansion cohort only; optional for dose escalation) - For the dose expansion portion ONLY, patient must: 1) have progression of disease with erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) tumors must be EGFR T790M negative confirmed by central testing prior to treatment (If EGFR-T790M status is unknown, patient may consent for trial for biopsy and testing for EGFR T790M will be performed as part of the initial biopsy for the trial: patients who test positive for EGFR T790M by central testing will be ineligible for the dose expansion), 3) be treatment naive for 3rd generation EGFR-TKI (CO-1686 and osimertinib [AZD9291]) and mTOR inhibitors - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 28 days prior to start of protocol therapy; the CT from a combined positron emission tomography (PET)/CT may be used if it is of diagnostic quality; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies are allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Hemoglobin >= 90 g/L (or >= 9 g/dL) - Platelets >= 100 x 10^9/L - Calculated creatinine clearance of > 50 mL/min using Cockcroft Gault equation equation or 24-hour urine sampling - Total bilirubin =< 1.5 institutional upper limit of normal - Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Fasting plasma glucose =< 130 mg/dL (or 7.2 mmol/L) - Glycosylated hemoglobin (Hb A1c) =< 7% - Fasting triglycerides =< 300 mg/dL (3.42 mmol/L) - Cholesterol =< 300 mg/dL (7.75 mmol/L) - Fridericia's correction formula (QTcF) =< 470 msec - Patients must have had sufficient time between a prior therapy and resolution of toxicities from the prior therapies prior to registration as follows: - Prior EGFR inhibitor: A minimum of 7 days must have elapsed from the last dose of the prior EGFR inhibitor and resolution of any drug-related toxicity to =< grade 1 except for alopecia - Chemotherapy: A minimum of 21 days must have elapsed from the last dose and resolution of toxicity to =< grade 1 excluding =< grade 2 peripheral neuropathy or alopecia - Surgery: A minimum of 21 days must have elapsed following major surgery and resolution of toxicity to < grade 1 and complete wound healing must have occurred - Radiation: A minimum of 14 days must have elapsed following radiation therapy and resolution of all radiation induced toxicity excluding alopecia - Treatment with an investigational drug: A minimum of 3 months or five half-lives of the compound, whichever is greater, must have elapsed from last treatment date - Ability to understand and the willingness to sign a written informed consent document - Available for follow-up of their disease after treatment until progressive disease is documented and resolution of related adverse events until < grade 2 Exclusion Criteria: - Any serious intercurrent or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol including but not limited to: - Uncontrolled diabetes mellitus (fasting plasma glucose > 130 mg/dL or 7.2 mmol/L) - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease - Active infections - Gastrointestinal disease limiting the ability to swallow oral medications or absorb oral medications including refractory nausea and vomiting, chronic gastrointestinal diseases, inflammatory bowel disease; malabsorption syndromes - Patients with enteric stomata or significant bowel resection - Prior history of corneal ulceration - Patients with any evidence of severe or uncontrolled systemic liver disease including those with known hepatitis B and hepatitis C (excluding treated hepatitis C that has been cured) - Active bleeding diatheses - Significant active cardiovascular or pulmonary disease including: - Uncontrolled hypertension (i.e., systolic blood pressure > 180 mmHg, diastolic blood pressure > 95 mmHg); use of anti-hypertensive agents to control hypertension before cycle 1 day 1 is allowed - Pulmonary hypertension - Uncontrolled asthma or oxygen (O2) saturation < 90% by arterial blood gas analysis or pulse oximetry on room air - Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement - History of arrhythmia requiring an implantable cardiac defibrillator - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) e.g. --- L858R ---

Primary Outcomes

Description: Toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4 (CTCAE v4). CTCAE version 5.0 will be utilized beginning April 1, 2018.

Measure: Maximum tolerated dose of sapanisertib in combination with osimertinib in patients with EGFRmutant (m) non-small cell lung cancer (NSCLC)

Time: 28 days

Description: Toxicities will be graded according to the NCI CTCAE v4. CTCAE version 5.0 will be utilized beginning April 1, 2018.

Measure: Dose-limiting toxicity (DLT) of sapanisertib in combination with osimertinib in patients with EGFRm NSCLC

Time: 28 days

Secondary Outcomes

Description: Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

Measure: Non-DLTs associated with the administration of sapanisertib and osimertinib

Time: Up to 30 days after completion of study treatment

Description: PK analyses will be descriptive and will permit the evaluation of the PK profile of Tsapanisertib when combined with osimertinib.

Measure: Pharmacokinetic (PK) profiles of sapanisertib in combination with osimertinib

Time: Baseline, and at 1, 2, 4, 6, 8, and 24 hours post-sapanisertib administration, before administration and at 1, 2, 4, 6, 8, and 24 hours post-sapanisertib on day 26 of course 1; and day 1 of course 2

Description: Will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Response rate

Time: Up to 2 years

Description: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Disease control rate

Time: Up to 2 years

Description: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Progression free survival

Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years

Description: Will be assessed using RECIST 1.1. Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Response rate of patients with T790M- NSCLC in an expansion cohort

Time: Up to 2 years

Description: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Disease control rate of patients with T790M- NSCLC in an expansion cohort

Time: Up to 2 years

Description: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Progression free survival of patients with T790M- NSCLC in an expansion cohort

Time: At 6 months

Description: Predictors of clinical outcomes will be investigated using logistic regression, Cox proportional hazards regression and or generalized estimating equations as appropriate. Potential predictors include clinical predictors and molecular correlates analyzed in tumor and blood. Descriptive statistics and plotting of data will also be used to better understand potential relationships.

Measure: Biomarkers of response and resistance to the combination, explored by studying baseline biopsies, resistance biopsies, and serial plasma deoxyribonucleic acid specimens

Time: Up to 2 years

32 Randomized Blinded Phase III Assessment of Second or Third-Line Chemotherapy With Docetaxel + Plinabulin Compared to Docetaxel + Placebo in Patients With Advanced Non-Small Cell Lung Cancer and With at Least One Measurable Lung Lesion

To compare the overall survival of NSCLC patients receiving 2nd- or 3rd-line systemic therapy with docetaxel + plinabulin (DP Arm) to patients treated with docetaxel + placebo (D5W) (D Arm) for advanced or metastatic disease. Secondary purposes of the study are: - To compare the neutropenia (incidence of Grade 4 neutropenia [absolute neutrophil count (ANC) < 0.5 × 10^9/L]) on Day 8 (+/- 1 day) of Cycle 1), DoR, neutrophil count on Day 8 (+/- 1 day) of Cycle 1, incidence of docetaxel dose reduction and/or docetaxel dose withheld in Cycle 2 due to neutropenia in Cycle 1, QoL (EORTC QLQ-C30 [item 30, average overall quality of life over all observable weeks]), ORR, and PFS in patients with NSCLC treated in the DP Arm to patients treated in the D Arm as 2nd- or 3rd-line therapy for advanced or metastatic disease. - To compare the safety and adverse events profile of the DP Arm to D Arm. - To compare dose intensity of docetaxel (percent dose administered compared to dose assigned) between the 2 treatment arms. - To evaluate population pharmacokinetics in patients enrolled in China and rest of world (RoW).

NCT02504489 Non-Small Cell Lung Cancer Drug: Docetaxel + Plinabulin (DP) Drug: Docetaxel (D)
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Radiographic tumor assessment is to be performed within 28 days prior to randomization. 5. patients with nonsquamous NSCLC must have been tested for EGFR exon 19 deletion and Exon 21 L858R substitution mutation. --- L858R ---

Primary Outcomes

Description: Overall survival of NSCLC patients receiving 2nd- or 3rd-line systemic therapy

Measure: Overall Survival

Time: Approximately 2 years after study initiation

Secondary Outcomes

Description: Incidence of Grade 4 neutropenia on Day 8 of Cycle 1

Measure: Grade 4 neutropenia

Time: During 1st 21-day cycle

Description: Neutrophil count on Day 8 of Cycle 1

Measure: Neutrophil count

Time: During 1st 21-day cycle

Description: incidence of docetaxel dose reduction and/or docetaxel dose withheld in Cycle 2 due to neutropenia in Cycle 1

Measure: docetaxel dose reduction and/or docetaxel dose withheld

Time: During 2nd 21-day cycle

Description: Average Quality of Life score over all observed weeks (scale 0 - 30, higher value represents better outcome)

Measure: Quality of Life (EORTC QLQ-C30)

Time: Approximately 2 years after study initiation.

Description: Overall response rate

Measure: ORR

Time: Approximately 2 years after study initiation.

Description: Progress-free survival

Measure: PFS

Time: Approximately 2 years after study initiation.

Description: Duration of response

Measure: DoR

Time: Approximately 2 years after study initiation.

33 Phase II Study of ASP8273 — An Open-Label, Study of the Oral Administration of ASP8273 in Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor-NaïvePatients With Non-Small Cell Lung Cancer Harboring EGFR Mutations

The purpose of this study is to determine the safety, the antitumor activity and the pharmacokinetics of ASP8273 in EGFR tyrosine kinase inhibitor (EGFR-TKI)-naïve patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations.

NCT02500927 EGFR-TKI-naïve Patients With NSCLC Harboring EGFR Activating Mutations Drug: ASP8273 Capsules Drug: ASP8273 Capsules A
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

- Patients confirmed to have the deletion of exon 19 (del ex19), L858R, G719X, or L861Q mutation among the EGFR activating mutations (patients at the study site who are documented to have any of the above-stated EGFR activating mutations can be enrolled in the study). --- L858R ---

Primary Outcomes

Measure: Safety assessed by AEs

Time: Up to 18 months

Measure: Safety assessed by Laboratory tests

Time: Up to 18 months

Measure: Safety assessed by Vital signs

Time: Up to 18 months

Measure: Safety assessed by Percutaneous oxygen saturation (SpO2)

Time: Up to 18 months

Measure: Safety assessed by Body weight

Time: Up to 18 months

Description: ECG: Electrocardiogram

Measure: Safety assessed by 12-lead ECG

Time: Up to 18 months

Measure: Safety assessed by Ophthalmologic examination

Time: Up to 18 months

Measure: Safety assessed by Chest X-ray examination

Time: Up to 18 months

Measure: Safety assessed by Chest computed tomography (CT) examination

Time: Up to 18 months

Measure: Safety assessed by ECOG Performance Status

Time: Up to 18 months

Secondary Outcomes

Description: The overall response rate is defined as the proportion of subjects whose best overall response is rated as Complete response (CR) or Partial Response (PR)among all analyzed subjects

Measure: Overall response rate

Time: Up to 18 months

Description: The disease control rate is defined as the proportion of subjects whose best overall response is rated as Complete response (CR), Partial Response (PR), or Stable disease (SD) among all analyzed subjects

Measure: Disease control rate

Time: Up to 18 months

Measure: Plasma concentrations of unchanged ASP8273

Time: Up to Day1 of Cycle 3

34 A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Asia Pacific Patients With Locally Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed With Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Whose Tumours Harbour a T790M Mutation Within the Epidermal Growth Factor Receptor Gene

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Asia Pacific Patients with Locally Advanced/Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene

NCT02442349 Non-Small Cell Lung Cancer Drug: AZD9291
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

- Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). --- L858R ---

Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a phase II, open label, single arm study assessing the safety and efficacy of AZD9291 (80 mg, orally, once daily) in Asia Pacific patients with a confirmed diagnosis of Epidermal Growth Factor Receptor (EGFR) sensitising mutation positive (ie, G719X, exon 19 deletion, L858R, L861Q) and T790M mutation positive (hereafter referred to as EGFRm+ and T790M+) un-resectable, locally advanced or metastatic NSCLC (Stage IIIB-IV), who have progressed on an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor(EGFR-TKI), either as first line treatment or following one line of EGFR-TKI and one line of platinum containing doublet chemotherapy. --- L858R ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR) According to RECIST 1.1

Time: RECIST tumour assessments every 6 weeks from time of first dose until objective disease progression, for an average of approximately 12 months. Results are based on the data cut off of 04 March 2016 (about 18 weeks after LSFD).

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.

Measure: Disease Control Rate (DCR) According to RECIST 1.1

Time: RECIST tumour assessments every 6 weeks from time first dose until date of progression, for an average of approximately 12 months. Results are based on the data cut off of 04 March 2016 (about 18 weeks after LSFD).

35 A Phase II Trial of Hypofractionated Radiotherapy for Limited Metastatic NSCLC Harboring Sensitizing EGFR Mutations After First Line TKI Therapy

To evaluate the efficacy and toxicity of patients treated with hypofractionated radiotherapy for limited metastatic NSCLC harboring sensitizing EGFR mutations after first line TKI therapy. An exploratory biomarker analysis in blood and tumor samples is also planned.

NCT02788058 Lung Adenocarcinoma EGFR Positive Non-small Cell Lung Cancer Drug: EGFR-TKI Radiation: Thoracic Hypofractionated Radiotherapy
MeSH: Carcinoma, Non-Small-Cell Lung Adenocarcinoma Adenocarcinoma of Lung
HPO: Non-small cell lung carcinoma

Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma harboring sensitizing EGFR mutations (L858R, exon 19 deletion), and became oligometastatic disease after 3 months TKI, evaluated by PET/CT scan, brain MRI, and abdomen ultrasound (≤6 discrete lesions of disease, exclusive of the brain metastases, ≤3 lesions in the liver, ≤3 lesions in the lung); - All sites of disease must be amenable to definitive RT; - An intrathoracic lymph nodal station is considered 1 discrete lesion, according to IASLC lymph nodal station map; - Age 18 years or older; - ECOG Performance Status 0-2; - Adequate bone marrow, liver and renal function, as specified below: Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L; Hemoglobin ≥ 8 g/dL; Platelets ≥ 100 x 109/L; Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) ; AST and ALT ≤ 2.5 x ULN or ≤ 5 x ULN if liver metastases are present; Serum creatinine ≤ 1.5 x upper limit of normal or creatinine clearance ≥ 60ml/min for patients with creatinine levels above institutional normal; - For women of child-bearing potential, negative pregnancy test within 14 days prior to starting treatment; - Men and women of childbearing age must be willing to use effective contraception while on treatment and for at least 3 months thereafter; - Patients and their family signed the informed consents; Exclusion Criteria: - Received chemotherapy before TKI therapy; - Brain parenchyma or leptomeningeal disease; - Any site of disease that is not amenable to definitive RT; - Concurrent malignancies other than non-melanoma skin cancer that require active ongoing treatment; - Any medical co-morbidities that would preclude radiation therapy. --- L858R ---

Primary Outcomes

Measure: Progression free survival

Time: 3 years

Secondary Outcomes

Measure: Frequency of T790M mutation before treatment detected by ctDNA

Time: 1 months

Measure: Abundance of T790M mutation before treatment detected by ctDNA

Time: 1 months

Measure: Frequency of T790M mutation after radiotherapy detected by ctDNA

Time: 3 months

Measure: Abundance of T790M mutation after radiotherapy detected by ctDNA

Time: 3 months

Measure: Frequency of T790M mutation after 1 year detected by ctDNA

Time: 1 year

Measure: Abundance of T790M mutation after 1 year detected by ctDNA

Time: 1 year

Description: We will assess the rate of symptomatic radiation pneumonitis in patients who received the radiation therapy.

Measure: Rate of CTCAE grade 2 or higher radiation pneumonitis

Time: 1 years

Description: FACT-E score at the 4 months after docetaxel consolidation therapy

Measure: To assess the short-term quality of life (QOL)

Time: 4 months

36 A Phase II Trial of Hypofractionated Radiotherapy Combined With Thymosin for Metastatic NSCLC Patients Who Showed Stable Disease After First Line TKI Therapy

The investigators postulated that the exploitation of the pro-immunogenic effects of radiotherapy with thymosin might result in abscopal responses among patients with metastatic cancer. The research is designed to evaluate the efficacy and toxicity of patients treated with hypofractionated radiotherapy combined with thymosin alpha 1. An exploratory biomarker analysis in blood and tumor samples is also planned.

NCT02787447 Lung Adenocarcinoma Drug: TKI Radiation: Thoracic Hypofractionated Radiotherapy Drug: Thymosin Alpha 1
MeSH: Adenocarcinoma Adenocarcinoma of Lung

Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma harboring sensitizing EGFR mutations (L858R, exon 19 deletion), and showed stable disease after 3 months TKI, evaluated twice by PET/CT scan, brain MRI, and abdomen ultrasound (≥3 measurable lesions, and these lesions haven't received local therapy) - Age 18 years or older - ECOG Performance Status 0-2 - Adequate bone marrow, liver and renal function, as specified below: Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L; Hemoglobin ≥ 8 g/dL; Platelets ≥ 100 x 109/L; Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) ; AST and ALT ≤ 2.5 x ULN or ≤ 5 x ULN if liver metastases are present; Serum creatinine ≤ 1.5 x upper limit of normal or creatinine clearance ≥ 60ml/min for patients with creatinine levels above institutional normal - For women of child-bearing potential, negative pregnancy test within 14 days prior to starting treatment - Men and women of childbearing age must be willing to use effective contraception while on treatment and for at least 3 months thereafter - Patients and their family signed the informed consents Exclusion Criteria: - Received chemotherapy before TKI therapy - Brain parenchyma or leptomeningeal disease - Concurrent malignancies other than non-melanoma skin cancer that require active ongoing treatment - Any medical co-morbidities that would preclude radiation therapy. --- L858R ---

Primary Outcomes

Description: To assess the proportion of patients with an abscopal response (defined as at least a 30% decrease in the longest diameter of the best responding abscopal lesion) at 1-6 months after the radiation therapy

Measure: The proportion of patients with an abscopal response assessed at 1-6 months after the radiation therapy

Time: 1-6 months

Secondary Outcomes

Description: FACT-E score at the 4 months after docetaxel consolidation therapy

Measure: To assess the short-term quality of life (QOL)

Time: 4 months

Description: The investigators will assess the rate of symptomatic radiation pneumonitis in patients who received the radiation therapy

Measure: Rate of CTCAE grade 2 or higher radiation pneumonitis

Time: 1 years

Measure: Overall Survival

Time: 2 years

37 Combination of Gefitinib With Chemotherapy or Anti-angiogenesis as 1st Line Treatment in Advanced NSCLC Patients Detected With Bim Deletion or Low EGFR Activating Mutation Abundance

This is a single arm phase II clinical trial, which aims to evaluate the effectiveness of combination of gefitinib and doublet chemotherapy or antiangiogenesis in advanced non-small cell lung cancer patients with EGFR activating mutation, accompanied with Bim deletion or low activating EGFR mutation abundance.

NCT02930954 Non-small-cell Lung Cancer Drug: Gefitinib Drug: pemetrexed or gemcitabine plus carboplatin, Drug: bevacizumab
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

Inclusion Criteria: - Histologically documented, locally advanced or recurrent (stage IIIb and not amenable to combined modality treatment) or metastatic (stage IV) non-small cell lung cancer, anti-cancer treatment naiive - EGFR exon 19 deletion or exon 21 L858R. --- L858R ---

- Bim deletion by realtime PCR, or low abundance for EGFR mutation, for 19Del less than 4.9%, for L858R less than 9.5%. --- L858R ---

- Unhealed bone fracture or wound for long time Inclusion Criteria: - Histologically documented, locally advanced or recurrent (stage IIIb and not amenable to combined modality treatment) or metastatic (stage IV) non-small cell lung cancer, anti-cancer treatment naiive - EGFR exon 19 deletion or exon 21 L858R. --- L858R ---

Primary Outcomes

Description: From start of anti-cancer therapy untill progression or death

Measure: Progression free survival

Time: 8 weeks

Secondary Outcomes

Description: evaluated in the 36th since treatment begain

Measure: overall survival

Time: 36 months

Description: toxicities related to anti-cancer therapy

Measure: side effect

Time: 8 weeks

Description: evaluated since treatment began

Measure: quality of life

Time: 24 months

38 Phase II, Open-Label Study of Erlotinib (Tarceva®) Treatment in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Present Activating Mutations in the Tyrosine Kinase Domain of the Epidermal Growth Factor Receptor

This single arm, open-label study will evaluate the efficacy and safety of erlotinib (Tarceva) in participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations.

NCT01260181 Non-Squamous Non-Small Cell Lung Cancer Drug: Erlotinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Mutations in the EGFR included exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21.. Median Time Taken From the First Response Until Disease Progression Based on RECIST v 1.1 as Determined by the Investigator. --- L858R ---

Primary Outcomes

Description: Objective response (OR) was based on criteria related to changes in size of target lesions according to modified RECIST. Target lesions were selected on the basis of their size (lesions with the longest diameter) as well as the feasibility of reproducible repeated measurements. OR was the sum of complete response (CR) and partial response (PR) four at least 4 weeks during treatment. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

Measure: Percentage of Participants With Objective Response (Complete Response [CR]/Partial Response [PR]) Based on Computer Tomography (CT) or Magnetic Resonance Imaging (MRI) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1

Time: Baseline up to 5 years (assessed at Baseline, every 8 weeks until disease progression or death or end of treatment period [up to 5 years])

Secondary Outcomes

Description: Kaplan Meier estimate of the median PFS was defined as the time at which half of the participants have progressed (progressive disease [PD]) based on RECIST tumor response criteria or died from any cause, whichever occurred first. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Patients who had not died or progressed at the time of the final analysis were censored at the date of last contact.

Measure: Progression Free Survival (PFS) Based on CT or MRI According to RECIST v 1.1

Time: Baseline up to 5 years (assessed at Baseline, every 8 weeks until disease progression or death or end of treatment period [up to 5 years])

Description: Overall Survival (OS) was defined as the time between the date of randomization and the date of death due to any cause.

Measure: Overall Survival

Time: Baseline up to 5 years

Description: An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

Measure: Percentage of Participants With Adverse Events

Time: Baseline up to 5 years

Description: Mutations in the EGFR included exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21.

Measure: Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Mutation in Study Population

Time: Screening (21 days prior to Day 1)

Description: The response duration was defined as the time of initial response (complete response (CR) /partial response (PR) whichever is first recorded) until documented disease progression. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Disease progression was defined as At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).

Measure: Median Time Taken From the First Response Until Disease Progression Based on RECIST v 1.1 as Determined by the Investigator

Time: Baseline up to 5 years (assessed at Baseline, every 8 weeks until disease progression or death or end of treatment period [up to 5 years])

39 Phase II Multi-center Study of Pembrolizumab in Combination With Platinum-based Doublet Chemotherapy in Patients With EGFR Mutation and ALK Positive NSCLC (Non-Small Cell Lung Cancer) With Progressive Disease Following Prior Tyrosine Kinase Inhibitors (TKIs)

Investigators hypothesize that addition of pembrolizumab will enhance the efficacy of carboplatin and pemetrexed in EGFR (epidermal growth factor receptor) mutation and ALK (anaplastic lymphoma kinase) positive NSCLC patients who have disease progression following prior TKIs (tyrosine kinase inhibitors).

NCT03242915 Non-small Cell Lung Cancer Drug: Pembrolizumab Drug: Carboplatin Drug: Pemetrexed
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung Disease Progression
HPO: Neoplasm of the lung Non-small cell lung carcinoma

If the patient is lost to follow-up, survival will be censored on the last date the patient was known to be alive.. Inclusion Criteria: - Exon 19 deletion or Exon 21 L858R or L861Q or exon 18 G719X or S7681 EGFR mutation positive NSCLC patients, or ALK rearranged NSCLC patients previously treated with a tyrosine kinase inhibitor with progressive and measurable disease. --- L858R ---

Inclusion Criteria: - Exon 19 deletion or Exon 21 L858R or L861Q or exon 18 G719X or S7681 EGFR mutation positive NSCLC patients, or ALK rearranged NSCLC patients previously treated with a tyrosine kinase inhibitor with progressive and measurable disease. --- L858R ---

Primary Outcomes

Description: The primary endpoint is Response Rate (RR) defined as the rate of complete and partial response. Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be non-pathological in size (<10mm short axis). Partial Response (PR): Persistence of one or more non-target lesion(s) but does not qualify for PD. Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: the appearance of one or more new lesions is also considered progression).

Measure: The number of patients that respond to treatment

Time: 12 months

Secondary Outcomes

Description: PFS is defined as the duration of time from registration to time of progression. Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: the appearance of one or more new lesions is also considered progression).

Measure: Progression free survival (PFS) time

Time: 12 months

Description: Overall survival is defined as the time from registration to time of death. If the patient is lost to follow-up, survival will be censored on the last date the patient was known to be alive.

Measure: Overall survival (OS) time

Time: 12 months

40 A Randomized Phase II Study of Gefitinib Alone Versus Gefitinib Plus Thalidomide for Advanced Non-small Cell Lung Cancer With Epidermal Growth Factor Receptor Activating Mutations

EGFR-TKIs are the standard first-line treatment option for EGFR-mutant NSCLC. After a randomized phase II trial, JO25567 was presented at 2014 ASCO, the synergistic effect of progression-free survival(PFS) could be expected when EGFR TKI, Gefitinib is combined with Antiangiogenesis agent thalidomide, Therefore Chinese data of treating EGFR mutation positive NSCLC patients with Gefitinib and thalidomide is significantly necessary for developing new standard treatment in first-line therapy in Chinese EGFR mutant NSCLC patients. In this study, The investigators will investigate the efficacy and safety of Gefitinib and thalidomide combination compare to Gefitinib alone in Chinese EGFR-mutant NSCLC patients.

NCT03341494 NSCLC Stage IV Chemotherapy Effect Drug: Thalidomide

Inclusion Criteria: - Pathologically confirmed stage IIIB & IV non-small cell lung cancer other than squamous cell carcinoma - Patients with one or more measurable lesion based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1) - Locally diagnosed sensitive EGFR mutation positive (Exon 19 deletion or L858R) - ECOG performance 0~1 - Age ≥ 19 years and - No previous treatment Adequate organ function by following: - ANC ≥1,500/uL, hemoglobin ≥9.0g/dL, platelet ≥100,000/uL - Serum bilirubin < 1 x UNL, AST (SGOT) and ALT (SGPT) < 2.5 x UNL, If Liver metastasis, Serum bilirubin < 3 x UNL, AST (SGOT) and ALT (SGPT) < 5 x UNL - Serum Cr ≤ 1 x UNL - Patients who have had undergone radiotherapy are acceptable if patients meet all of the following criteria: - No history of irradiation to pulmonary tumor lesions. --- L858R ---

- In case of irradiation to non-pulmonary sites: at least two weeks must have passed at the date of inclusion since the last irradiation of the sites - At the time of registration, at least the following period has passed since last date of the prior therapy or procedure: - Surgery(including exploratory/ examination thoracotomy): 4 weeks - Pleural cavity drainage: 1 weeks - Pleurodesis without anti-neoplastic agents (inclusive of BRM such as Picibanil): 2 week - Biopsy accompanied by incision (including thoracoscopic biopsy): 2 week - Procedure for trauma (exclusive of patients with unhealed wound): 2 weeks - Transfusion of blood, preparation of hematopoietic factor: 2 week - Puncture and aspiration cytology: 1 week - Other investigational product: 4 weeks - Written informed consent form Exclusion Criteria: - • Previous history of malignancy within 3 years from study entry except treated non-melanomatous skin cancer, uterine cervical cancer in situ, or thyroid cancer - Prior chemotherapy or systemic anti-cancer therapy for metastatic disease but postoperative adjuvant or neoadjuvant therapy of 6 months or more previously is allowed - Patients who received previous treatment for lung cancer with drugs - Symptomatic or uncontrolled central nervous system (CNS) metastases - Patients with increased risk of bleeding, clinically significant cardiovascular diseases, a history of thrombosis or thromboembolism in the 6 months prior to treatment, gastrointestinal problems, and neurologic problems - Any significant ophthalmologic abnormality - Pre-existing parenchymal lung disease such as pulmonary fibrosis - Known allergic history of Erlotinib or Bevacizumab - Interstitial lung disease or fibrosis on chest radiogram - Active infection, uncontrolled systemic disease (cardiopulmonary insufficiency, fatal arrhythmias, hepatitis) - Pregnant or nursing women Inclusion Criteria: - Pathologically confirmed stage IIIB & IV non-small cell lung cancer other than squamous cell carcinoma - Patients with one or more measurable lesion based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1) - Locally diagnosed sensitive EGFR mutation positive (Exon 19 deletion or L858R) - ECOG performance 0~1 - Age ≥ 19 years and - No previous treatment Adequate organ function by following: - ANC ≥1,500/uL, hemoglobin ≥9.0g/dL, platelet ≥100,000/uL - Serum bilirubin < 1 x UNL, AST (SGOT) and ALT (SGPT) < 2.5 x UNL, If Liver metastasis, Serum bilirubin < 3 x UNL, AST (SGOT) and ALT (SGPT) < 5 x UNL - Serum Cr ≤ 1 x UNL - Patients who have had undergone radiotherapy are acceptable if patients meet all of the following criteria: - No history of irradiation to pulmonary tumor lesions. --- L858R ---

Primary Outcomes

Description: progression-free survival

Measure: PFS

Time: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to at least 36 months

Secondary Outcomes

Description: Overall Response Rate

Measure: ORR

Time: through study completion, and average of 2 years

Description: Overall Survival

Measure: OS

Time: From date of randomization until the date of death or date of last visit/contact, whichever came first, assessed to at least 36 months

41 Phase II Randomized Assessing Pelvic Irradiation Combined With Cisplatin Alone or Cisplatin Plus Cetuximab in Patients With Carcinoma of the Cervix Stage IB2, II and III

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether radiation therapy given together with cisplatin is more effective with or without cetuximab in treating patients with cervical cancer. PURPOSE: This randomized phase II trial is studying giving radiation therapy together with cisplatin to see how well it works compared with radiation therapy and cisplatin given together with cetuximab in treating patients with stage IB, stage II, or stage IIIB cervical cancer.

NCT00957411 Cervical Cancer Biological: cetuximab Drug: cisplatin
MeSH: Uterine Cervical Neoplasms
HPO: Cervical polyp Cervix cancer

- Study the correlation between treatment response and analysis of EGFR mutations (exons 18-21 of the tyrosine kinase domain including the two hot spots L858R and E746-A750). --- L858R ---

Primary Outcomes

Measure: Recurrence-free survival at 2 years

Secondary Outcomes

Measure: Response as assessed by MRI after radiochemotherapy and before surgery according to RECIST criteria

Measure: Toxicity according to NCI CTCAE v3.0

42 A Phase II Trial of Adjuvant Erlotinib in Patients With Resected, Early Stage Non-Small Cell Lung Cancer (NSCLC) With Confirmed Mutations in the Epidermal Growth Factor Receptor (EGFR)

In this research study erlotinib will be given to eligible participants whose lung cancer has been removed by surgery. Eligible patients have adenocarcinoma, a type of non-small lung cancer, and must have 1 or more of the following characteristics: be female, be of Asian or Pacific Rim descent and/or be a never smoker. The potential participant's tumor will be examined for Epidermal growth factor (EGFR) mutations. EGFR is a protein that is overexpressed in most non-small cell lung cancers. Some EGFR has been found to have specific mutations and the participant must have one of these mutations in his tumor. Erlotinib blocks this protein and may control tumor growth and increase survival. Previous research has shown that erlotinib is most effective for people who have these specific mutations in the EGFR.

NCT00567359 Non-small Cell Lung Cancer Drug: Erlotinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

The median amount of time measured from the time of registration until the time of disease recurrence or death.. Inclusion Criteria: - Pathologically confirmed diagnosis of NSCLC of adenocarcinoma histology - Stage IA-B, IIA-B, or IIIA by the American Joint Committee on Cancer 7th edition staging criteria - Patients must have undergone surgical resection with curative intent within 6 months of enrollment - Sufficient tumor tissue available for EGFR mutation analysis - At least ONE of the following patient characteristics: previously detected deletion 19 or L858R EGFR mutation, female sex, history of never smoking, or Asian/Pacific Rim ethnicity (to be enrolled in the screening portion of trial). --- L858R ---

- 18 years of age or older - Tumor samples must have either exon 19 deletion mutations or the exon 21 L858R point mutation - ECOG Performance status of 0,1, or 2 - Adequate organ function as outlined in protocol Exclusion Criteria: - Radiographic evidence of recurrent NSCLC prior to erlotinib treatment - Confirmed T790M resistance mutation in the primary tumor sample - Prior exposure to EGFR tyrosine kinase inhibitors - Known hypersensitivity to erlotinib, gefitinib, or any closely related drug - Pregnant or breastfeeding women - Any evidence of clinically active interstitial lung disease - Current use of enzyme-inducing anti-epileptic drugs, including carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone - Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study - Use of any non-FDA approved or investigational agent within 2 weeks of enrolling onto the trial, or failure to recover from the side effects of any of these agents Inclusion Criteria: - Pathologically confirmed diagnosis of NSCLC of adenocarcinoma histology - Stage IA-B, IIA-B, or IIIA by the American Joint Committee on Cancer 7th edition staging criteria - Patients must have undergone surgical resection with curative intent within 6 months of enrollment - Sufficient tumor tissue available for EGFR mutation analysis - At least ONE of the following patient characteristics: previously detected deletion 19 or L858R EGFR mutation, female sex, history of never smoking, or Asian/Pacific Rim ethnicity (to be enrolled in the screening portion of trial). --- L858R ---

- 18 years of age or older - Tumor samples must have either exon 19 deletion mutations or the exon 21 L858R point mutation - ECOG Performance status of 0,1, or 2 - Adequate organ function as outlined in protocol Exclusion Criteria: - Radiographic evidence of recurrent NSCLC prior to erlotinib treatment - Confirmed T790M resistance mutation in the primary tumor sample - Prior exposure to EGFR tyrosine kinase inhibitors - Known hypersensitivity to erlotinib, gefitinib, or any closely related drug - Pregnant or breastfeeding women - Any evidence of clinically active interstitial lung disease - Current use of enzyme-inducing anti-epileptic drugs, including carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone - Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study - Use of any non-FDA approved or investigational agent within 2 weeks of enrolling onto the trial, or failure to recover from the side effects of any of these agents Inclusion Criteria: - Pathologically confirmed diagnosis of NSCLC of adenocarcinoma histology - Stage IA-B, IIA-B, or IIIA by the American Joint Committee on Cancer 7th edition staging criteria - Patients must have undergone surgical resection with curative intent within 6 months of enrollment - Sufficient tumor tissue available for EGFR mutation analysis - At least ONE of the following patient characteristics: previously detected deletion 19 or L858R EGFR mutation, female sex, history of never smoking, or Asian/Pacific Rim ethnicity (to be enrolled in the screening portion of trial). --- L858R --- --- T790M --- --- L858R ---

- 18 years of age or older - Tumor samples must have either exon 19 deletion mutations or the exon 21 L858R point mutation - ECOG Performance status of 0,1, or 2 - Adequate organ function as outlined in protocol Exclusion Criteria: - Radiographic evidence of recurrent NSCLC prior to erlotinib treatment - Confirmed T790M resistance mutation in the primary tumor sample - Prior exposure to EGFR tyrosine kinase inhibitors - Known hypersensitivity to erlotinib, gefitinib, or any closely related drug - Pregnant or breastfeeding women - Any evidence of clinically active interstitial lung disease - Current use of enzyme-inducing anti-epileptic drugs, including carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone - Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study - Use of any non-FDA approved or investigational agent within 2 weeks of enrolling onto the trial, or failure to recover from the side effects of any of these agents Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung - Erlotinib is a pill taken daily and participants may continue to receive erlotinib for up to two years, as long as the cancer does not return and they do not experience any unacceptable side effects. --- L858R ---

Primary Outcomes

Description: The number of participants alive and free from disease recurrence 2 years after enrollment. Participants were monitored for disease recurrence with the use of surveillance radiographs. When possible and medically appropriate, tissue biopsies were obtained to prove recurrence.

Measure: 2-year Disease-free Survival

Time: 2 years

Secondary Outcomes

Description: Adverse events were assessed using Common Terminology Criteria for Adverse Events (CTCAE 3.0) from the start of treatment until 30 days after the end of treatment. Serious adverse events were defined as adverse events that were grade 3 or greater and deemed to be possibly, probably or definitely related to the study treatment.

Measure: Number of Participants With Treat Related Serious Adverse Events

Time: From the start of treatment until 30 days after the end of treatment, up 13 months total

Description: The median amount of time from the time of registration until death due to any cause

Measure: Median Overall Survival

Time: From the time of registration until death, up to approximately 9 years

Description: The median amount of time measured from the time of registration until the time of disease recurrence or death.

Measure: Median Disease Free Survival

Time: From registration to disease recurrence or death, up to approximately 9 years

43 A Phase II Trial of AZD9291 (Osimertinib) With or Without Bevacizumab in Patients With EGFR Mutation Positive NSCLC and Brain Metastases

This phase II trial studies how well osimertinib with or without bevacizumab works in treating patients with EGFR positive non-small cell lung cancer that has spread to the brain. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as bevacizumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving osimertinib with or without bevacizumab may work better in treating patients with non-small cell lung cancer.

NCT02971501 EGFR Activating Mutation EGFR Exon 19 Deletion Mutation EGFR NP_005219.2:p.L858R Lung Carcinoma Metastatic in the Brain Lung Non-Small Cell Carcinoma Biological: Bevacizumab Other: Laboratory Biomarker Analysis Drug: Osimertinib
MeSH: Carcinoma Lung Neoplasms
HPO: Carcinoma Neoplasm of the lung

Analysis will be completed using Lasso-based elastic net method.. Inclusion Criteria: - Non-small cell lung cancer (NSCLC) with an activating EGFR mutation (exon 19 deletion, L858R point mutation, or any other mutation known to be associated with EGFR TKI sensitivity); presence of an activating EGFR mutation may be documented in tumor tissue or by plasma testing if performed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory - No prior treatment with an EGFR TKI; patient may have received prior chemotherapy for early-stage or advanced disease but this is not required; prior immunotherapy is not allowed - Patients must have at least one measurable CNS lesion that is asymptomatic, untreated, and does not require local therapy at the time of enrollment; measurable CNS disease is defined as a brain metastasis that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 5 mm (>= 0.5 cm) with brain magnetic resonance imaging (MRI); if the lesion is 5-10 mm in size and is the only measurable disease, MRI imaging must be performed with 1.5 mm slice thickness or less; a history of previously treated brain metastases is allowed, however any lesion present at the time of whole brain radiotherapy or included in the stereotactic radiotherapy field (or within 2 mm of the treated lesion) will NOT be considered "untreated" unless it is new or documented to have progressed unequivocally since treatment - Patients are not required to have measurable systemic (i.e. --- L858R ---

aortic aneurysm, history of aortic dissection) - Clinically significant peripheral vascular disease - Any of the following cardiac criteria: - Mean resting corrected QT interval (Fridericia's correction formula [QTcF]) > 470 ms obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived corrected QT (QTc) value - Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval - Evidence of bleeding diathesis or coagulopathy (including clinically significant hemoptysis) - Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD9291 (osimertinib) - Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4 - Any evidence of severe or uncontrolled systemic diseases, including, but not limited to, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV); screening for chronic conditions is not required - History of hypersensitivity active or inactive excipients of AZD9291 (osimertinib) or drugs with a similar chemical structure or class to AZD9291 (osimertinib) - Absolute neutrophil count < 1.5 x 10^9/L - Platelet count < 100 x 10^9/L - Hemoglobin < 90 g/L - Alanine aminotransferase > 2.5 times upper limit of normal (ULN) if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases; aspartate aminotransferase > 2.5 times ULN if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases - Total bilirubin > 1.5 times ULN if no liver metastases or > 3 times ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases - Serum creatinine > 1.5 times ULN concurrent with creatinine clearance < 50 mL/min (measured or calculated by Cockcroft and Gault equation)—confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN - Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements Inclusion Criteria: - Non-small cell lung cancer (NSCLC) with an activating EGFR mutation (exon 19 deletion, L858R point mutation, or any other mutation known to be associated with EGFR TKI sensitivity); presence of an activating EGFR mutation may be documented in tumor tissue or by plasma testing if performed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory - No prior treatment with an EGFR TKI; patient may have received prior chemotherapy for early-stage or advanced disease but this is not required; prior immunotherapy is not allowed - Patients must have at least one measurable CNS lesion that is asymptomatic, untreated, and does not require local therapy at the time of enrollment; measurable CNS disease is defined as a brain metastasis that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 5 mm (>= 0.5 cm) with brain magnetic resonance imaging (MRI); if the lesion is 5-10 mm in size and is the only measurable disease, MRI imaging must be performed with 1.5 mm slice thickness or less; a history of previously treated brain metastases is allowed, however any lesion present at the time of whole brain radiotherapy or included in the stereotactic radiotherapy field (or within 2 mm of the treated lesion) will NOT be considered "untreated" unless it is new or documented to have progressed unequivocally since treatment - Patients are not required to have measurable systemic (i.e. --- L858R ---

Primary Outcomes

Description: The two study arms will be compared for PFS with Kaplan-Meier estimates and log-rank tests. The Rothman confidence interval (CI), and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the PFS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.

Measure: Progression free survival (PFS)

Time: From start of treatment to time of progression (in CNS or non-CNS disease) or death, whichever occurs first, assessed up to 2 years

Secondary Outcomes

Description: The two study arms will be compared for OS with Kaplan-Meier estimates and log-rank tests. The Rothman CI, and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the OS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.

Measure: Overall survival (OS)

Time: From start of treatment to death, assessed up to 2 years

Description: The two study arms will be compared for OS with Kaplan-Meier estimates and log-rank tests. The Rothman CI, and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the OS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.

Measure: OS rate

Time: At 12 months

Description: Assessed by Common Terminology Criteria for Adverse Events. Adverse medical events will be tabulated. National Cancer Institute toxicity grade 1 to grade 4 laboratory abnormalities will be listed.

Measure: Incidence of adverse events

Time: Up to 2 years

Description: Will be estimated using the 95% confidence CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively.

Measure: Overall response rate

Time: Up to 2 years

Description: Will be estimated using the 95% confidence CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively.

Measure: Intracranial response rate

Time: Up to 2 years

Description: Will be assessed by Response Assessment in Neuro-Oncology Brain Metastases.

Measure: Time to intracranial progression

Time: Up to 2 years

Measure: Brain metastasis response rate

Time: Up to 2 years

Measure: Time to central nervous system (CNS) progression

Time: From start of treatment to time of progression in the CNS, assessed up to 2 years

Description: Assessed by Response Assessment in Neuro-Oncology Criteria-Glioblastoma Multiforme. Will be estimated using the 95% confidence interval CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively. The generalized non-linear model and logistic regression will be applied for multivariable data analysis. The adjusted p-value and 95% CI of the odds ratios will be reported.

Measure: Intracranial response

Time: Up to 2 years

Description: Will be determined by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1.

Measure: Objective response defined as a complete or partial response

Time: Up to 2 years

Other Outcomes

Description: Analysis will be completed using Lasso-based elastic net method.

Measure: Molecular characterization

Time: Up to 2 years

Description: Analysis will be completed using Lasso-based elastic net method.

Measure: Circulating tumor deoxyribonucleic acid assessed in plasma

Time: Up to 2 years

Description: Analysis will be completed using Lasso-based elastic net method.

Measure: Angiogenic signature assessed in plasma by multiplex panel array

Time: Up to 2 years

Description: Analysis will be completed using Lasso-based elastic net method.

Measure: Biomarker analysis of angiogenesis and signaling pathways

Time: Up to 2 years

Description: Analysis will be completed using Lasso-based elastic net method.

Measure: Changes in the tumor immune microenvironment

Time: Baseline to 2 years

44 Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of Alflutinib in Patients With Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent

Alflutinib Mesylate Tablets is a Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor which can efficient suppress the EGFR T790M drug-resistant mutation tumor cell in Xenograft mouse model. This study aims at local advanced or metastatic non-small cell lung cancer patients with T790M drug-resistant mutation.

NCT02973763 NSCLC Drug: Alflutinib
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including at least one of G719X, exon 19 deletion, L858R, L861Q mutation) 5. Documented evidence of definitely EGFR T790M+ state in the tumor tissue after disease progression on the most recent treatment regimen (irrespective of whether this is EGFR TKI or chemotherapy). --- L858R ---

Primary Outcomes

Description: Assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram, ophthalmic examinations, RECIST1.1, and NCI CTCAE v4.03

Measure: Incidence and Severity of Treatment-Emergent Adverse Events

Time: Adverse events will be collected from baseline until 28 days after the last dose

Secondary Outcomes

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out Cmax.

Measure: Maximum Plasma Concentration [Cmax] of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out tmax.

Measure: Peak Plasma Time [tmax] of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day1 to figure out AUC.

Measure: Area under the plasma concentration versus time curve (AUC) of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out terminal rate constant.

Measure: Terminal rate constant of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out clearance.

Measure: Clearance of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out half life.

Measure: Half life of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out volume of distribution.

Measure: Volume of distribution of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out mean resistance time.

Measure: Mean resistance time of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Cmax of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state Cmax of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: tmax of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state tmax of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Cmin of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state Cmin (Minimum Plasma Concentration) of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: AUC of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state AUC of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Clearance of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state clearance of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Accumulation ratio of Alflutinib and 2 metabolites following multiple doses.

Measure: Accumulation ratio of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Time dependency of Alflutinib and 2 metabolites following multiple doses.

Measure: Time dependency of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Evaluation of objective response rate assessed by RECIST 1.1

Measure: Objective response rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

Description: Duration of response assessed by RECIST 1.1

Measure: Duration of response of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate progression free survival

Measure: Progression free survival of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate disease progression rate

Measure: Disease progression rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

Description: Clinical benefit rate was calculated by adding up complete remission, partial remission and stabilization of disease assessed by RECIST 1.1

Measure: Clinical benefit rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

45 Open Label Multicenter Phase I/II Study of the Safety and Efficacy of PDR001 Administered to Patients With Advanced Malignancies

The purpose of this "first-in-human" study of PDR001 is to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of PDR001 administered i.v. as a single agent to adult patients with solid tumors. By blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2, PDR001 inhibits the PD-1 immune checkpoint, resulting in activation of an antitumor immune response by activating effector T-cells and inhibiting regulatory T-cells. This study has been designed as a phase I/II, multi-center, open-label study starting with a phase I dose escalation part followed by a phase II part. PDR001 will be administered every 2 weeks until patient experiences unacceptable toxicity, progressive disease per immune related Response Criteria (irRC) and/or treatment is discontinued at the discretion of the investigator or the patient.

NCT02404441 Melanoma NSCLC Triple Negative Breast Cancer Anaplastic Thyroid Cancer Other Solid Tumors Biological: PDR001
MeSH: Thyroid Neoplasms Triple Negative Breast Neoplasms Thyroid Carcinoma, Anaplastic
HPO: Anaplastic thyroid carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Only patients with EGFR mutation-negative tumor are eligible (defined as negative for exon 19 deletions and for the L858R mutation in EGFR at a minimum; however, if more extensive EGFR mutation testing has been performed, the tumor must not harbor any known activating EGFR mutations in Exons 18-21 in order to be considered EGFR mutation-negative). --- L858R ---

Primary Outcomes

Description: To estimate the recommended phase 2 dose (RP2D) and/or the maximum tolerated dose (MTD) for PDR001

Measure: Part l: The exposure (AUC(0-336h)) after first dose of treatment

Time: First 28 days of treatment

Description: To estimate the RP2D and/or the MTD for PDR001

Measure: Part l: Incidence of dose limiting toxicities (DLTs)

Time: First 28 days of treatment

Description: As per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 - to estimte the anti-tumor activity of PDR001. Each cycle = 28 days

Measure: Part ll: Overall response Rate (ORR)

Time: when all patients have completed at least 6 cycles of treatment or discontinued treatment. An average of 1 year duration is expected.

Secondary Outcomes

Description: Safety as assessed by Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), including changes in laboratory parameters, vital signs and electrocardiograms (ECGs) Tolerability as assessed by dose interruptions, reductions and dose intensity

Measure: Safety and Tolerability as assessed by incidence and severity of adverse events, dose interruptions, reductions and dose intensity

Time: continuously during study until 30 days after post study treatment

Description: To assess emergence of anti-PDR001 antibodies following one or more intravenous (i.v.) infusions of PDR001. Each cycle = 28 days; End of treatment = expected to be in average 1 year after the start of study treatment

Measure: Presence and/or concentration of anti-PDR001

Time: Cycle 1 day 1; Cycle 2 day 1; Cycle 3 day 1; Cycle 4 day 1; Cycle 5 day 1; Cycle 6 day 1; End of Treatment.

Description: Preliminary antitumor activity of PDR001

Measure: Overall Response Rate (ORR) - Phase l only

Time: every 8 weeks until cycle 11 and then every 12 weeks from the start of study until end of disease progression follow-up. An average of 1 year duration is expected.

Description: Preliminary antitumor activity of PDR001

Measure: Progression Free Survival (PFS) - Phase l/ll

Time: every 8 weeks until cycle 11 and then every 12 weeks from the start of study until end of disease progression follow-up. An average of 1 year duration is expected.

Description: Preliminary antitumor activity of PDR001

Measure: Duration of Response (DOR) - Phase l/ll

Time: every 8 weeks until cycle 11 and then every 12 weeks from the start of study until end of disease progression follow-up. An average of 1 year duration is expected.

Description: Preliminary antitumor activity of PDR001

Measure: Disease Control Rate (DCR) - Phase l/ll

Time: every 8 weeks until cycle 11 and then every 12 weeks from the start of study until end of disease progression follow-up. An average of 1 year duration is expected.

Description: Preliminary antitumor activity of PDR001

Measure: Overall Response Rate (ORR) per immune related Response Criteria - Phase ll only

Time: every 8 weeks until cycle 11 and then every 12 weeks from the start of study until end of disease progression follow-up. An average of 1 year duration is expected.

Description: e.g., AUC, Cmax, Tmax, half-life to characterize the pharmacokinetic profile of PDR001. End of treatment = expected to be in average 1 year after the start of study treatment

Measure: Composite Serum pharmacokinetics (PK) parameters

Time: cycles 1 days 1, 2, 3, 4, 8, 11, 15. Cycle 2 day 1. Cycle 3 days 1, 2, 3, 4, 8, 11, 15. Cycle 4 day 1, Cycle 5 day 1, Cycle 6 day 1, End of Treatment.

Description: To characterize the pharmacokinetic profile of PDR001. End of treatment = expected to be in average 1 year after the start of study treatment

Measure: Serum concentration vs. time profiles

Time: cycles 1 days 1, 2, 3, 4, 8, 11, 15. Cycle 2 day 1. Cycle 3 days 1, 2, 3, 4, 8, 11, 15. Cycle 4 day 1, Cycle 5 day 1, Cycle 6 day 1, End of Treatment.

46 Phase I/Ib Trial of Single Agent PBF-509 and in Combination With PDR001 for Patients With Advanced NSCLC

The purpose of this study is to determine the safety, tolerability, feasibility and preliminary efficacy of the administration of PBF-509 (Adenosine A2a receptor antagonist) as single agent or in combination with PDR001 (programmed cell death 1 receptor antibody (PD-1 Ab)) to NSCLC patients.

NCT02403193 Non-small Cell Lung Cancer (NSCLC) Drug: PBF-509_80 mg Drug: PBF-509_160 mg Drug: PBF-509_320 mg Drug: PBF-509_640 mg Drug: Combo PBF-509 (160 mg) + PDR001 Drug: Combo PBF-509 (320 mg) + PDR001 Drug: Combo PBF-509 (640 mg) + PDR001 Drug: RP2D (PBF-509+PDR001)_immuno naïve Drug: Experimental: RP2D (PBF-509+PDR001)_immuno treated
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

2. Patients must previously have received at least one prior line of therapy for their disease 3. EGFR mutation with exon 19 deletion or L858R mutation (Exon 21) or ALK rearrangement positive must have failed prior TKI therapy 4. Able, willing to give written consent for available archival tumor samples (not mandatory) and tumor biopsies before and during protocol therapy (mandatory). --- L858R ---

Primary Outcomes

Description: The MTD evaluation will be based on the DLT Evaluable Population which includes all patients enrolled in the dose-escalation portion of the trial, who receive the protocol-assigned treatment with PBF-509 and complete the safety follow-up through the DLT evaluation period, or experience a DLT during the DLT evaluation period.

Measure: Maximum Tolerated Dose (MTD) of PBF-509 as single agent

Time: 28 days

Description: The MTD evaluation will be based on the DLT Evaluable Population which includes all patients enrolled in the dose-escalation portion of the trial, who receive the protocol-assigned treatment with PDR001 and PBF-509 and complete the safety follow-up through the DLT evaluation period, or experience a DLT during the DLT evaluation period.

Measure: Maximum Tolerated Dose (MTD) of the combination (PBF-509+PDR001) treatment

Time: 56 days

Secondary Outcomes

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the time (in minutes) to reach the maximum "PBF-509" concentration in plasma samples of patients after oral administration of PBF-509.

Measure: Time to PBF-509 peak concentration in plasma "Tmax"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the time (in minutes) to reach the maximum "PBF-509" concentration in plasma samples of patients during a dosing interval at steady state.

Measure: Time to PBF-509 peak concentration in plasma at steady state "Tmax,ss"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the maximum plasma concentration (ng/mL) of PBF-509 observed after administration.

Measure: PBF-509 peak concentration in plasma "Cmax"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the maximum plasma concentration (ng/mL) of PBF-509 observed during a dosing interval at steady state.

Measure: PBF-509 peak concentration in plasma at steady state"Cmax,ss"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the area under the concentration-time curve from zero up to ∞ with extrapolation of the terminal phase. "AUC(0-inf)" will be given in Amount·time/ volume units

Measure: The area under PBF-509 plasma concentration-time curve to infinite time "AUC(0-inf)"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the area under the concentration-time curve from zero up to a definite time t. "AUC(0-t)" will be given in Amount·time/ volume units.

Measure: The area under PBF-509 plasma concentration-time curve up to time 't' "AUC(0-t)"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the area under the concentration-time curve over the dosing interval. "AUC(0-τ)" will be given in Amount·time/ volume units.

Measure: The area under PBF-509 plasma concentration-time curve over the dosing interval "AUC(0-τ)"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the terminal half-life of PBF-509 in plasma. "t½" will be given in hours (h)

Measure: PBF-509 half-life in plasma " t½"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the apparent volume of distribution during terminal phase after oral / extravascular administration. "Vd/F" will be given in Volume or volume/kg units.

Measure: PBF-509 apparent volume of distribution following extravascular administration"Vd/F"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the apparent total plasma or serum clearance of drug after oral administration. "Cl/F" will be given in the Volume/ time or volume/ time/ kg units.

Measure: PBF-509 total body clearance following extravascular administration "Cl/F"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the accumulation ratio calculated from Cmax,ss at steady state and Cmax after single dosing.

Measure: The PBF 509 accumulation index "Rac"

Time: 8 days

Description: ORR: Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). ORR is defined as confirmed complete response (CR) or partial response (PR) based on modified RECIST v1.1.

Measure: Efficacy as measured by Objective response rate (ORR)

Time: 3 years

Description: The disease control rate (DCR) will be estimated considering the following variables: Complete response (CR), Partial response (PR) and stable disease (SD) as described by Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). These variables will be assessed based on Imaging-based evaluation methods as chest x-ray, conventional computed tomography (CT) and magnetic resonance imaging (MRI) that will be performed every 2 cycles of 28 days administration

Measure: Efficacy as measured by Disease control rate (DCR)

Time: 3 years

Description: Duration of response (DoR) is defined as the duration from the first documentation of OR to the first documented disease progression or death due to any cause, whichever occurs first.

Measure: Efficacy as measured by duration of response (DoR)

Time: 3 years

Description: Progression-free survival (PFS) will be measured from the start of treatment until the documentation of disease progression or death due to any cause, whichever occurs first. For subjects who are alive and progression-free at the time of data cut-off for analysis, PFS will be censored at the last tumor assessment date.

Measure: Efficacy as measured by progression-free survival (PFS)

Time: 3 years

Description: Overall survival (OS) will be determined as the time from the start of treatment until death due to any cause.

Measure: Efficacy as measured by overall survival (OS)

Time: 3 years

47 An Open-label, Single-arm Phase IV Study of Afatinib in Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer Who Have Poor Performance Status and Whose Tumors Have the Common Epidermal Growth Factor Receptor (EGFR) Mutations, Exon 19 Deletions or Exon 21(L858R) Substitution Mutations

There is a medical need for improving treatment of poor performance status patients with EGFR driver mutations and documenting safety and tolerability of existing agents.

NCT02695290 Carcinoma, Non-Small-Cell Lung ErbB Receptors Drug: Afatinib
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

An Open-label, Single-arm Phase IV Study of Afatinib in Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer Who Have Poor Performance Status and Whose Tumors Have the Common Epidermal Growth Factor Receptor (EGFR) Mutations, Exon 19 Deletions or Exon 21(L858R) Substitution Mutations. --- L858R ---

The staging is based on American Joint Committee on Cancer (AJCC) Tumor Node Metastatic (TNM) classification of malignant tumors, 7th edition - Evidence of common EGFR activating mutations (Del 19 and/or L858R) - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 or 3 - Adequate organ function, defined as all of the following: - Absolute neutrophil count (ANC) > 1500 / mm3 - Platelet count >75,000 / mm3. --- L858R ---

Primary Outcomes

Description: Percentage of patients with occurrence of Adverse Events (AEs) leading to dose reduction of afatinib.

Measure: Percentage of Patients With Occurrence of Adverse Events (AEs) Leading to Dose Reduction of Afatinib

Time: Up to 98 days

Secondary Outcomes

Description: Percentage of patients with occurrence of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher diarrhoea, rash/acne+, stomatitis+ and paronychia+ (+ represents grouped term).

Measure: Percentage of Patients With Occurrence of CTCAE Grade 3 or Higher Diarrhoea, Rash/Acne+, Stomatitis+ and Paronychia+ (+ Represents Grouped Term)

Time: Up to 98 days

Description: Time to first dose reduction of afatinib caused by Adverse Events (AEs) defined as time from the date of the first administration of afatinib to the first dose reduction of afatinib caused by AEs.

Measure: Time to First Dose Reduction of Afatinib Caused by Adverse Events (AEs)

Time: Up to 98 days

48 Frequency and Abundance of T790M Mutation on Circulating Tumor DNA in Patients With Non-small Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Treatment Failure: a Perspective Observational Study

The purpose of this study is to compare the frequency and abundance of T790M mutation among the different Clinical modes of EGFR-TKI failure.

NCT02418234 Non-small Cell Lung Cancer Stage III Non-Small-Cell Lung Cancer Metastatic Other: mutation detection Other: ARMS and ddPCR Genetic: ctDNA analysis
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

- Investigator confirmed progression according RECIST 1.1 during EGFR-TKI treatment within 28 days of the enrollment - Activating mutation (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) in the EGFR gene or have had at least partial response with EGFR TKI lasting ≥ 6 months - Patient must be able to comply with the protocol Exclusion Criteria: - Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 defined disease progression for more than 28 days while on previous EGFR-TKI treatment. --- G719A --- --- L858R ---

Primary Outcomes

Description: The investigators will describe the number of T790M mutation on ctDNA detected by ARMS assay in patients with non-small cell lung cancer (NSCLC) resistant to tyrosine kinase inhibitors (TKIs).

Measure: Number of Patients With T790M Mutation Detected by Amplification Refractory Mutation System (ARMS) Assay

Time: up to 2 years

Description: The investigators will describe the abundance of T790M mutation on ctDNA detected by ddPCR assay in patients with NSCLC resistant to TKIs.

Measure: Abundance of T790M Mutation Detected by Digital Droplet PCR (ddPCR) Assay in Each Individual Patient

Time: up to 2 years

Secondary Outcomes

Description: The investigators will describe the number of participants with T790M mutation in each different clinical mode of TKI failure by ARMS and ddPCR, and employ chi-square test to analyze the distribution of T790M mutation by ARMS and ddPCR in patients among the different Clinical modes of TKI failure.

Measure: Number of T790M Mutation by ARMS and ddPCR Assays in Each Different Clinical Modes of TKI Failure

Time: up to 2 years

Description: The investigators will employ Analysis of Variance (ANOVA) method to analyze the differences of T790M mutation by ddPCR in patients among the different Clinical modes of TKI failure.

Measure: Differences of T790M Mutation by ddPCR Among the Different Clinical Modes of TKI Failure

Time: up to 2 years

49 A Multicenter, Randomized, Double-Blind Study of Erlotinib in Combination With Ramucirumab or Placebo in Previously Untreated Patients With EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer

The main purpose of this study is to evaluate the safety and efficacy of ramucirumab in combination with erlotinib as compared to placebo in combination with erlotinib in participants with stage IV non small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation (Del19 and L858R). Safety and tolerability of ramucirumab in combination with erlotinib will be assessed in the first portion (Part A) before proceeding to the second portion of this study (Part B). The purpose of Part C is to determine the efficacy and safety of ramucirumab in combination with gefitinib in previously untreated East Asian participants with EGFR mutation-positive metastatic NSCLC and of ramucirumab in combination with osimertinib in those participants whose disease progressed on ramucirumab and gefitinib and that have T790M - positive metastatic NSCLC.

NCT02411448 Metastatic Non-Small Cell Lung Cancer Drug: Ramucirumab Drug: Placebo Drug: Erlotinib Drug: Gefitinib Drug: Osimertinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

A Study of Ramucirumab (LY3009806) in Combination With Erlotinib in Participants With EGFR Mutation-Positive Metastatic NSCLC The main purpose of this study is to evaluate the safety and efficacy of ramucirumab in combination with erlotinib as compared to placebo in combination with erlotinib in participants with stage IV non small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation (Del19 and L858R). --- L858R ---

- Eligible for first-line treatment with erlotinib based on documented evidence of tumor harboring an activating EGFR mutation [exon 19 deletion or exon 21 (L858R) substitution mutation]. --- L858R ---

Primary Outcomes

Measure: Progression Free Survival (PFS)

Time: Randomization to Measured Progressive Disease or Death from Any Cause (Estimated as 37 Months)

Measure: Number of Participants with One or More Drug Related Adverse Events (AEs) or Any Serious AEs

Time: Cycle 1 Day 1 through End of Study (Estimated as 38 Months)

Secondary Outcomes

Measure: Overall Survival (OS)

Time: Randomization to Date of Death from Any Cause (Estimated as 47 Months)

Measure: Objective Response Rate (ORR)

Time: Randomization to Disease Progression (Estimated as 37 Months)

Measure: Disease Control Rate (DCR)

Time: Randomization to Disease Progression (Estimated as 37 Months)

Measure: Duration of Response (DoR)

Time: Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Estimated as 37 Months)

Measure: Pharmacokinetics (PK): Minimum Concentration (CMIN) of Ramucirumab

Time: Cycle 2 Predose through Cycle 14 Predose (Estimated as 28 Months)

Measure: Number of Participants with Anti-Ramucirumab Antibodies

Time: Cycle 1 Predose through Follow-up (Estimated as 38 Months)

Measure: Change from Baseline on the Lung Cancer Symptom Scale (LCSS)

Time: Baseline, End of Study (Estimated as 37 Months)

Measure: Change from Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L)

Time: Baseline, End of Study (Estimated as 37 Months)

50 Randomized Double-blinded Comparative Trial to Study the Add-on Activity of Combination Treatment of Nicotinamide on Progression Free Survival for EGFR Mutated Lung Cancer Terminal Stage Patients Being Treated With Gefitinib or Erlotinib

Nicotinamide is an inhibitor of human sirtuins (HDAC III), and is found to re-activate epigenetically silenced tumor suppressors, RUNX3 (runt-related gene 3) and others, in cancer cells. Nicotinamide was found to be effective in several animal cancer models including lung, bladder, liver, etc. The purpose of this study is to determine whether nicotinamide is also effective in the treatment of human lung cancer.

NCT02416739 Non-Small-Cell Lung Carcinoma Drug: Nicotinamide
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Operation-impossible stage 4 non-small-cell lung carcinoma (NSCLC), or recurred terminal stage NSCLC after previous operation or radiation therapy - EGFR mutated (exon 19 deletion or L858R mutation) - Life expectation more than 3 months - More than 1 measurable lesions by RECIST 1.1 which were not exposed to radiation previously - ECOG (Eastern Cooperative Oncology Group ) performance status grade 0~2 - Who signed the informed consent form Exclusion Criteria: - Who had received chemotherapy or EGFR tyrosin kinase inhibitors previously, except whom had received operation at least 6 months ago and received supplementary chemotherapy - Who has metastasized brain lesion that needs operation or radiation therapy - Above grade 2, CTCAE (Common Toxicity Criteria for Adverse Effects) 4.0 criteria for blood, liver and kidney - Who does Not agree to contraception - Who has allergy to nicotinamide Inclusion Criteria: - Operation-impossible stage 4 non-small-cell lung carcinoma (NSCLC), or recurred terminal stage NSCLC after previous operation or radiation therapy - EGFR mutated (exon 19 deletion or L858R mutation) - Life expectation more than 3 months - More than 1 measurable lesions by RECIST 1.1 which were not exposed to radiation previously - ECOG (Eastern Cooperative Oncology Group ) performance status grade 0~2 - Who signed the informed consent form Exclusion Criteria: - Who had received chemotherapy or EGFR tyrosin kinase inhibitors previously, except whom had received operation at least 6 months ago and received supplementary chemotherapy - Who has metastasized brain lesion that needs operation or radiation therapy - Above grade 2, CTCAE (Common Toxicity Criteria for Adverse Effects) 4.0 criteria for blood, liver and kidney - Who does Not agree to contraception - Who has allergy to nicotinamide Non-Small-Cell Lung Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung The standard therapy to the EGFR (epidermal growth factor receptor) mutation positive non-small-cell lung cancer patients who are not eligible to operation is to administer EGFR-TKIs (tyrosine kinase inhibitors, gefitinib or erlotinib). --- L858R ---

Inclusion Criteria: - Operation-impossible stage 4 non-small-cell lung carcinoma (NSCLC), or recurred terminal stage NSCLC after previous operation or radiation therapy - EGFR mutated (exon 19 deletion or L858R mutation) - Life expectation more than 3 months - More than 1 measurable lesions by RECIST 1.1 which were not exposed to radiation previously - ECOG (Eastern Cooperative Oncology Group ) performance status grade 0~2 - Who signed the informed consent form Exclusion Criteria: - Who had received chemotherapy or EGFR tyrosin kinase inhibitors previously, except whom had received operation at least 6 months ago and received supplementary chemotherapy - Who has metastasized brain lesion that needs operation or radiation therapy - Above grade 2, CTCAE (Common Toxicity Criteria for Adverse Effects) 4.0 criteria for blood, liver and kidney - Who does Not agree to contraception - Who has allergy to nicotinamide Inclusion Criteria: - Operation-impossible stage 4 non-small-cell lung carcinoma (NSCLC), or recurred terminal stage NSCLC after previous operation or radiation therapy - EGFR mutated (exon 19 deletion or L858R mutation) - Life expectation more than 3 months - More than 1 measurable lesions by RECIST 1.1 which were not exposed to radiation previously - ECOG (Eastern Cooperative Oncology Group ) performance status grade 0~2 - Who signed the informed consent form Exclusion Criteria: - Who had received chemotherapy or EGFR tyrosin kinase inhibitors previously, except whom had received operation at least 6 months ago and received supplementary chemotherapy - Who has metastasized brain lesion that needs operation or radiation therapy - Above grade 2, CTCAE (Common Toxicity Criteria for Adverse Effects) 4.0 criteria for blood, liver and kidney - Who does Not agree to contraception - Who has allergy to nicotinamide Non-Small-Cell Lung Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung The standard therapy to the EGFR (epidermal growth factor receptor) mutation positive non-small-cell lung cancer patients who are not eligible to operation is to administer EGFR-TKIs (tyrosine kinase inhibitors, gefitinib or erlotinib). --- L858R --- --- L858R ---

Primary Outcomes

Description: Cox regression analysis

Measure: Hazard ratio (PFS) of the nicotinamide arm to the placebo arm

Time: two year

Secondary Outcomes

Description: chi-square test of complete response and partial response (RECIST 1.1)

Measure: Response rate

Time: two year

Description: measured by the cancer-related QOL questionaire response (questioned at each visit)

Measure: Difference in quality of life between the nicotinamide arm and the placebo arm

Time: two year

Description: Cox regression analysis

Measure: Overall survival

Time: two year

51 Clinical Activity of Icotinib in Patients With Advanced Non-small-cell Lung Cancer Harbouring Uncommon EGFR Mutations: a Single-arm, Prospective, Phase 2 Study

This study aims to evaluate the efficacy of icotinib, a first generation EGFR TKI, in non-small cell lung cancer patients harboring uncommon EGFR mutation

NCT02961270 Non-small Cell Lung Cancer Drug: Icotinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Patients with stage IIIB/IV non-small cell lung cancer - Patients with uncommon epidermal growth factor receptor (EGFR) mutation - Targeted-therapy-naive patients - Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 - Evaluable target lesions according to RECIST 1.1 for tumour response assessment Exclusion Criteria: - Wild-type EGFR - Positive 19 del and/or 21 L858R mutation - Previous treatment with EGFR TKIs such as gefitinib, erlotinib, and afatinib - Patients who have documented history of interstitial lung disease Inclusion Criteria: - Patients with stage IIIB/IV non-small cell lung cancer - Patients with uncommon epidermal growth factor receptor (EGFR) mutation - Targeted-therapy-naive patients - Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 - Evaluable target lesions according to RECIST 1.1 for tumour response assessment Exclusion Criteria: - Wild-type EGFR - Positive 19 del and/or 21 L858R mutation - Previous treatment with EGFR TKIs such as gefitinib, erlotinib, and afatinib - Patients who have documented history of interstitial lung disease Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R ---

Inclusion Criteria: - Patients with stage IIIB/IV non-small cell lung cancer - Patients with uncommon epidermal growth factor receptor (EGFR) mutation - Targeted-therapy-naive patients - Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 - Evaluable target lesions according to RECIST 1.1 for tumour response assessment Exclusion Criteria: - Wild-type EGFR - Positive 19 del and/or 21 L858R mutation - Previous treatment with EGFR TKIs such as gefitinib, erlotinib, and afatinib - Patients who have documented history of interstitial lung disease Inclusion Criteria: - Patients with stage IIIB/IV non-small cell lung cancer - Patients with uncommon epidermal growth factor receptor (EGFR) mutation - Targeted-therapy-naive patients - Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 - Evaluable target lesions according to RECIST 1.1 for tumour response assessment Exclusion Criteria: - Wild-type EGFR - Positive 19 del and/or 21 L858R mutation - Previous treatment with EGFR TKIs such as gefitinib, erlotinib, and afatinib - Patients who have documented history of interstitial lung disease Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L858R ---

Primary Outcomes

Measure: progression-free survival

Time: 10 months

Secondary Outcomes

Measure: tumor response rate

Time: 2 months

Measure: overall survival

Time: 24 months

52 A Multicenter, Randomized,Double-Blind Study of Gefitinib in Combination With Apatinib or Placebo in Previously Untreated Patients With EGFR Mutation-Positive Advanced Non-squamous Non-Small-Cell Lung Cancer

The main purpose of this study is to evaluate the safety and efficacy of Apatinib in combination with Gefitinib as compared to placebo in combination with Gefitinib in participants with stage ⅢB-IV Non-squamous non-small-cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation (Del19 and L858R). Safety and tolerability of Apatinib in combination with Gefitinib will be assessed in the first portion (Part A) before proceeding to the second portion of this study (Part B).

NCT02824458 EGFR Tyrosine Kinase Inhibitors Plus VEGFR Inhibitors Drug: Apatinib Drug: Gefitinib Drug: Placebo
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

A Study of Gefitinib With or Without Apatinib in Patients With Advanced Non-squamous Non-Small-Cell Lung Cancer Harboring EGFR Mutations The main purpose of this study is to evaluate the safety and efficacy of Apatinib in combination with Gefitinib as compared to placebo in combination with Gefitinib in participants with stage ⅢB-IV Non-squamous non-small-cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation (Del19 and L858R). --- L858R ---

5. Documented evidence of tumor harboring an activating EGFR mutation (Example 19 del and L858R) . --- L858R ---

Primary Outcomes

Description: Determine the safety, tolerability and DLTs of Apatinib in Combination With Gefitinib

Measure: (Part A) Determine Dose-Limiting Toxicity (DLT) of Apatinib in combination with Gefitinib

Time: 1 months

Description: MTD was determined by testing increasing doses up to 750 mg daily (qd) on dose escalation cohorts 1 to 3 with 3 patients each. MTD reflects highest dose of drug that did not cause an unacceptable side effect (= Dose Limiting Toxicity (DLT) in more than 30% of patients; e.g., hematologic toxicities like Common Toxicity Criteria (CTC) Grade 4 Neutropenia in specific conditions, platelets < 25,000 cells/mL; specific non-hematologic/biochemical toxicities CTC Grade 3 or 4; additionally, any toxicity considered by the investigator severe enough was designated a DLT); CTC Version 2 were used.

Measure: (Part A) Maximum Tolerated Dose (MTD) of Apatinib in Combination With Gefitinib

Time: 1 months

Description: Time from the date of enrolment until documented progression or death, whichever occurs first.

Measure: (Part B) Progression Free Survival (PFS)

Time: Randomization to Measured Progressive Disease or Death from Any Cause (Estimated as 42 Months)

Secondary Outcomes

Description: Time from the date of enrolment until death from any cause.

Measure: (Part B) Overall Survival (OS)

Time: Randomization to Date of Death from Any Cause (Estimated as 50 Months)

Description: Best overall response (complete remission or partial remission) across all assessment time-points according to RECIST Criteria 1.1, during the period from enrolment to termination of trial treatment

Measure: (Part B) Objective Response Rate (ORR)

Time: Randomization to Disease Progression (Estimated as 42 Months)

Description: Achievement of objective response or stable disease for at least 6 weeks

Measure: (Part B) Disease Control Rate (DCR)

Time: Randomization to Disease Progression (Estimated as 42 Months)

Description: Interval from the date of first documentation of objective response by RECIST to the date of first documented progression or relapse

Measure: (Part B) Duration of Response (DoR)

Time: Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Estimated as 42 Months)

Description: Time to progression disease

Measure: (Part B) Time to progression disease (TTPD)

Time: Randomization to Measured Progressive Disease (Estimated as 42 Months)

Measure: (Part B) Quality of Life (QoL) questionnaire

Time: Baseline, End of Study (Estimated as 50 Months)

Description: including adverse events, physical examination, vital signs (including Blood Pressure(BP)), clinical chemistry and hematology

Measure: (Part A + B) Safety assessment : Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Time: Randomization to Measured Progressive Disease (Estimated as 50 Months)

Description: Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration

Measure: (Part A) Area Under roc Curve (last)

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

Description: Area under the plasma concentration time profile after single dose from time zero to the next dose

Measure: (Part A) Area Under roc Curve (tau)

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

Description: Maximum observed plasma concentration

Measure: (Part A) Cmax

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

Description: Time for Cmax

Measure: (Part A) Tmax

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

Description: Terminal half life

Measure: (Part A) t½a

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

Description: Predose concentration during multiple dosing

Measure: (Part A) Ctrough

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

Description: Apparent clearance

Measure: (Part A) The Apparent Clearance(CL/F)

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

Description: Apparent volume of distribution

Measure: (Part A) The Apparent Volume of Distribution (Vd/F)

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

Description: Metabolite to parent ratio for Area Under roc Curve (tau)

Measure: (Part A) The Metabolite to Parent Ratio of Area Under roc Curve (tau)

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

Description: Metabolite to parent ratio for Cmax

Measure: (Part A) The Metabolite to Parent Ratio of Css,max(MRCmax)

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

53 A Phase II Study of Erlotinib and Chemotherapy for Patients With Stage IB-IIIA NSCLC With EGFR Mutations (ECON)

The purpose of this study is to try to improve the odds that your cancer may be cured. Pemetrexed and cisplatin are traditional chemotherapy drugs that have been shown to help some patients with non-small cell lung cancer. Many different types of cancer cells, including your type of lung cancer, have a protein on their surface called the epidermal growth factor receptor (EGFR). Stimulation of these receptors can result in growth of cancer cells and progression of cancer. In addition, your cancer has an EGFR mutation (a specific abnormality in the genetic code for EGFR). Erlotinib (TarcevaTM) is a newer drug which has shown benefit for patients with lung cancers that contain an EGFR mutation. Erlotinib works by blocking this receptor and depriving the cancer cells of this message to grow and multiply. In this research study, we plan to combine erlotinib with traditional chemotherapy drugs to see if the combination works better than chemotherapy alone. The main purpose of this research is to find out the good and bad effects that the combination of these 3 drugs (pemetrexed, cisplatin and erlotinib) has when given to patients with early stage non-small cell lung cancer before surgery. A secondary purpose is to find out the good and bad effects that occur when erlotinib is given to patients after surgery for 2 years.

NCT00577707 Non Small Cell Lung Cancer Lung Cancer Drug: erlotinib Drug: Pemetrexed Drug: Cisplatin Procedure: Resection
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Pathologic confirmation of NSCLC - Patients must have previously untreated stage IB-IIIA NSCLC (T1-3N0-2M0) - Patients must have lung cancer with a documented EGFR activating mutation (exon 19 deletion, L858R, L861Q) - Patients must be candidates for resection with curative intent - Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT) - Age greater or equal to 18 years - Karnofsky performance status greater or equal to 70% - Normal marrow function: leukocytes greater than or equal to 3,000/μl, absolute neutrophil count greater than or equal to 1,500/μl, platelets greater than or equal to 100,000/μl, hemoglobin greater than or equal to 9 gm/dl - Adequate renal function, with creatinine less than or equal to 1.3 mg/dl or calculated creatinine clearance greater to or equal to 60ml/min by Cockroft and Gault equation using parameters of age, weight (kg), and baseline serum creatinine (mg/dl) - Adequate hepatic function: Total bilirubin within normal limits, AST < 1.5 X UNL, alkaline phosphatase < 1.5 X UNL - Women of childbearing age must have a negative urine or blood pregnancy test - Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter - Patients must have ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior chemotherapy or radiation therapy, with the exception of chemotherapy for nononcologic conditions (ie, methotrexate for the treatment of rheumatoid arthritis) - Prior treatment with gefitinib, erlotinib, or other drugs that target EGFR - Patients must not be receiving any other investigational agents - Any evidence of interstitial lung disease (patients with chronic stable radiographic changes who are asymptomatic need not be excluded) - Patients who report a hearing deficit at baseline, even if it does not require a hearing aid or intervention, or interfere with activities of daily life (CTCAE grade 2 or higher) - Peripheral neuropathy > grade 1 - Known HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with the study drugs. --- L858R ---

- Other serious illness or medical condition including unstable cardiac disease requiring treatment, history of significant neurologic or psychiatric disorders (including psychotic disorders, dementia, or seizures), or active uncontrolled infection - Women who are pregnant or breast-feeding - Psychiatric illness or social situation that would limit compliance with study requirements Inclusion Criteria: - Pathologic confirmation of NSCLC - Patients must have previously untreated stage IB-IIIA NSCLC (T1-3N0-2M0) - Patients must have lung cancer with a documented EGFR activating mutation (exon 19 deletion, L858R, L861Q) - Patients must be candidates for resection with curative intent - Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT) - Age greater or equal to 18 years - Karnofsky performance status greater or equal to 70% - Normal marrow function: leukocytes greater than or equal to 3,000/μl, absolute neutrophil count greater than or equal to 1,500/μl, platelets greater than or equal to 100,000/μl, hemoglobin greater than or equal to 9 gm/dl - Adequate renal function, with creatinine less than or equal to 1.3 mg/dl or calculated creatinine clearance greater to or equal to 60ml/min by Cockroft and Gault equation using parameters of age, weight (kg), and baseline serum creatinine (mg/dl) - Adequate hepatic function: Total bilirubin within normal limits, AST < 1.5 X UNL, alkaline phosphatase < 1.5 X UNL - Women of childbearing age must have a negative urine or blood pregnancy test - Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter - Patients must have ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior chemotherapy or radiation therapy, with the exception of chemotherapy for nononcologic conditions (ie, methotrexate for the treatment of rheumatoid arthritis) - Prior treatment with gefitinib, erlotinib, or other drugs that target EGFR - Patients must not be receiving any other investigational agents - Any evidence of interstitial lung disease (patients with chronic stable radiographic changes who are asymptomatic need not be excluded) - Patients who report a hearing deficit at baseline, even if it does not require a hearing aid or intervention, or interfere with activities of daily life (CTCAE grade 2 or higher) - Peripheral neuropathy > grade 1 - Known HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with the study drugs. --- L858R ---

Primary Outcomes

Description: Complete Response (CR): Disappearance of all clinical evidence of tumor. Partial Response (PR): A 50% or greater decrease in the sum of the products of measured lesions. No simultaneous increase in the size of any lesion or the appearance of new lesions may occur. Non-measurable lesions must remain stable or regress for this category. Minor Response (MR): A > 25% and < 50% decrease in the sum of the products of measured lesions. No simultaneous increase in the size of any lesion or the appearance of new lesions may occur. Non-measurable lesions must remain stable or regress for this category. Stable Disease (SD): A less than 25% decrease. This includes a decrease of less than 25% in the sum of the products of the measured lesions, and any increase of less than 25% in the sum of the products of the measured lesions. There may be no appearance of new disease sites for this category. Progressive Disease (PD): A ≥25% increase in one or more lesions, or appearance of new lesions.

Measure: Number of Patients With Pathologic Complete Response Rate

Time: Patients will undergo a CT scan of chest every 3 months for year 1 and every 4 months for year 2. In years 3 and 4, a chest CT or chest x-ray every 6 months.

Secondary Outcomes

Measure: Number of Participants With Response After 21 Days of Single Agent Erlotinib for Stage IB-IIIA NSCLC With a Known EGFR Mutation

Time: calculate the response rate after 21 days of single agent erlotinib

Measure: Number of Patients With a Response Rate, 3-year Overall Survival and Median Survival of Patients With a Known EGFR Mutation Receiving Neoadjuvant Chemotherapy and Erlotinib (and Adjuvant Erlotinib).

Time: 3 years

54 A Phase 3, Randomized, Double-Blinded, Placebo-Controlled Study of ARQ 197 Plus Erlotinib Versus Placebo Plus Erlotinib in Previously Treated Subjects With Locally Advanced or Metastatic, Non-Squamous, Non-Small-Cell Lung Cancer With Wild-type Epidermal Growth Factor Receptor

The primary objective of this study is to determine if the combination regimen of ARQ 197 with erlotinib will improve overall survival (OS) compared to erlotinib monotherapy in subjects with locally advanced or metastatic non-squamous NSCLC with wild-type EGFR who have received 1 or 2 prior systemic anti-cancer therapies in the Intent-to-Treat (ITT) population.

NCT01377376 Non-small-cell Lung Cancer Drug: ARQ 197 and Erlotinib Drug: Placebo and Erlotinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria 1. Male or female at least 20 years of age with life expectancy ≥ 3 months 2. Histologically or cytologically confirmed surgically unresectable locally advanced or metastatic (stage IIIB/IV) non-squamous NSCLC with wild-type (excluding major activating mutation (exon 19 deletion and/or exon 21 L858R mutation)) EGFR gene status confirmed by a highly sensitive PCR assay 3. Evaluable disease according to RECIST, Version 1.1 4. Received one or two prior lines of systemic anti-cancer therapy for advanced or metastatic disease, one of which must be a platinum-based therapy 5. ECOG performance status of 0 or 1 6. --- L858R ---

Any other significant co-morbid condition that, in opinion of the investigator/sub-investigator, would impair study participation or cooperation Inclusion Criteria 1. Male or female at least 20 years of age with life expectancy ≥ 3 months 2. Histologically or cytologically confirmed surgically unresectable locally advanced or metastatic (stage IIIB/IV) non-squamous NSCLC with wild-type (excluding major activating mutation (exon 19 deletion and/or exon 21 L858R mutation)) EGFR gene status confirmed by a highly sensitive PCR assay 3. Evaluable disease according to RECIST, Version 1.1 4. Received one or two prior lines of systemic anti-cancer therapy for advanced or metastatic disease, one of which must be a platinum-based therapy 5. ECOG performance status of 0 or 1 6. --- L858R ---

Primary Outcomes

Measure: Overall survival

Secondary Outcomes

Measure: Progression free survival

Description: Each assessment will be determined based on RECIST criteria version 1.1 by investigator

Measure: Objective response rate

Measure: Number of patients with adverse events

55 A Phase 3, Randomized Study of Nivolumab Plus Ipilimumab in Combination With Chemotherapy vs Chemotherapy Alone as First Line Therapy in Stage IV Non-Small Cell Lung Cancer

The purpose of this study is to determine whether Nivolumab, Ipilimumab combined with chemotherapy is more effective than chemotherapy by itself when treating stage IV NSCLC as the first treatment given for the disease

NCT03215706 Non-Small Cell Lung Cancer Biological: Ipilimumab Biological: Nivolumab Drug: Carboplatin Drug: Paclitaxel Drug: Pemetrexed Drug: Cisplatin
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Participants with histologically confirmed Stage IV or recurrent NSCLC squamous or non-squamous histology, with no prior systemic anticancer therapy - Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1 - Measurable disease by CT or MRI per response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) criteria - Participants must have PD-L1 IHC testing with results performed by a central laboratory during the screening period Exclusion Criteria: - Participants with known epidermal growth factor receptor (EGFR) mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution mutations) are excluded - Participants with known anaplastic lymphoma kinase (ALK) translocations which are sensitive to available targeted inhibitor therapy are excluded - Participants with untreated CNS metastases are excluded. --- L858R ---

Primary Outcomes

Description: To compare the efficacy of nivolumab + ipilimumab combined with chemotherapy versus (vs)chemotherapy

Measure: Overall Survival (OS)

Time: Up to 31 months

Secondary Outcomes

Description: To compare the efficacy of nivolumab + ipilimumab combined with chemotherapy vs chemotherapy

Measure: Progression Free Survival (PFS)

Time: Up to 31 months

Description: To compare the efficacy of nivolumab + ipilimumab combined with chemotherapy vs chemotherapy

Measure: Overall Response Rate (ORR)

Time: Up to 31 months

Description: In participants with different PD-L1 levels

Measure: ORR

Time: Up to 31 months

Description: In participants with different PD-L1 levels

Measure: PFS

Time: Up to 31 months

Description: In participants with different PD-L1 levels

Measure: OS

Time: Up to 31 months

Measure: ORR, PFS, OS: In association with tumor mutation numbers

Time: Up to 31 months

56 Randomized Phase III Study Testing Nivolumab and Ipilimumab Versus a Carboplatin Based Doublet in First Line Treatment of PS 2 or Elderly (More Than 70 Years Old) Patients With Advanced Non-small Cell Lung Cancer

Lung cancer is the most common cancer in the world and the leading cause of cancer-related deaths in Western countries. Unfortunately, at the time of diagnosis, the majority of patients already have metastatic disease and a systemic, palliative treatment is the primary therapeutic option. Guidelines for PS 2 patients or older than 75 years old patients at the time of diagnosis recommend for fit patients a carboplatin doublet chemotherapy. Nivolumab has proven efficacy in 3rd line squamous cell lung carcinoma and is superior to chemotherapy in 2nd line treatment of squamous and non-squamous lung cancer in term of overall survival. In 1st line, nivolumab failed to show superiority compared to a platin based doublet in terms of progression free survival and overall survival in tumors ≥ 5% PD-L1 expression. The association Nivolumab plus Ipilimumab showed encouraging results in first line setting in phase 1 study. The investigators think that with regard to the manageable toxicity of nivolumab in lung cancer population and the possibility to obtain long responses, this association could be a valid option for this population of elderly and/or PS2 patients in term of overall survival.

NCT03351361 Advanced Non Small Cell Lung Cancer Drug: Nivolumab + Ipilimumab Drug: Chemotherapy
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

- Known activating mutation of EGFR (del LREA exon 19, mutation L858R or L861X of exon 21, mutation G719A/S in exon 18) or EML4-ALK or ROS-1 translocation - Superior at caval syndrome - Uncontrolled infectious status - All concurrent radiotherapy - Concurrent administration of one or several other anti-tumor therapies. --- L858R ---

Primary Outcomes

Measure: Overall survival

Time: From date of randomization until the date of date of death from any cause, whichever came first, assessed up to 3 years maximum

Secondary Outcomes

Measure: Survival rate

Time: 1 year

Description: according to RECIST 1.1

Measure: Objective response rate

Time: 2 years

Measure: Progression free survival

Time: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years maximum

Description: according to CTCAE version 4.0

Measure: Safety

Time: 2 years

Description: according to CTCAE version 4.0

Measure: Tolerability

Time: 2 years

Description: according to EQ-5D questionnaire

Measure: Quality of life

Time: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years maximum

Description: according to EORTC QLQ-ELD14 questionnaire

Measure: Quality of life

Time: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years maximum

Description: testing by immunochemistry

Measure: PD-L1

Time: 2 years

Description: according to geriatric mini data set

Measure: Geriatric evaluation

Time: inclusion and 2 months

57 Phase II Trial to Evaluate Trametinib in Patients With Advanced NF1-mutant Non-small Cell Lung Cancer

Phase II trial to evaluate trametinib in patients with locally advanced non-squamous, non-small cell lung cancer (NSCLC) whose tumors harbor a non-synonymous NF-1 mutation, with progressive disease on at least one prior line of therapy.

NCT03232892 Non-small Cell Lung Cancer Drug: Trametinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neurofibromatosis 1 Neurofibromatoses
HPO: Neoplasm of the lung Neurofibromas Non-small cell lung carcinoma

bevacizumab, ipilumimab) 4. Patients with a known activating mutation in epidermal growth factor receptor (EGFR) (Exon 19 deletion, G719A, S768I, V769L, T790M, L833F, L858R, L861Q), must have progressed or been intolerant to treatment with a first-line EGFR tyrosine kinase inhibitor (TKI) (erlotinib, afatinib, or gefitinib). --- G719A --- --- S768I --- --- V769L --- --- T790M --- --- L833F --- --- L858R ---

Primary Outcomes

Description: The ORR is defined as the best overall response recorded from the start of the treatment until disease progression or recurrence from the start of treatment.

Measure: Objective Response Rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria.

Time: From start of treatment up to 4 years, or until disease progression, whichever comes first

Secondary Outcomes

Description: The DR for Complete Response (CR) and Partial Response (PR) will be measured from the date that the best response is first recorded until the date that PD is documented. For patients who continue treatment post progression, the date of Disease Progression (PD) documentation will be used for analysis.

Measure: Duration of Response (DR) according to RECIST Version 1.1 criteria.

Time: From start of treatment up to 4 years, or until disease progression, whichever comes first

Description: DCR will be defined as the percentage of patients who have achieved CR, PR, or Stable Disease (SD) for at least 12 weeks.

Measure: Disease Control Rate (DCR) according to RECIST Version 1.1 criteria.

Time: From start of treatment up to 4 years, or until disease progression, whichever comes first

Description: PFS will be calculated as 1+ the number of days from the first dose of study drugs to documented radiographic progression or death due to any cause over a period of 1 year. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis.

Measure: Progression Free Survival (PFS) according to RECIST Version 1.1 criteria.

Time: From start of treatment up to 4 years, or until disease progression, whichever comes first

Description: OS will be calculated as 1+ the number of days from the first dose of study drugs to death due to any cause over a period of 1 year.

Measure: Overall Survival (OS) according to RECIST Version 1.1 criteria.

Time: From start of treatment up to 4 years, or until disease progression, whichever comes first

58 A Multicentre, Open-label, Single-arm, Molecular Profiling Study of Patients With EGFR Mutation-positive Locally Advanced or Metastatic NSCLC Treated With Osimertinib

A multicentre, open-label, single-arm, molecular profiling study of patients with EGFR mutation-positive locally advanced or metastatic NSCLC treated with osimertinib

NCT03239340 EGFR Mutation Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer Drug: Osimertinib
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

PFS will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, epidermal growth factor receptor (EGFR) Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived circulating tumour deoxyribonucleic acid (ctDNA).. ORR in patient subgroups defined by molecular profile. --- T790M --- --- L858R ---

PFS will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, epidermal growth factor receptor (EGFR) Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived circulating tumour deoxyribonucleic acid (ctDNA).. ORR in patient subgroups defined by molecular profile. --- T790M --- --- L858R --- --- L858R ---

ORR will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. TTD in patient subgroups defined by molecular profile. --- T790M --- --- L858R ---

ORR will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. TTD in patient subgroups defined by molecular profile. --- T790M --- --- L858R --- --- L858R ---

TTD will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. Tumour shrinkage/depth of response in patient subgroups defined by molecular profile. --- T790M --- --- L858R ---

TTD will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. Tumour shrinkage/depth of response in patient subgroups defined by molecular profile. --- T790M --- --- L858R --- --- L858R ---

Tumour shrinkage/depth of response will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. Proportion of patients with pre-specified characteristics will be summarised by molecular profile. --- T790M --- --- L858R ---

Tumour shrinkage/depth of response will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. Proportion of patients with pre-specified characteristics will be summarised by molecular profile. --- T790M --- --- L858R --- --- L858R ---

These will be summarized by subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. Adverse events graded by Common Terminology Criteria for Adverse Events version 4.0. --- T790M --- --- L858R ---

These will be summarized by subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. Adverse events graded by Common Terminology Criteria for Adverse Events version 4.0. --- T790M --- --- L858R --- --- L858R ---

Primary Outcomes

Description: To characterize the frequency of genetic and proteomic markers at disease progression regardless of their prevalence.

Measure: Proportion of patients with a given tumour genetic and proteomic marker at the point of disease progression as defined by the Investigator

Time: Tumour Genetic and Proteomic markers will be assessed from tissue samples collected prior to initiation of treatment and at the time of disease progression for max 4.2 years

Secondary Outcomes

Description: PFS is defined as the time from first dose of osimertinib until the date of Investigator assessed RECIST 1.1-defined progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from therapy or receives another anticancer therapy prior to progression.

Measure: Progression-free survival (PFS)

Time: At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years

Description: ORR is defined as the number (%) of patients with at least one visit response of complete response or partial response that is confirmed at least 4 weeks later.

Measure: Objective Response Rate (ORR)

Time: At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years

Description: DoR is defined as the time from the date of first documented response, (that is subsequently confirmed) until date of documented progression or death in the absence of disease progression, the end of response should coincide with the date of progression or death from any cause used for the PFS endpoint.

Measure: Duration of Response (DoR)

Time: From time of first documented response until date of documented progression or death in the absence of disease progression or end of study up to max 4.2 years

Description: TTD is defined as the time from the date of first dose of osimertinib to the earliest of treatment discontinuation or death.

Measure: Time toTreatment Discontinuation or Death (TTD)

Time: At every visit from enrolment to end of treatment or death or end of study for max 4.2 years

Description: TFST is defined as the time from the date of first dose of osimertinib to the earlier of the date of anticancer therapy start date following study treatment discontinuation, or death.

Measure: Time to first subsequent therapy or Death (TFST)

Time: At every visit from enrolment to start of first subsequent therapy or death or end of study for max 4.2 years

Description: Percentage of patients who have a best overall response, complete response, partial response or stable disease.

Measure: Disease Control Rate

Time: At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years

Description: PFS will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, epidermal growth factor receptor (EGFR) Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived circulating tumour deoxyribonucleic acid (ctDNA).

Measure: PFS in patient subgroups defined by molecular profile

Time: At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years

Description: ORR will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.

Measure: ORR in patient subgroups defined by molecular profile

Time: At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years

Description: TTD will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.

Measure: TTD in patient subgroups defined by molecular profile

Time: At every visit from enrolment to start of first subsequent therapy or death or end of study for max 4.2 years

Description: Tumour shrinkage is defined as the best change from baseline in the sum of diameters of target lesions. Tumour shrinkage/depth of response will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.

Measure: Tumour shrinkage/depth of response in patient subgroups defined by molecular profile

Time: At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years

Description: The patient characteristics will include: gender (male/female), age (<65yrs/>65yrs), race (Asian/non Asian), and WHO Performance Status (0/1). These will be summarized by subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.

Measure: Proportion of patients with pre-specified characteristics will be summarised by molecular profile

Time: At baseline

Other Outcomes

Description: To summarize the safety and tolerability profile of osimertinib as first-line EGFR tyrosine kinase inhibitor therapy for patients with EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer

Measure: Adverse events graded by Common Terminology Criteria for Adverse Events version 4.0

Time: At every visit from signing informed consent until 28 days after last dose of study treatment

59 GioTag: Real-world Data Study on Sequential Therapy With Gi(l)Otrif®/ Afatinib as First-line Treatment Followed by Osimertinib in Patients With EGFR Mutation Positive Advanced Non-small Cell Lung Cancer

This is a non-interventional, multi-country, multi-centre cohort study based on existing data from medical records of patients with EGFR mutation-positive advanced NSCLC treated with afatinib (Gi(l)otrif®) as the first-line treatment followed by osimertinib in case the T790M resistance mutation was developed.

NCT03370770 Carcinoma, Non-Small-Cell Lung Drug: Afatinib Drug: Osimertinib
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

Inclusion Criteria: - Patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) - The tumour harbours common EGFR mutations (Del19, L858R) at start of first-line treatment - Patients who initiated second-line osimertinib treatment for acquired T790M mutation at least 10 months prior to data entry, AND who were treated with afatinib (Gi(l)otrif®) in the first-line - Patients treated with osimertinib within an EAP/CUP or regular clinical practice - Age ≥ 18 years - Signed and dated written informed consent per regulations (Exemption of a written informed consent for NIS based on existing data in countries per local regulations and legal requirements) Exclusion Criteria: - Patients who received drug(s) other than osimertinib as the second-line treatment and/or patients who received drug(s) other than afatinib (Gi(l)otrif®) as the first-line treatment - Patients with active brain metastases at start of treatment (either afatinib/Gi(l)otrif® or osimertinib) Inclusion Criteria: - Patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) - The tumour harbours common EGFR mutations (Del19, L858R) at start of first-line treatment - Patients who initiated second-line osimertinib treatment for acquired T790M mutation at least 10 months prior to data entry, AND who were treated with afatinib (Gi(l)otrif®) in the first-line - Patients treated with osimertinib within an EAP/CUP or regular clinical practice - Age ≥ 18 years - Signed and dated written informed consent per regulations (Exemption of a written informed consent for NIS based on existing data in countries per local regulations and legal requirements) Exclusion Criteria: - Patients who received drug(s) other than osimertinib as the second-line treatment and/or patients who received drug(s) other than afatinib (Gi(l)otrif®) as the first-line treatment - Patients with active brain metastases at start of treatment (either afatinib/Gi(l)otrif® or osimertinib) Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung null --- L858R ---

Inclusion Criteria: - Patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) - The tumour harbours common EGFR mutations (Del19, L858R) at start of first-line treatment - Patients who initiated second-line osimertinib treatment for acquired T790M mutation at least 10 months prior to data entry, AND who were treated with afatinib (Gi(l)otrif®) in the first-line - Patients treated with osimertinib within an EAP/CUP or regular clinical practice - Age ≥ 18 years - Signed and dated written informed consent per regulations (Exemption of a written informed consent for NIS based on existing data in countries per local regulations and legal requirements) Exclusion Criteria: - Patients who received drug(s) other than osimertinib as the second-line treatment and/or patients who received drug(s) other than afatinib (Gi(l)otrif®) as the first-line treatment - Patients with active brain metastases at start of treatment (either afatinib/Gi(l)otrif® or osimertinib) Inclusion Criteria: - Patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) - The tumour harbours common EGFR mutations (Del19, L858R) at start of first-line treatment - Patients who initiated second-line osimertinib treatment for acquired T790M mutation at least 10 months prior to data entry, AND who were treated with afatinib (Gi(l)otrif®) in the first-line - Patients treated with osimertinib within an EAP/CUP or regular clinical practice - Age ≥ 18 years - Signed and dated written informed consent per regulations (Exemption of a written informed consent for NIS based on existing data in countries per local regulations and legal requirements) Exclusion Criteria: - Patients who received drug(s) other than osimertinib as the second-line treatment and/or patients who received drug(s) other than afatinib (Gi(l)otrif®) as the first-line treatment - Patients with active brain metastases at start of treatment (either afatinib/Gi(l)otrif® or osimertinib) Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung null --- L858R --- --- T790M --- --- L858R ---

Primary Outcomes

Measure: Time on treatment with afatinib (Gi(l)otrif®) followed by osimertinib

Time: 24 months

Secondary Outcomes

Measure: Type and proportion of acquired resistance mutations after osimertinib

Time: 24 months

60 e- Ab Sensor-based Real-time Detection of Mutant EGFR in Clinical Specimens From Patients of Non-small Cell Lung Cancer

The purpose of this study is to develop a real-time diagnostic technique with e- Ab sensor for specific EGFR mutation detection in clinical specimens of NSCLC patients, the investigators conduct a prospective clinical study. In comparison with results from direct sequencing of EGFR, the investigators evaluate the performance of e- Ab sensor, including reproducibility, sensitivity, specificity, and cross-reaction (such as detection of EGFR mutations other than L858R and DelL746-A750). The potential factors which may interfere with the results would be investigated. With such technique, the investigators can obtain EGFR mutation information of NSCLC patients in cost-saving and time-saving way and can offer more individualized treatment for the investigators patients.

NCT01359436 Non-small Cell Lung Cancer (NSCLC) Device: Electrosensing antibody probing system (e- Ab sensing)
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

In comparison with results from direct sequencing of EGFR, the investigators evaluate the performance of e- Ab sensor, including reproducibility, sensitivity, specificity, and cross-reaction (such as detection of EGFR mutations other than L858R and DelL746-A750). --- L858R ---

In comparison with results from direct sequencing of EGFR, we evaluate the performance of e- Ab sensor, including reproducibility, sensitivity, specificity, and cross-reaction (such as detection of EGFR mutations other than L858R and DelL746-A750). --- L858R ---

However, only some EGFR mutations are associated with sensitivity to tyrosine kinase inhibitor treatment, especially deletion in exon 19 and L858R mutation in exon 21.4-5 Two recent phase III randomized clinical trials evaluated gefitinib treatment and chemotherapy in patients of advanced NSCLC with sensitive EGFR mutaions.6-7 --- L858R ---

8 For detection for specific EGFR mutations, mutation-specific monoclonal antibodies were developed to detect E746-A750 deletion in exon 19 and L858R in exon 21. --- L858R ---

In the study by Akhiko Kawahara et al, IHC assay of NSCLC tumor specimens with anti-delE746-A750 antibody showed a sensitivity of 79%, which was 83% by IHC assay with anti-L858R antibody.10 --- L858R ---

IHC assay with anti-L858R antibody also showed high specificity but low sensitivity (97% and 36%, respectively). --- L858R ---

For anti-L858R antibody, the sensitivity was 76%-95% and the positive predicted value was 99%-100%. --- L858R ---

Electrosensing antibody probing system (e- Ab sensor), which was developed for the rapid and sensitive detection of hapten, proteins, or viral antigen in medical samples, will be used for analyzing the interaction kinetics between mutation specific anti-EGFR and its antigen (EGFR with E746-A750 deletion or L858R mutation) present in the specimens of patients with lung cancer. --- L858R ---

In comparison with results from direct sequencing of EGFR, we evaluate the performance of e- Ab sensor, including reproducibility, sensitivity, specificity, and cross-reaction (such as detection of EGFR mutations other than L858R and DelL746-A750). --- L858R ---

Primary Outcomes

Description: In comparison with results from direct sequencing of EGFR, we evaluate the performance of e- Ab sensor, including reproducibility, sensitivity, specificity, and cross-reaction (such as detection of EGFR mutations other than L858R and DelL746-A750)

Measure: The performance of e- Ab sensor

Time: 1 day

61 A Phase Ib Open-label Clinical Trial of Continuous Once Daily Oral Treatment Using BIBW 2992 Plus Cetuximab (Erbitux®) in Patients With Non-small Cell Lung Cancer With Progression Following Prior Erlotinib (Tarceva®) or Gefitinib (Iressa®)

The primary objective of this trial is to determine the maximum tolerated dose (MTD) and recommended Phase II doses for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib or gefitinib. Overall safety, pharmacokinetics and anti-tumor activity for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib, gefitinib or BIBW 2992 will be evaluated as secondary objectives. Initially a standard, 3+3 dose escalation will be performed to determine the MTD of BIBW 2992 when administered together with cetuximab in patients with advanced non small cell lung cancer and acquired resistance to erlotinib or gefitinib. Subsequently, the preliminary efficacy and safety of the identified MTD of cetuximab administered with BIBW 2992 will be explored in a combo arm via a further expansion of MTD cohort up to a total of 140 EGFR mutation positive NSCLC with acquired resistance to erlotinib/gefitinib. Furthermore, the safety and preliminary anti-tumor activity of the combination therapy in EGFR mutant NSCLC patients who developed acquired resistance (AR) to BIBW 2992, will be assessed in a sequential arm. The sequential arm will use a two-stage design with an early stopping rule after 12 patients with acquired resistance to BIBW 2992 have received up to 5 courses of BIBW 2992 plus cetuximab. If no responses are seen in 12 patients during 5 courses of combination therapy, accrual in the sequential arm will stop. If 1 or more responses are observed, the sequential arm will expand up to about 40 patients.

NCT01090011 Carcinoma, Non-Small-Cell Lung Drug: Cetuximab Drug: Cetuximab Drug: BIBW 2992 Drug: BIBW 2992
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

Progression-Free Survival was defined as the duration of time from start of treatment until the day of objective tumour progression confirmed by tumour imaging (PD according to RECIST 1.1) or death.. Inclusion criteria: 1. Pathologically or cytologically confirmed Stage IIIB/IV non-small cell lung cancer or recurrent disease following locoregional treatment 2. Either or both of the following: 1) A tumor which harbors an Epidermal Growth Factor Receptor (EGFR) -mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) from previous tumor biopsy or surgery. --- L858R ---

Women of childbearing potential (WOCBP), or men who are able to father a child, unwilling to use a medically acceptable method of contraception during the trial; pregnancy or breast-feeding Inclusion criteria: 1. Pathologically or cytologically confirmed Stage IIIB/IV non-small cell lung cancer or recurrent disease following locoregional treatment 2. Either or both of the following: 1) A tumor which harbors an Epidermal Growth Factor Receptor (EGFR) -mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) from previous tumor biopsy or surgery. --- L858R ---

Primary Outcomes

Description: A DLT was defined as an AE or laboratory abnormality that a) related to the study regimen; b) or met any of the following criteria: CTCAE Grade 2 or higher decrease in cardiac left ventricular function CTCAE Grade 2 diarrhea lasting for 7 or more days, despite appropriate use of standard anti-diarrheal therapy CTCAE Grade ≥3 diarrhea despite appropriate use of standard anti-diarrheal therapy for at least 2 days CTCAE Grade ≥3 nausea and/or vomiting despite appropriate use of standard anti-emetics for at least 3 days CTCAE Grade ≥3 rash despite standard medical management CTCAE Grade ≥3 fatigue lasting for more than 7 days CTCAE Grade 4 hypomagnesaemia or Grade 3 hypomagnesaemia with clinical significant sequelae All other toxicities of CTCAE Grade ≥3 (except alopecia, and allergic reaction) leading to an interruption of afatinib and/or cetuximab for more than 14 days until recovery to baseline or Grade 1, whichever was higher.

Measure: The Primary Endpoint is the Occurrence of Dose Limiting Toxicity (DLT).

Time: from day 1 treatment until progression or undue toxicity, up to 28 days

Secondary Outcomes

Description: Safety of afatinib when administered together with cetuximab as indicated by intensity and incidence of adverse events, graded according to the U.S. National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version (v) 3.0

Measure: Highest CTCAE Grade

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Measure: Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Measure: Frequency (%) of Patients With Adverse Events Leading to Dose Reduction

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Description: Frequency (%) of patients with adverse events leading to treatment discontinuation

Measure: Frequency (%) of Patients With Adverse Events Leading to Treatment Discontinuation

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Measure: Frequency (%) of Patients With Adverse Events Leading to Death

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Description: Frequency (%) of patients with drug-related serious adverse events

Measure: Frequency (%) of Patients With Related Serious Adverse Events

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Description: Area Under the Concentration-time Curve (AUC) of Afatinib in plasma at steady state over a uniform dosing interval tau (15 days) (AUCtau,ss) after oral administration of Afatinib and cetuximab combination therapy

Measure: Area Under the Concentration-time Curve (AUC) on Day 15 of Plasma Afatinib for the Combination Arm

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Minimum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmin,ss). Maximum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmax,ss).

Measure: Concentration of Afatinib in Plasma for the Combination Arm

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Peak-trough fluctuation (PTF) of plasma afatinib for the combination arm. PTF = 100*(Cmax-Cmin)/Caverage where Caverage = AUC/time, where time equals 24 hours.

Measure: Peak-trough Fluctuation (PTF)

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Terminal half-life of Afatinib in plasma at steady state (t1/2,ss)

Measure: t1/2,ss

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: mean residence time of Afatinib in the body at steady state after oral administration (MRTpo,ss) for 15 days

Measure: MRTpo,ss

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Apparent clearance of afatinib in plasma at steady state after extravascular multiple dose administration (CL/F,ss)

Measure: CL/F,ss,15

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Apparent volume of distribution during the terminal phase λz at steady state following extravascular administration (Vz/F,ss) for 15 days

Measure: Vz/F,ss

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Predose plasma concentrations (Cpre,ss) of Afatinib at Course 1, Visit 2, 3, 4 and 5, at Course 2, Visit 1 and 2 and at Course 3, Visit 1.

Measure: Predose Plasma Concentrations of Afatinib for the Combination Arm

Time: Up to 57 days

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Disease control = CR + PR + SD.

Measure: Disease Control (CR, PR and Stable Disease (SD) Determined by RECIST v1.1)

Time: up to 116 weeks

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Objective tumor response = CR + PR.

Measure: Objective Tumor Response (Complete Response [CR] and Partial Response [PR]) Determined by RECIST v1.1)

Time: up to 116 weeks

Description: Duration of objective response was measured from the time measurements criteria were met for CR/PR (whichever was first recorded) until the first date that recurrent or PD was objectively documented (taking as reference for PD the smallest measurements recorded since treatment started).

Measure: Duration of Objective Response (According to RECIST v1.1)

Time: up to 116 weeks

Description: Duration of disease control was defined as the time from the start of treatment to the time of progression or death (whichever occurred first), among patients with evidence SD, PR or CR.

Measure: Duration of Disease Control (According to RECIST v1.1)

Time: up to 116 weeks

Description: Progression-Free Survival was defined as the duration of time from start of treatment until the day of objective tumour progression confirmed by tumour imaging (PD according to RECIST 1.1) or death.

Measure: Progression-Free Survival (PFS) Time

Time: up to 116 weeks

62 A Multi-centre Observational Study on Dynamic Changes of Circulating Tumor DNA in Late Stage NSCLC Patients Under Gefitinib Treatment

A multi-centre observational, non-interventional study is to dynamically monitor the changes of circulating tumor DNA (ctDNA) in late stage NSCLC patients under Gefitinib treatment.

NCT02804100 Carcinoma, Non-Small-Cell Lung Bronchial Neoplasms Carcinoma, Bronchogenic Lung Diseases Lung Neoplasms
MeSH: Carcinoma Neoplasms Lung Diseases Carcinoma, Non-Small-Cell Lung Lung Neoplasms Bronchial Neoplasms Carcinoma, Bronchogenic
HPO: Abnormal lung morphology Bronchial neoplasm Carcinoma Neoplasm Neoplasm of the lung Non-small cell lung carcinoma

- Activating EGFR mutations (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) - Able to comply with the required protocol and followed-up procedures, and able to receive oral medications Exclusion Criteria: - Histologically confirmed small cell lung cancer or other metastatic tumors - Patient had received prior chemotherapy or EGFR-TKIs treatment - Patients who harbor Exon20 T790M mutation Inclusion Criteria: - Provision of informed consent - Histologically confirmed stage IIIB/IV NSCLC. --- G719A --- --- L858R ---

- Activating EGFR mutations (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) - Able to comply with the required protocol and followed-up procedures, and able to receive oral medications Exclusion Criteria: - Histologically confirmed small cell lung cancer or other metastatic tumors - Patient had received prior chemotherapy or EGFR-TKIs treatment - Patients who harbor Exon20 T790M mutation Carcinoma, Non-Small-Cell Lung Bronchial Neoplasms Carcinoma, Bronchogenic Lung Diseases Lung Neoplasms Carcinoma Neoplasms Lung Diseases Carcinoma, Non-Small-Cell Lung Lung Neoplasms Bronchial Neoplasms Carcinoma, Bronchogenic null --- G719A --- --- L858R ---

Primary Outcomes

Measure: dynamic changes of circulating tumor DNA in late stage NSCLC patients under Gefitinib treatment

Time: 2 years

63 A Randomized Phase II/III Trial of Afatinib Plus Cetuximab Versus Afatinib Alone in Treatment-Naive Patients With Advanced, EGFR Mutation Positive Non-small Cell Lung Cancer (NSCLC)

This randomized phase II/III trial studies how well afatinib dimaleate with cetuximab works and compares it with afatinib dimaleate alone in treating patients with newly diagnosed stage IV or recurrent (has come back), epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, may block tumor growth in different ways by targeting certain cells. It is not yet known whether afatinib dimaleate is more effective when given alone or with cetuximab in treating patients with non-small cell lung cancer.

NCT02438722 Recurrent Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer Drug: Afatinib Dimaleate Biological: Cetuximab Other: Laboratory Biomarker Analysis
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV (American Joint Committee on Cancer [AJCC] 7th Edition) or recurrent non-small cell lung cancer (NSCLC) - Patients must have documented presence of an EGFR exon 19 deltion or exon 21 (L858R) substitution mutation; T790M mutation or other molecular abnormality will be allowed as long as it accompanies one of the mutations listed above; EGFR testing must be performed using a Food and Drug Administration (FDA)-approved test or in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. --- L858R ---

Crohn's disease, malabsorption, etc) - Patients must be able to swallow medication by oral route - Patients must not have a history of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia or myocardial infarction within 6 months prior to registration; if clinically indicated, echocardiogram or multigated acquisition (MUGA) must be performed and cardiac ejection fraction must be >= 50% - Patients must not have had major surgery within 28 days prior to registration or be scheduled for surgery during the projected course of protocol treatment; tumor biopsy is allowed - Patients must not have a known history of active hepatitis B infection (defined as presence of hepatitis B surface antigen [Hep B sAg] and/ or Hep B deoxyribonucleic acid [DNA]), active hepatitis C infection (defined as presence of hepatitis C [Hep C] ribonucleic acid [RNA]) and/or known human immunodeficiency virus (HIV) seropositive - Patients must not have any other concomitant serious illness or organ system dysfunction which in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the study drug - Patients must not be planning to receive any other investigational agents during the course of protocol treatment - Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to afatinib and/or cetuximab - Prestudy history and physical must be obtained with 28 days prior to registration - Patients must have Zubrod performance status of 0 - 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years - Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV (American Joint Committee on Cancer [AJCC] 7th Edition) or recurrent non-small cell lung cancer (NSCLC) - Patients must have documented presence of an EGFR exon 19 deltion or exon 21 (L858R) substitution mutation; T790M mutation or other molecular abnormality will be allowed as long as it accompanies one of the mutations listed above; EGFR testing must be performed using a Food and Drug Administration (FDA)-approved test or in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. --- L858R ---

Primary Outcomes

Measure: OS (phase III)

Time: From date of registration to date of death due to any cause, assessed up to 3 years

Measure: PFS (phase II)

Time: From date of registration to date of first documentation of progression or symptomatic deterioration or death due to any cause, assessed up to 3 years

Secondary Outcomes

Measure: PFS

Time: From date of registration to date of first documentation of progression or symptomatic deterioration or death due to any cause, assessed up to 3 years

Description: Compared between arms using a chi-squared test of independence at the 1-sided 5% level.

Measure: Response rates

Time: Up to 3 years

Measure: Time to treatment discontinuation

Time: From date of registration to date of discontinuation of treatment or death due to any cause, assessed up to 3 years

Measure: Time to treatment failure

Time: From date of registration to date of first documentation of progression or symptomatic deterioration, early discontinuation of treatment, or death due to any cause, assessed up to 3 years

Description: Assessed using a chi-squared or Fisher's exact test (as appropriate) at the 1-sided 5% level.

Measure: Toxicity rates assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

Time: Up to 3 years

Other Outcomes

Description: For each of these markers, a one-sample t-test (or Wilcoxon signed-rank test) will be used to test the null hypothesis that the absolute difference between the copy number after progression and the copy number in the pre-treatment specimen (or an appropriate transformation of the difference, determined after exploratory data analysis) is not equal to zero.

Measure: Change in copy number alterations in MET, EGFR, and HER2, analyzed using fluorescence in situ hybridization

Time: Baseline up to 3 years (after disease progression)

Description: To evaluate if EGFRs/EGFR T790M is lower at progression than in pre-treatment specimens among patients with results available for pre-treatment and progression, a one-sample t-test (or Wilcoxon signed-rank test) will be used to test the null hypothesis that the difference between the progression ratio and the pre-treatment ratio (or an appropriate transformation of the difference, determined after exploratory data analysis) is greater than zero in favor of the alternative that the difference is less than zero.

Measure: Change in the ratio of sensitizing EGFR mutation to EGFR T790 mutation

Time: Baseline up to 3 years (at progression)

Description: To evaluate the hypothesis that H-score positive status at baseline is associated with absolute difference in PFS (and OS) among patients randomized to receive afatinib dimaleate monotherapy a test of interaction will be performed at the 1-sided 20% level.

Measure: EGFR immunohistochemistry H-score

Time: Baseline

Description: Tumor marker levels over time will be evaluated using a linear mixed model for continuous markers and using generalized estimating equations for binary markers. A landmark analysis will be used to evaluate the correlation between post-randomization biomarker values and PFS and OS (from the landmark timepoint) using a Cox proportional hazards model.

Measure: Levels of circulating tumor markers

Time: Up to 3 years

Description: To evaluate if the presence of de novo T790M mutation is associated with primary resistance to afatinib dimaleate, PFS and OS will be compared between T790M mutation positive and negative patients randomized to the afatinib dimaleate monotherapy arm using a log-rank test..

Measure: Presence of de novo EGFR T790M mutation or other molecular alterations

Time: Baseline

Description: To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). Cox regression will be used to assess the predictive association of the ratio in the afatinib dimaleate monotherapy arm with both OS and PFS

Measure: Ratio of sensitizing EGFR mutation to EGFR T790 mutation

Time: Up to 3 years

64 Correlation Between Epithelial Growth Factor Receptor(EGFR) Mutation Using cfDNA and CTCs in Patients With Non-Small Cell Lung Cancer

Correlation of epithelial growth factor receptor mutation in blood of lung cancer patient and clinical outcome.

NCT02422628 Lung Cancer
MeSH: Lung Neoplasms
HPO: Neoplasm of the lung

3. Tumor harboring EGFR mutation including activating mutation L858R, Del19 or/and resistant mutation T790M, or/and rare mutation G719, S768, L861 4. Treatment naive 5. Patients will receive EGFR-TKI as first line treatment. --- L858R ---

3. Tumor with no EGFR mutation detected (mutation L858R, Del19 or/and resistant mutation T790M, or/and rare mutation G719, S768, L861) 4. EGFR TKI treatment naïve and without any EGFR TKI treatment in the following process ------- Exclusion criteria For exclusion in the study of NSCLC patients and control subjects should fulfill the following criteria: 1. Subjects should not enter the study if any of the following exclusion criteria are fulfilled: Involvement in the planning and/or conduct of the study (applies to staff at the study site) 2. Previous enrolment in the present study 3. --- L858R ---

Primary Outcomes

Measure: Progressive disease measured by RECIST criteria after receiving 1st line EGFR-TKI

Time: 3 years

65 Phase II Study of AZD9291 in Patients With Advanced Stage Non-small Cell Lung Cancer Following Prior EGFR TKI Therapy With EGFR and T790M Mutations Detected in Plasma Circulating Tumor DNA (PLASMA)

Circulating tumor DNA (ctDNA) is a highly specific and effective biomarker for the detection of EGFR mutation status. We hypothesise AZD9291 is efficacious in patients with EGFR sensitizing mutations and T790M detected in plasma ctDNA. This is a prospective, open label, multi-centre single arm phase II study assessing the efficacy and safety of AZD9291 monotherapy in patients with stage IIIB or IV harboring sensitising EGFR mutation (exon 19 deletions or exon 21 L858R substitution mutations) and T790M who have progressed following prior treatment with an approved EGFR TKI. Approximately 106 subjects will be enrolled. All patients must have documented radiological progression on EGFR-TKI treatment and on the last treatment administered prior to enrolling in the study.

NCT02811354 Carcinoma, Non-Small-Cell Lung Drug: AZD9291
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

This is a prospective, open label, multi-centre single arm phase II study assessing the efficacy and safety of AZD9291 monotherapy in patients with stage IIIB or IV harboring sensitising EGFR mutation (exon 19 deletions or exon 21 L858R substitution mutations) and T790M who have progressed following prior treatment with an approved EGFR TKI. --- L858R ---

3. Locally advanced/metastatic NSCLC not amenable to curative surgery or radiotherapy 4. Documentation of activating EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations) at the time of initial diagnosis 5. Radiological documentation of disease progression: following 1st line EGFR TKI treatment but who have not received further treatment OR following prior therapy with an EGFR TKI and a platinum-based doublet chemotherapy. --- L858R ---

7. Plasma sample must harbour an EGFR mutation known to be associated with EGFR TKI sensitivity (exon 19 deletion, L858R). --- L858R ---

This is a prospective, open label, multi-centre single arm phase II study assessing the efficacy and safety of AZD9291 monotherapy in patients with stage IIIB or IV harboring sensitising EGFR mutation (exon 19 deletions and exon 21 L858R substitution mutations) and T790M who have progressed following prior treatment with an approved EGFR TKI. --- L858R ---

Target patient population: Patients will be > 18 years of age, with a diagnosis of locally advanced/metastatic NSCLC not amenable to curative surgery or radiotherapy with documented activating EGFR mutations (exon 19 deletions and exon 21 L858R substitution mutations) at the time of initial diagnosis, have radiological disease progression following either 1st line EGFR TKI treatment OR following prior therapy with an EGFR TKI and a platinum-based doublet chemotherapy. --- L858R ---

Plasma sample must harbour an EGFR mutation known to be associated with EGFR TKI sensitivity (exon 19 deletion, L858R as well as presence of T790M by central lab testing from a plasma sample taken after confirmation of disease progression on the most recent treatment regimen. --- L858R ---

Primary Outcomes

Measure: Objective response rate (ORR)

Time: From the time of their first treatment with daily AZD9291 till 28 days after discontinuation

Secondary Outcomes

Measure: Progression free survival (PFS)

Time: From the time of their first treatment with daily AZD9291 till 28 days after discontinuation

Measure: Duration of response (DoR)

Time: From the time of their first treatment with daily AZD9291 till 28 days after discontinuation

Measure: Disease control rate (DCR)

Time: From the time of their first treatment with daily AZD9291 till 28 days after discontinuation

Measure: Tumour shrinkage

Time: From the time of their first treatment with daily AZD9291 till 28 days after discontinuation

Measure: Overall survival (OS)

Time: From the time of their first treatment with daily AZD9291 till 28 days after discontinuation

66 Phase I/II Study of Dasatinib and Osimertinib (AZD9291) in Patients With Advanced Non-small Cell Lung Cancer With EGFR Mutations

This is a study for patients with advanced non-small cell lung cancer with changes to their cancer cells called EGFR mutations. Mutated EGFR is important in the growth of cancer cells. Medical studies have shown that patients with EGFR mutation-positive lung cancer gain more benefit from targeted therapy drugs such as EGFR inhibitors than with standard chemotherapy. However, a significant proportion of patients carrying these sensitizing mutations do not respond well to the first-generation EGFR-TKIs (erlotinib and gefitinib), indicating the existence of intrinsic resistance mechanisms. Moreover, despite initial response to EGFR-TKIs, acquired resistance is inevitable in all patients. The investigators have recently shown that Cripto-1 overexpression in EGFR mutant NSCLC contributes to the intrinsic resistance to EGFR-TKIs through activation of the SRC oncogene. They have also shown that a combination of an EGFR-TKI (both erlotinib and osimertinib) and a Src inhibitor are synergistic in Cripto-1 overexpressing tumors in the laboratory. This study will be testing a combination of two drugs, dasatinib and osimertinib, to overcome resistance to EGFR-TKIs. Osimertinib (AZD9291) is a third-generation EGFR-TKI, which selectively blocks the activity of EGFR mutants, but spares that of wild type. The advantage of using osimertinib is that it inhibits not only the sensitizing EGFR mutations, but also the T790M mutant, which is the most common mechanism of acquired resistance. Dasatinib is a potent, orally available ABL1/SRC TKI, approved for the treatment of chronic myeloid leukemia (CML) in first-line and in patients with imatinib-resistant disease or intolerant, and is being actively studied in patients with advanced solid tumors. The first part of the study will involve finding the highest dose of dasatinib that can be given with osimertinib without causing severe side effects, finding out the side effects seen by giving dasatinib at different dose levels with osimertinib, and measuring the levels of dasatinib and osimertinib in blood at different dose levels. The second part will determine the effects of the combination of dasatinib and osimertinib and determine if the amount of Cripto-1 protein in your tumor or blood makes you more likely to have a good response to the combination of dasatinib and osimertinib.

NCT02954523 EGFR Gene Mutation Nonsmall Cell Lung Cancer Drug: Dasatinib Drug: Osimertinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

- Presence of sensitizing EGFR mutations (deletion in exon 19, L858R in exon 21, G719X, and L861Q). --- L858R ---

The most predominant EGFR mutations are in-frame deletions in exon-19 and L858R missense mutation, and patients carrying these mutations are mostly sensitive to the EGFR-targeted tyrosine kinase inhibitors (TKIs). --- L858R ---

The advantage of using AZD9291 is that it inhibits not only the mutants of exon-19 deletion and L858R, but also the T790M mutant, which is the most common mechanism of acquired resistance. --- L858R ---

Primary Outcomes

Description: Number of patients with drug related adverse events and number of patients who can tolerate dosing of dasatinib when given in combination with osimertinib

Measure: Phase I : Number of patients with drug-related adverse events as assessed by CTCAEv4.0

Time: 9 months

Description: The rate of patients non-responding (progressive disease or stable disease lasting 4 months or less) to the combination of osimertinib and dasatinib

Measure: Phase II : Number of patients that do not progress according to RECIST v1.1

Time: 9 months

Secondary Outcomes

Description: Number of patients with treatment-related adverse events in the phase II study, who are treated at the same dose that has been selected based on the phase I part

Measure: Number of patients with treatment-related adverse events in the phase II study

Time: 18 months

Description: To describe the concentration of osimertinib when administered with dasatinib. Blood is obtained from patients before each cycle and 4 hours after start of the first 2 cycles.

Measure: Concentration of orimertinib in blood

Time: 18 months

Description: Determination of the time between the start of the experimental treatment and progression of the tumor

Measure: Progression-free survival

Time: 3 years

Description: Determination of the time between start of the experimental treatment and death

Measure: Overall survival

Time: 3 years

Description: Determination of the duration of the response to the treatment, calculated from start of treatment in case of partial response and from the declaration of complete response in case of complete response. The end of the response will be when the tumor progresses

Measure: Duration of response

Time: 3 years

67 A Study to Assess the Efficacy of Erlotinib for Leptomeningeal Carcinomatosis in EGFR Mutation Positive Non-small Cell Lung Cancer

To assess the efficacy and safety of erlotinib for non-small cell lung cancer patients with leptomeningeal carcinomatosis

NCT00830245 Leptomeningeal Carcinomatosis Non-small Cell Lung Cancer Drug: Erlotinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung Carcinoma Meningeal Carcinomatosis
HPO: Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: 1. Age >18 2. Histologically or pathologically proven non-small cell lung cancer (NSCLC) 3. Leptomeningeal carcinomatosis confirmed by CSF cytology 4. A patients with EGFR mutation (including exon 19 deletion, L858R) 5. ECOG performance status 0-3 6. Expected life time more than at least 4 weeks 7. --- L858R ---

A patient who refused to sign the informed consent Inclusion Criteria: 1. Age >18 2. Histologically or pathologically proven non-small cell lung cancer (NSCLC) 3. Leptomeningeal carcinomatosis confirmed by CSF cytology 4. A patients with EGFR mutation (including exon 19 deletion, L858R) 5. ECOG performance status 0-3 6. Expected life time more than at least 4 weeks 7. --- L858R ---

Primary Outcomes

Measure: Overall survival

Time: 1 year

Secondary Outcomes

Measure: Cytology negative conversion rate

Time: 1 month, 2 months, 3 months, 4 months

Measure: Neurologic symptom improvement

Time: 1 month, 2 months, 3 months, 4 months

Measure: Response rate (extra-cranial disease)

Time: 2 months, 4 months

Measure: Response rate (brain)

Time: 2 months, 4 months

Measure: Quality of life

Time: 1 month, 2 months, 3 months, 4 months

Measure: Toxicities

Time: 1 month, 2 months, 3 months, 4 months

Measure: Prognostic factors

Time: N-A

68 Phase II Study of Erlotinib With or Without Hydroxychloroquine in Patients With Previously Untreated Advanced NSCLC and EGFR Mutations

The purpose of this research study is to learn if adding hydroxychloroquine (HCQ) to erlotinib helps treat non-small cell lung cancer (NSCLC). Another goal of this research study is to learn more about NSCLC and how it may respond to study treatment. Erlotinib (Tarceva) is a type of drug called a tyrosine kinase inhibitor (TKI). TKIs block a protein called the epidermal growth factor receptor (EGFR). EGFR may control tumor growth and tumor cell survival. However, although TKI drugs can work for some lung cancer patients for a period of time, eventually the tumor finds a way to resist or counteract the TKI treatment and it begins to grow again. Hydroxychloroquine (HCQ) is a drug approved by the FDA for treating malaria, rheumatoid arthritis, and several other diseases. Laboratory research suggests that when HCQ is given with a TKI, it may help delay or prevent TKI resistance from developing.

NCT00977470 Non-small Cell Lung Cancer Drug: Erlotinib Drug: Hydroxychloroquine
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

Specifically, patients harboring the most common mutations, deletions in exon 19 or the L858R mutation in exon 21 are eligible. --- L858R ---

Primary Outcomes

Description: A measure of progression-free survival in patients with advanced non small-cell lung cancer (NSCLC) and EGFR mutations treated with erlotinib as compared with patients treated with erlotinib plus hydroxychloroquine (HCQ). Disease progression is defined as at least a 20% increase in the sum of the longest diameter of target lesions, as seen on CT scan, or the appearance of one or more new lesions on CT scan.

Measure: Median Progression Free Survival

Time: From start of treatment until report of disease progression, assessed up to 10 years.

Description: This trial can detect a difference in proportions alive without progression at 9 months from 50% in the erlotinib arm to 77% in the erlotinib plus hydroxychloroquine (HCQ) arm, using an alpha of 0.15 and power of 85%, using the two-sided Likelihood Ratio test. Progression is defined as at least a 20% increase in the size of existing lesions or the appearance of one or more new lesions.

Measure: Nine-month Progression-free Survival Rate

Time: Nine months

Secondary Outcomes

Description: To evaluate the safety of treatment with erlotinib with and without hydroxychloroquine (HCQ). All participants receiving study treatment were evaluated for safety. Parameters included laboratory tests, hematological abnormalities, physical exam findings and spontaneous reports of adverse events reported by participants. Toxicities were evaluated and graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = fatal.

Measure: Treatment Related Toxicity, > 10% Frequency, Any Grade

Time: 2 years

Description: Response is assessed via spiral CT scan, done at baseline and after every 2 cycles of study treatment. Standard RECIST (Response Evaluation Criteria in Solid Tumors) was used. Complete Response (CR) = disappearance of all target lesions; Partial Response (PR) = at least a 30% decrease in the size of target lesions, as compared to baseline; Progressive Disease (PD) = at least at 20% increase in the size of target lesions, or the appearance of one or more new lesions; Stable Disease (SD) = neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease. Response rate = CR + PR. Disease control rate = CR + PR + SD

Measure: Objective Tumor Response Rate Following Treatment With Erlotinib and With Erlotinib/HCQ.

Time: 2 years

Measure: Overall Survival of Patients Treated With Erlotinib and With Erlotinib/HCQ

Time: Until death

Other Outcomes

Description: Serial circulating tumor cell (CTC) analyses will be performed on peripheral blood and correlated with disease response.

Measure: Circulating Tumor Cell Quantification

Time: Until disease progression (median of 10.8 months)

Description: Correlation of molecular and genetic tumor characteristics with disease response. Genomic DNA will be extracted from tumor tissue and direct sequencing analysis will be performed to identify additional mutations.

Measure: EGFR Mutational Status

Time: 2 years

Description: [18F]-FMISO-PET/CT was performed on a 64-slice PET/CT scanner and tracer uptake was assessed using SUV (standardized uptake value), normalizing the radioactivity measured in tissue by the injected dose and the body weight of the patient. Mean and maximum SUV and threshold volume of FMISO uptake were measured to quantify the extent of hypoxia in the primary tumor. Imaging was performed before and after initiation of therapy with erlotinib.

Measure: Percent of Participants in Which FMISO-PET ([18F]-Fluoromisonidazole-positron Emission Tomography) is Able to Detect and Quantify Changes in Tumor Hypoxia After Erlotinib.

Time: 12 weeks

69 A Phase I/II, Open-label, Multi-center Study to Evaluate Safety, Tolerability, Pharmacokinetics and Anti-tumor Activity of AZD3759 in Chinese Patients With EGFRm+ NSCLC With Central Nervous System (CNS) Metastases

This is a multi-center, open-label, dose escalation and phase I/II study, consisting of dose escalation in Part A and phase II study in Part B.

NCT03360929 Non Small Cell Lung Cancer Drug: AZD3759
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

3. Histologically or cytologically confirmed non-small cell lung cancer with activating mutation in EGFR gene (including Exon19Del and/or L858R). --- L858R ---

Primary Outcomes

Description: AE.SAE,vital signs, physical examination,laboratory examinations etc.

Measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

Time: 21 days after the first dose

Description: ORR, DCR, DOR, PFS and tumor size changing compared with baseline according to RECIST 1.1

Measure: anti-tumor activity

Time: every 6 weeks

Secondary Outcomes

Description: Peak Plasma Concentration (Cmax)

Measure: Peak Plasma Concentration (Cmax)

Time: Pre-dose and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h(C0D2) and 48h(C0D3) after the first single-dose(C0D1) ;Pre-dose of C1D1,C1D8, C1D15, C1D21 and C2D1 and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h post dose on C1D21 during multiple dosing.

Description: Area under the plasma concentration versus time curve (AUC)

Measure: Area under the plasma concentration versus time curve (AUC)

Time: Pre-dose and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h(C0D2) and 48h(C0D3) after the first single-dose(C0D1) ;Pre-dose of C1D1,C1D8, C1D15, C1D21 and C2D1 and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h post dose on C1D21 during multiple dosing.

70 A Randomized Phase I Trial to Evaluate Concurrent Or Sequential Ipilimumab, Nivolumab, and Stereotactic Body Radiotherapy in Patients With Stage IV Non-Small Cell Lung Cancer (COSINR Study)

Trial Design - Patients with stage IV non-small cell lung cancer are randomized to nivolumab/ipilimumab plus either sequential or concurrent stereotactic body radiotherapy (SBRT). - The primary endpoint is the phase I safety endpoint of SBRT dose for each body site. - The same starting SBRT dose levels are used in each arm. If two or more patients experience a dose-limiting toxicity (DLT) at the starting dose level, then the reduced dose level will be used (Section 7.1—Page 72). - DLT is defined as any grade ≥3 toxicity possibly, likely, or definitely related to SBRT plus nivolumab/ipilimumab (the combination and not the individual components). - Irradiated metastases will be grouped into one of five locations, which have different SBRT doses, and the DLTs will be attributed to the relevant organ system. - The starting and decreased SBRT dose levels are found in Table 2 (Page 20). - SBRT will be delivered in 3-5 fractions over the course of 1-1.5 weeks. - Patients in the sequential arm will begin immunotherapy between 1-7 days after completion of SBRT - Given the accrual data for IRB15-1130, the investigators anticipate that approximately 1/3 of patients will contribute metastasis to 2 locations. Since there are 2 arms, and 5 metastasis locations with 6 patients per location for the starting dose level, this translates to 40 patients for the starting dose level, and another 40 patients should each of the 5 locations require de-escalation to the lower dose level. - Secondary endpoints include comparisons of efficacy and toxicity between the arms, as well as interrogation of changes in the immune microenvironment induced by the two approaches.

NCT03223155 Stage IV Small Cell Lung Cancer Drug: Nivolumab Drug: Ipilimumab Radiation: Stereotactic body radiation therapy
MeSH: Lung Neoplasms Small Cell Lung Carcinoma
HPO: Neoplasm of the lung Small cell lung carcinoma

- 12. Patients whose tumors known to harbor an exon 19 deletion or exon 21 L858R EGFR mutation must have progressed on or had intolerance to an EGFR TKI. --- L858R ---

Primary Outcomes

Description: To determine the recommended SBRT dose to various metastatic locations in patients with stage IV NSCLC when delivered prior to or concurrently with nivolumab and ipilimumab.

Measure: Number of serious adverse events

Time: Up to 4 years

Secondary Outcomes

Description: To estimate and compare rates of ≥ grade 3-4 adverse events, by organ system, by CTCAEv4.0 that occur within 3 months from the start of SBRT when given prior to or concurrently with nivolumab/ipilimumab.

Measure: Number of adverse events of grade 3-4 or higher

Time: Up to 4 years

Description: To estimate and compare the rates of long-term adverse events (after 3 months) from the end of SBRT when given prior to or concurrently with nivolumab/ ipilimumab.

Measure: Rate of long term adverse events

Time: Up to 4 years

Description: Summarize and compare the response rate to determine the progression-free survival at 6 months with SBRT given either prior to or concurrently with nivolumab/ipilimumab.

Measure: Rate of response

Time: From the start of treatment until the date of first documented progression or date of death from any cause, whichever comes first, up to 100 months

Description: To determine and compare the control of lesion(s) (SBRT treated and non-treated) when given either prior to or concurrently with nivolumab/ipilimumab.

Measure: Rate of lesion control

Time: Up to 4 years

Description: To evaluate and compare changes in the tumor microenvironment induced by radiation when given prior to or concurrently with nivolumab/ipilimumab.

Measure: Rate of change in tumor microenvironment

Time: Up to 4 years

Description: To evaluate whether response to therapy correlates with PD-L1 expression levels among patients treated with nivolumab/ipilimumab either concurrently or sequential to SBRT.

Measure: Rate of PD-L1 expression levels response

Time: Up to 4 years

Description: To explore whole PBMC by measuring peripheral blood cell T cell subset IFNγ ELISPOT levels throughout the study course and correlate with response to treatment.

Measure: Measure of peripheral blood cell T cell levels

Time: From the start of treatment, not to exceed 4 years

Description: To explore peripheral blood T cell receptor deep sequencing quantification of T cell receptor (TCR) repertoire changes throughout the study course and how TCR repertoire may correlate with progression free survival and/or overall survival.

Measure: Quantification of T cell receptor

Time: From the start of treatment until the date of first documented progression or date of death from any cause, whichever comes first, up to 100 months

71 Phase II, Multicenter, Single-arm, Open-label Study to Evaluate the Efficacy of Olmutinib(Olita®) in Patients With NSCLC Who Harboring T790M Mutation Confirmed Using DNA Extracted From Extracellular Vesicles in Bronchoalveolar Lavage Fluid

The purpose of this study is to evaluate the efficacy of Olmutinib(Olita®) in patients with T790M-positive non-small cell lung cancer (NSCLC) confirmed using DNA extracted from extracellular vesicles of bronchoalveolar lavage fluid.

NCT03228277 Non Small Cell Lung Cancer Drug: Olmutinib
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

4. Confirmation that the tumor harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group performance status of 0 to 2 6. --- L858R ---

Primary Outcomes

Description: defined as the proportion of patients who achieved complete remission(CR) or partial remission(PR) based on RECIST version 1.1

Measure: Objective response rate (ORR)

Time: Change from baseline at every 6 weeks until disease progression or withdrawal from study, assessed up to 12 months

Secondary Outcomes

Description: defined as the proportion of patients with a documented CR, PR, and SD during the treatment cycles according to the RECIST version 1.1

Measure: Disease control rate (DCR)

Time: Change from baseline at every 6 weeks until disease progression or withdrawal from study, assessed up to 12 months

Description: defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first

Measure: Progression-free survival (PFS)

Time: Change from baseline at every 6 weeks until disease progression or withdrawal from study, assessed up to 12 months

72 MELROSE: Phase 2 Study Evaluating MEchanisms of Resistance on Tumor Tissue and Liquid Biopsy in Patients With EGFR Mutated Nonpretreated Advanced Lung Cancer Receiving OSimErtinib Until and Beyond Radiological Progression : the MELROSE Trial

Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The AURA 3 study (T790M-positive advanced non-small-cell lung cancer in progression after first-line EGFR-TKI therapy, shown that the median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months p<0.001). In addition, clinical data show that patients with mutated EGFR NSCLC receiving osimertinib in first line, presented an objective response rate of 77 % with a disease control rate of 98 % and a median PFS was 19.3 months. Finally, The FLAURA study randomized phase 3 study clearly demonstrated the superiority of osimertinib compared with erlotinib or gefitinib in EGFR mutated nonpretreated NSCLC (median PFS of 18.9 months versus 10.2 months). However, several issues remain unknown or debated : - What are the mechanisms of resistance to osimertinib prescribed in first-line? - What are the consequences of prolonged exposure to osimertinib on the expression of markers of response to immunotherapy? - Is there an association between kinetic parameters of ctDNA (circulating tumor DNA) and prediction of response to osimertinib and/ or and prediction of therapeutic escape under osimertinib? In order to respond to all these questions, this phase II trial will be the first to systemically analyze the mechanisms of resistance to Osimertinib based on the analysis of biopsy, and collection of plasma from all patients during the course of treatment.

NCT03865511 Non-small Cell Lung Cancer Drug: TAGRISSO® 80mg (Osimertinib) Genetic: Tumor biopsies Genetic: ctDNA analysis
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19 deletions, L858R), either alone or in combination with other EGFR mutations. --- L858R ---

Primary Outcomes

Description: Analyze of the proportion of patients with a given genetic marker on tumor biopsy (including, but not limited to, EGFR mutations, HER2 (Human Epidermal Growth factor receptor 2), and cMET expression and/or amplification) at the point of clinical disease progression.

Measure: Examination of the genetic profile at the point of disease progression in EGFRm+ (mutated Epidermal Growth Factor Receptor) patients receiving osimertinib as first-line EGFR TKI therapy compared to baseline.

Time: At clinical disease progression (approximately 22 months)

Secondary Outcomes

Description: Progression free survival rate at one year defined by time from first study dose to first event between Radiological Progression Disease and death, or one year if no event. The rPFS is defined according to RECIST 1.1.

Measure: Clinical objective : To assess efficacy of Osimertinib

Time: Every 3 months up to one year after first study dose

Description: Radiological Progression Free Survival (rPFS): Time from first study dose to first event between rPFS or death. The rPFS is defined according to RECIST 1.1.

Measure: Clinical objective : To assess efficacy of Osimertinib

Time: Every 3 months until radiological disease progression (approximately 22 months)

Description: Clinical Progression Free Survival (cPFS): Time from first study dose to off-osimertinib.

Measure: Clinical objective : To assess efficacy of Osimertinib

Time: Every month until clinical disease progression (approximately 22 months)

Description: Overall survival

Measure: Clinical objective : To assess efficacy of Osimertinib

Time: From first dose to end of study or date of death from any cause, whicheever comes first, assessed every 3 months (approximately 48 months)

Description: Objective Response Rate (ORR)

Measure: Clinical objective : To assess efficacy of Osimertinib

Time: every 3 months until radiological disease progression (approximately 22 months)

Description: Duration of Response (DoR): Disease Control Rate (DCR)

Measure: Clinical objective : To assess efficacy of Osimertinib: Duration of Response (DoR): Disease Control Rate (DCR)

Time: every 3 months until radiological disease progression (approximately 22 months)

Description: Monitoring of Adverse events (grade 3 and 4)

Measure: Clinical objective : To assess safety of Osimertinib with Monitoring of Adverse events (grade 3 and 4)

Time: monthly from first study dose until 15 days after last study dose

Description: By the study of the expression of molecules involved in the efficacy of check point inhibitors determined by immunohistochemistry (PD-L1; CD73; CD4; CD8) on tumor tissue collected at progression

Measure: Biological objective : To evaluate the consequence of osimertinib treatment on the expression of targets of immune check point inhibitors

Time: At baseline and at clinical disease progression (approximately 22 months)

Description: Analyze of mutation at progression on tumor tissue and ctDNA

Measure: Biological objective : To evaluate diagnostic accuracy of ctDNA to detect mutation

Time: At baseline and monthly until clinical disease progression (approximately 22 months)

Description: Analyze of the presence of tumors ctDNA at baseline, clinical progression disease

Measure: Biological objective : To observe if the presence of ctDNA at baseline is a prognostic factor of clinical progression disease

Time: At baseline and monthly until clinical disease progression (approximately 22 months)

Description: Analyze of absolute quantities of ctDNA molecules presenting the EGFR mutation identified in the tumor, clinical progression disease

Measure: Biological objective : To demonstrate that the early kinetics of ctDNA is an indicator of response to osimertinib

Time: At baseline and monthly until clinical disease progression (approximately 22 months)

Description: Serial monitoring in ctDNA of molecular alterations identified in tissues collected at progression

Measure: Biological objective : To measure the biological progression (bPFS) in patients treated with osimertinib

Time: At baseline and monthly until clinical disease progression (approximately 22 months)

Description: Analyze of the EGFR mutation identified in the tumor biopsy and in the ctDNA

Measure: Biological objective : To compare the genetic profile of the ctDNA and the tumor biopsy

Time: At baseline and at clinical disease progression (approximately 22 months)

Description: Analyze of the absolute quantities of ctDNA molecules presenting the EGFR mutation monthly, radiological and clinical progression disease

Measure: Biological objective : To compare the kinetic of appearance of EGFR mutation and radiological and clinical progression disease

Time: At baseline and monthly until clinical disease progression (approximately 22 months)

73 to Evaluate SCT510 Compared to Avasitin Respectively Combined Paclitaxel and Carboplatin First-line Treatment of Locally Advanced and Metastatic or Recurrent Squamous Cell Non-small Cell Lung Cancer Efficacy and Safety

To evaluate the safety, efficacy and immunogenicity of SCT510 combined with paclitaxel and carboplatin compared with bevacizumab combined with paclitaxel and carboplatin in the first-line treatment of locally advanced metastatic or recurrent squamous cell non-small cell lung cancer.

NCT03792074 Non-squamous Cell Non-small Cell Lung Cancer Drug: SCT510 Drug: Bevacizumab Drug: Paclitaxel Drug: Carboplatin
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

21 (L858R, L861Q)) and ALK fusion.Subjects who have not previously undergone EGFR and ALK gene testing will need to undergo genetic testing during the screening period.Among them, subjects whose EGFR or ALK gene status cannot be determined for various reasons can be enrolled;Subjects who are known to have EGFR sensitive mutations and/or ALK fusion may also be enrolled if they are currently unable to obtain the corresponding targeted drugs (including the rejection of the subjects) and chemotherapy is standard treatment at the research center; 5. --- L858R ---

Primary Outcomes

Description: the proportion of subjects whose CR(complete response) and PR(partial response)combined , according to RECIST 1.1 criteria

Measure: Objective response rate

Time: 12 weeks

Secondary Outcomes

Description: the proportion of subjects whose CR(complete response) and PR(partial response)combined , according to RECIST 1.1 criteria

Measure: Objective response rate

Time: 18 week

Description: the proportion of subjects with CR(complete response), PR(partial response) and SD(Stable disease) combined,according to RECIST 1.1 criteria

Measure: Disease control rate

Time: 12 weeks and 18 weeks

Description: The time from the first assessment of CR(complete response) or PR(partial response) to the first assessment of PD(progressive disease) or any cause of death,according to RECIST 1.1 criteria

Measure: Duration of Response

Time: 3 years

Description: The time from randomization to PD(progressive disease) or any cause of death,according to RECIST 1.1 criteria

Measure: Progression free survival

Time: 3 years

Description: The proportion of subjects who survived longer than 1 year after randomization

Measure: 1-year overall survival rate

Time: 1 year

Description: Defined as the time from randomization of subjects to death from any cause

Measure: Overall survival

Time: 3 years

74 Anlotinib Combined With Pemetrexed And Carboplatin Followed by Maintenance Therapy With Anlotinib Plus Pemetrexed as the First-line Treatment in Patients With Advanced Nonsquamous Non-Small Cell Lung Cancer: A Single-arm, Multicenter, Exploratory Clinical Study.

In recent years, with the progress in the treatment field, Non-Small Cell Lung Cancer(NSCLC) has become the most successful cancer species in precision medicine. Patients with positive driving genes such as EGFR, ALK, ROS1, BRAF and so on have clearly targeted drugs, which bring survival benefits to patients.However, about 50% of patients still lack a clear driving gene target, which has become the focus of current research.In the field of wild-type NSCLC with negative driver genes, the classic first-line treatment regimen is the two-drug regimen containing platinum.The study by Kimura T in the first-line treatment of 54 wild-type advanced NSCLC patients with carboplatin and pemetrexed showed that the ORR, mPFS and mOS of patients with wild-type non-squamous NSCLC treated with carboplatin permetrexine were 35.8%, 5.4 months and 12.7 months respectively. Anlotinib is a multi-target receptor tyrosine kinase inhibitor in domestic research and development.In the phase Ⅲ study, patients who failed at least two kinds of systemic chemotherapy (third line or beyond) or drug intolerance were treated with anlotinib or placebo, the anlotinib group PFS and OS were 5.37 months and 9.46 months, the placebo group PFS and OS were 1.4 months and 6.37 months. The efficacy and safety of Anlotinib combined with Pemetrexed and Carboplatin followed by maintenance therapy with Anlotinib plus Pemetrexed as the first-line treatment in patients with advanced nonsquamous NSCLC deserve further exploration.

NCT03790228 Non-squamous Cell Non-Small Cell Lung Cancer Drug: Anlotinib Combined With Pemetrexed And Carboplatin
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Exclusion Criteria: - Small cell lung cancer (including lung cancer mixed with small cell lung cancer and non-small cell lung cancer),Lung sarcomatoid carcinoma; - Had histologically confirmed lung squamous cell carcinoma, or adenosquamous carcinoma; - Patients with pathological fracture in bone metastasis of non-small-cell lung cancer; - Tumor histology or cytology confirmed EGFR mutagenesis [EGFR sensitive mutations include 18 exon point mutations (G719X), 19 exon deletions, 20 exon S768I mutations and 21 exon point mutations (L858R and L861Q)] and ALK gene rearrangement positivity, include EGFR/ALK status cannot be determined for various reasons; - Imaging (CT or MRI) shows that the distance between tumor lesion and the large blood vessel is ≤ 5 mm, or there is a central tumor that invades the local large blood vessel; or there is a significant pulmonary cavity or necrotizing tumor; - Medical history and combined history: 1. Active brain metastases, cancerous meningitis, spinal cord compression, or imaging CT or MRI screening for brain or pia mater disease (a patient with brain metastases who have completed treatment and stable symptoms in 28 days before enrollment may be enrolled, but should be confirmed by brain MRI, CT or venography evaluation as no cerebral hemorrhage symptoms and metastases in midbrain, pons, cerebellum, medulla oblongata, or spinal cord, brain metastases and local radiotherapy after two weeks to allow group); 2. The patient is participating in other clinical studies or completing the previous clinical study in less than 4 weeks; 3. Had malignant tumors except NSCLC within 5 years before enrollment(except for patients with cervical carcinoma in situ , basal cell or squamous cell skin cancer who have undergone a curative treatment, local prostate cancer after radical resection, ductal carcinoma in situ or papillary thyroid cancer after radical resection); 4. Abnormal blood coagulation (INR > 1.5 or prothrombin time (PT) > ULN + 4 seconds or APTT > 1.5 ULN), with bleeding tendency or undergoing thrombolytic or anticoagulant therapy;Note: Under the premise of prothrombin time international normalized ratio (INR) ≤ 1.5, low-dose heparin (adult daily dose of 0.6 million to 12,000 U) or low-dose aspirin (daily dosage ≤ 100 mg) is allowed for preventive purposes; 5. Renal insufficiency: urine routine indicates urinary protein ≥ ++, or confirmed 24-hour urine protein ≥ 1.0g; 6. --- S768I --- --- L858R ---

Primary Outcomes

Description: PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause.

Measure: Progression-free survival,PFS

Time: each 42 days up to PD or death(up to 24 months)

Secondary Outcomes

Description: ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.prior to progression or any further therapy.

Measure: Objective Response Rate,ORR

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)

Description: Defined as the proportion of patients with a documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 1.1.

Measure: Disease Control Rate,DCR

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months).

Description: Defined as the time until death due to any cause.

Measure: Overall Survival,OS

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months) .

Description: Number of Participants with Adverse Events.

Measure: Safety(Number of Participants with Adverse Events )

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months).

75 A Single Arm, Multi-center Study to Assess the Efficacy and Safety of Docetaxel Combined With Carboplatin Plus Anlotinib as First Line Treatment in Non-squamous Non-small-cell Lung Cancer (NSCLC)

Anlotinib which has shown an affirmatory efficacy in ALTER0303 controlled trial as a 3rd-line treatment on advanced NSCLC is a tyrosine kinase inhibitor with a favorable safety profile in phase I trial which mainly targets VEGFR1/2/3, FGFR, PDGFR and c-kit. The purpose of this trail is to establish whether advanced non-squamous NSCLC patients could benefit from the combination treatment of docetaxel, carboplatin and anlotinib as the first-line and maintenance treatment.

NCT03799601 NSCLC Drug: Anlotinib Drug: Docetaxel Drug: Carboplatin

Exclusion Criteria: - Small cell lung cancer (including lung cancer mixed with small cell lung cancer and non-small cell lung cancer), Lung sarcomatoid carcinoma; - Had histologically confirmed lung squamous cell carcinoma, or adenosquamous carcinoma; - Patients with pathological fracture in bone metastasis induced by non-small-cell lung cancer; - Tumor histology or cytology confirmed EGFR mutagenesis [EGFR sensitive mutations include 18 exon point mutations (G719X), 19 exon deletions, 20 exon S768I mutations and 21 exon point mutations (L858R and L861Q)] and ALK gene rearrangement positivity, include EGFR/ALK status cannot be determined for various reasons; - Imaging (CT or MRI) shows that the distance between tumor lesion and the large blood vessel is ≤ 5 mm, or there is a central tumor that invades the local large blood vessel; or there is a significant pulmonary cavity or necrotizing tumor; Medical history and combined history: - Active brain metastases, cancerous meningitis, spinal cord compression, or imaging CT or MRI screening for brain or pia mater disease (a patient with brain metastases who have completed treatment and stable symptoms in 28 days before enrollment may be enrolled, but should be confirmed by brain MRI, CT or venography evaluation as no cerebral hemorrhage symptoms and metastases in midbrain, pons, cerebellum, medulla oblongata, or spinal cord, brain metastases and local radiotherapy after two weeks to allow group); - The patient is participating in other clinical studies or completing the previous clinical study in less than 4 weeks; - Had malignant tumors except NSCLC within 5 years before enrollment(except for patients with carcinoma in situ of the cervix , basal cell or squamous cell skin cancer who have undergone a curative treatment, local prostate cancer after radical resection, ductal carcinoma in situ or papillary thyroid cancer after radical resection); - Abnormal blood coagulation (INR > 1.5 or prothrombin time (PT) > ULN + 4 seconds or APTT > 1.5 ULN), with bleeding tendency or undergoing thrombolytic or anticoagulant therapy; Note: Under the condition of prothrombin time international normalized ratio (INR) ≤ 1.5, low-dose heparin (adult daily dose of 0.6 million to 12,000 U) or low-dose aspirin (daily dosage ≤ 100 mg) is allowed for preventive purposes; - Renal insufficiency: urine routine indicates urinary protein ≥ ++, or confirmed 24-hour urine protein ≥ 1.0g; - The effects of surgery or trauma have been eliminated for less than 14 days before enrollment in subjects who have undergone major surgery or have severe trauma; - Severe acute or chronic infections requiring systemic treatment; Suffering from severe cardiovascular disease: myocardial ischemia or myocardial infarction above grade II, poorly controlled arrhythmias (including men with QTc interval ≥ 450 ms, women ≥ 470 ms); according to NYHA criteria, grades III to IV Insufficient function, or cardiac color Doppler ultrasound examination indicates left ventricular ejection fraction (LVEF) <50%; - There is currently a peripheral neuropathy of ≥CTCAE 2 degrees, except for trauma; - Respiratory syndrome (≥CTC AE grade 2 dyspnea), serous effusion (including pleural effusion, ascites, pericardial effusion) requiring surgical treatment; Long-term unhealed wounds or fractures; - Decompensated diabetes or other ailments treated with high doses of glucocorticoids; - Factors that have a significant impact on oral drug absorption, such as inability to swallow, chronic diarrhea, and intestinal obstruction; - Clinically significant hemoptysis (daily hemoptysis greater than 50ml) within 3 months prior to enrollment; or significant clinically significant bleeding symptoms or defined bleeding tendency, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, baseline fecal occult blood ++ and above, or suffering from vasculitis; - Events of venous/venous thrombosis occurring within the first 12 months prior to enrollment, such as cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism; - Physical examination and laboratory findings: 1. --- S768I --- --- L858R ---

Primary Outcomes

Description: Clinical response of treatment according to RESIST v1.1 criteria (PFS, progression-free survival)

Measure: progression-free survival

Time: Estimated about 24 months.

Secondary Outcomes

Description: Clinical response of treatment according to RESIST v1.1 criteria (OS, overall survival)

Measure: Overall Survival

Time: Estimated about 24 months.

Description: Clinical response of treatment according to RESIST v1.1 criteria (DCR, disease control rate)

Measure: Disease Control Rate

Time: Estimated about 24 months.

Description: Clinical response of treatment according to RESIST v1.1 criteria (ORR, Overall Response Rate)

Measure: Overall Response Rate

Time: Estimated about 24 months.

76 A Randomized, Controlled, Open-label, Prospective Trial of S-1 Plus Gefitinib Versus Gefitinib Monotherapy for First-line Treatment of Advanced Non-squamous Non-small Cell Lung Cancer With EGFR-sensitive Mutation

To investigate the survival benefit of first-line therapy for patients with EGFR-sensitive mutation-positive advanced non-squamous non-small cell lung cancer treated with S-1plus gefitinib versus gefitinib monotherapy

NCT03457337 EGFR-sensitive Mutation-positive Advanced Non-squamous Non-small Cell Lung Cancer Treated With S-1plus Gefitinib Versus Gefitinib Monotherapy Drug: S-1 plus Gefitinib Drug: Gefitinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung Hypersensitivity
HPO: Allergy Neoplasm of the lung Non-small cell lung carcinoma

4. exon 19 deletion or exon 21 L858R for EGFR mutation. --- L858R ---

Primary Outcomes

Description: From start of anti-cancer therapy until progression or death.To evaluate the disease free survival of gefitinib combined with S-1 and gefitinib in patients with Pathological stage IIIc-IV NSCLC harbouring sensitive mutations of EGFR. Progression free survival (PFS)- defined as the time from initial medication to the first documented disease progression or death, whichever occurs first.

Measure: Progression free survival(PFS)

Time: 2 years

Secondary Outcomes

Description: To evaluate the overall survivalof gefitinib combined with S-1 and gefitinib in patients with Pathological stage IIIc-IV NSCLC harbouring sensitive mutations of EGFR in the 3 years since treatment begain

Measure: Overall survival(OS)

Time: 3 years

Description: To compare disease control rate of the two arms from start of anti-cancer therapy until progression

Measure: Disease control rate

Time: 2 years

Description: To compare objective response rate of the two arms from start of anti-cancer therapy until progression

Measure: Objective response rate(ORR)

Time: 2 years

Description: The safety and tolerability profile of gefitinib at a 250 mg daily dose relative to that of radiotherapy.

Measure: Number of Participants with Adverse Events

Time: 3 years

Other Outcomes

Description: Quality of Life Questionnaire(such as QLQ-C30 and QLQ-LC13) evaluated since treatment began.At the end of the trial, the differences between the two indicators were compared with Mixed-effects model repeated measures (MMRM), where the baseline was scored as a covariant and the treatment group as a fixed variable. In addition, the baseline values of the two scores, the value of each visit, and the change value of the baseline were statistically described.

Measure: Assessment of Health-related quality of life

Time: 3 years

77 Toripalimab Combined With Pemetrexed Plus Carboplatin for Treatment of Recurrent or Advanced Non-small-cell Lung Cancer With EGFR-mutation Positive and T790M Negative After Progression on EGFR-TKI Treatment:a Multi-center, Single Arm Phase II Study

JS001 combined with pemetrexed plus carboplatin for treatment of recurrent or advanced non-small-cell lung cancer with EGFR-mutation positive and T790M negative after progression on EGFR-TKI treatment:a multi-center, single arm phase II study

NCT03513666 NSCLC Combination Product: Drug intervention

Inclusion Criteria: Only the patients meeting all the following criteria can be eligible to participate in the trial: - Histologically and/or cytologically confirmed advanced or recurrent non-small cell lung cancer with EGFR sensitive mutation (exon 19 deletion, exon 21 L858R), and meeting the following conditions at the same time: - Previous first-line EGFR-TKI monotherapy with clinical benefit, followed by progression of disease; - No exon 20 T790M mutation after failure of EGFR-TKI therapy; - At least one measurable lesion (in accordance with RECIST 1.1); Exclusion Criteria: Patients who fulfill any of the following criteria must be excluded from the study: - Histologically or cytopathologically confirmed combined with small cell lung cancer component or squamous cell carcinoma component >10%; - Combined with other driver gene mutation with known drug therapy, including but not limited to ALK rearrangement, ROS1 mutation, BRAF600E mutation etc.; - Previous systemic chemotherapy for advanced NSCLC; - EGFR-TKI therapy within two weeks prior to enrollment; Inclusion Criteria: Only the patients meeting all the following criteria can be eligible to participate in the trial: - Histologically and/or cytologically confirmed advanced or recurrent non-small cell lung cancer with EGFR sensitive mutation (exon 19 deletion, exon 21 L858R), and meeting the following conditions at the same time: - Previous first-line EGFR-TKI monotherapy with clinical benefit, followed by progression of disease; - No exon 20 T790M mutation after failure of EGFR-TKI therapy; - At least one measurable lesion (in accordance with RECIST 1.1); Exclusion Criteria: Patients who fulfill any of the following criteria must be excluded from the study: - Histologically or cytopathologically confirmed combined with small cell lung cancer component or squamous cell carcinoma component >10%; - Combined with other driver gene mutation with known drug therapy, including but not limited to ALK rearrangement, ROS1 mutation, BRAF600E mutation etc.; - Previous systemic chemotherapy for advanced NSCLC; - EGFR-TKI therapy within two weeks prior to enrollment; NSCLC null --- L858R ---

Inclusion Criteria: Only the patients meeting all the following criteria can be eligible to participate in the trial: - Histologically and/or cytologically confirmed advanced or recurrent non-small cell lung cancer with EGFR sensitive mutation (exon 19 deletion, exon 21 L858R), and meeting the following conditions at the same time: - Previous first-line EGFR-TKI monotherapy with clinical benefit, followed by progression of disease; - No exon 20 T790M mutation after failure of EGFR-TKI therapy; - At least one measurable lesion (in accordance with RECIST 1.1); Exclusion Criteria: Patients who fulfill any of the following criteria must be excluded from the study: - Histologically or cytopathologically confirmed combined with small cell lung cancer component or squamous cell carcinoma component >10%; - Combined with other driver gene mutation with known drug therapy, including but not limited to ALK rearrangement, ROS1 mutation, BRAF600E mutation etc.; - Previous systemic chemotherapy for advanced NSCLC; - EGFR-TKI therapy within two weeks prior to enrollment; Inclusion Criteria: Only the patients meeting all the following criteria can be eligible to participate in the trial: - Histologically and/or cytologically confirmed advanced or recurrent non-small cell lung cancer with EGFR sensitive mutation (exon 19 deletion, exon 21 L858R), and meeting the following conditions at the same time: - Previous first-line EGFR-TKI monotherapy with clinical benefit, followed by progression of disease; - No exon 20 T790M mutation after failure of EGFR-TKI therapy; - At least one measurable lesion (in accordance with RECIST 1.1); Exclusion Criteria: Patients who fulfill any of the following criteria must be excluded from the study: - Histologically or cytopathologically confirmed combined with small cell lung cancer component or squamous cell carcinoma component >10%; - Combined with other driver gene mutation with known drug therapy, including but not limited to ALK rearrangement, ROS1 mutation, BRAF600E mutation etc.; - Previous systemic chemotherapy for advanced NSCLC; - EGFR-TKI therapy within two weeks prior to enrollment; NSCLC null --- L858R --- --- T790M --- --- L858R ---

Primary Outcomes

Description: The primary endpoint is the antitumor activities in this study

Measure: Objective response rate (ORR)

Time: 12 weeks

Secondary Outcomes

Description: Progression free survival (PFS)

Measure: PFS

Time: 18 months

Description: Overall survival (OS)

Measure: OS

Time: 18 months

Description: Duration of response (DOR)

Measure: DOR

Time: 18 months

78 A Randomized, Double-Blind, Phase 3 Study of Pemetrexed + Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in TKI-resistant EGFR-mutated Tumors in Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) Participants (KEYNOTE-789)

The purpose of this study is to evaluate the efficacy and safety of pemetrexed plus platinum chemotherapy (carboplatin or cisplatin) with or without pembrolizumab (MK-3475; KEYTRUDA®) in the treatment of adults with the following types of tyrosine kinase inhibitor (TKI)-resistant, epidermal growth factor receptor (EGFR)-mutated, metastatic non-squamous non-small cell lung cancer (NSCLC) tumors: 1) TKI-failures (including osimertinib [TAGRISSO®] failure) with T790M-negative mutation tumors, 2) T790M-positive mutation tumors with prior exposure to osimertinib, and 3) first-line osimertinib failure regardless of T790M mutation status. The primary study hypotheses are that the combination of pembrolizumab plus chemotherapy has superior efficacy compared to saline placebo plus chemotherapy in terms of: 1) Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) based on blinded independent central review, and 2) Overall Survival (OS). This study will be considered to have met its success criteria if the combination of pembrolizumab plus chemotherapy is superior to saline placebo plus chemotherapy in terms of PFS or OS.

NCT03515837 Non-small Cell Lung Cancer Biological: pembrolizumab Drug: pemetrexed Drug: carboplatin Drug: cisplatin Drug: saline solution
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

- Documentation of tumor activating EGFR mutation, specifically either DEL19 or L858R. --- L858R ---

Primary Outcomes

Description: PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. PFS will be assessed by blinded independent central review (BICR) using RECIST 1.1. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions is also considered PD. The PFS for participants will be presented.

Measure: Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

Time: Up to approximately 32 months

Description: OS is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis will be censored at the date of the last follow-up. The OS of participants will be presented.

Measure: Overall Survival (OS)

Time: Up to approximately 59 months

Secondary Outcomes

Description: ORR is defined as the percentage of participants in the analysis population who experience a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1. The ORR for participants will be presented.

Measure: Objective Response Rate (ORR) Per RECIST 1.1

Time: Up to approximately 32 months

Description: For participants who experience a response of CR or PR, DOR is defined as the time from the earliest date of qualifying response until earliest date of PD or death from any cause, whichever comes first. DOR will be assessed per RECIST 1.1 based on BICR. The DOR of participants who experience a CR or PR will be presented.

Measure: Duration of Response (DOR) Per RECIST 1.1

Time: Up to approximately 32 months

Description: The EORTC QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. For Global Health Status, participants are asked "How would you rate your overall health during the past week?" Individual responses are given on a 7-point scale (1=Very poor; 7=Excellent), with a higher score indicating a better outcome. The change from baseline in EORTC-QLQ-C30 score for Global Health Status will be presented.

Measure: Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 Item (QLQ-C30) Global Health Status (Item 29) Scale Score

Time: Baseline and Week 12, Week 27

Description: TTD is the time from baseline to first onset of 10 points or more decrease from baseline with confirmation by the subsequent visit of 10 points or more deterioration from baseline in the composite endpoint of cough [EORTC QLQ-Lung Cancer Module 13 (LC13) Item 1; How much did you cough?], chest pain [EORTC QLQ-LC13 Item 10; Have you had pain in your chest?], or dyspnea [EORTC QLQ-C30 Item 8; Were you short of breath?]. Individual responses are given on a 4-point scale (1=Not at all; 4=Very much), with a lower score indicating a better outcome. The time to true deterioration in the composite endpoint of cough, chest pain or dyspnea will be presented.

Measure: Time to True Deterioration (TTD) in the EORTC Questionnaire Composite Endpoint of Cough, Chest Pain or Dyspnea

Time: Up to approximately 32 months

Description: An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. The number of participants who experience an AE will be presented.

Measure: Adverse Events (AEs)

Time: Up to 90 days after last dose of study treatment (Up to approximately 42 months)

Description: The number of participants who discontinue study treatment due to an AE will be presented.

Measure: Study Treatment Discontinuations Due to AEs

Time: Up to approximately 39 months

Description: The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. For Quality of Life, participants are asked "How would you rate your overall quality of life during the past week?" Individual responses are given on a 7-point scale (1=Very poor; 7=Excellent), with a higher score indicating a better outcome. The change from baseline in EORTC-QLQ-C30 score for Quality of Life will be presented.

Measure: Change from Baseline in EORTC-QLQ-C30 Quality of Life (Item 30) Scale Score

Time: Baseline and Week 12, Week 27

79 An Observational, Multi-centre Study on EGFR T790M Mutation Testing Practices and Outcomes Conducted Among Locally Advanced/Metastatic NSCLC Patients Who Progressed on Previous EGFR Tyrosine-kinase Inhibitor (TKI) Therapy in Hong Kong

To describe the T790M mutation status of patients with locally advanced/metastatic NSCLC who progressed on previous EGFR TKI treatment in a real-world setting.

NCT03519958 Non-small Cell Lung Cancer Diagnostic Test: Plasma-tissue testing
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

Inclusion Criteria - Provision of written informed consent - Locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy - Confirmed EGFR sensitizing mutation (exon 19 deletion or exon 21 L858R ) in medical record - Progressed on previous EGFR TKI treatment, based on physician judgement, with or without additional lines of treatment - Suggested to undergo T790M mutation testing by treating physician, based on physician judgement Exclusion Criteria - Had been treated with osimertinib or any other 3rd generation T790M inhibitors - Enrollment in studies that prohibit participation in this observational study Inclusion Criteria - Provision of written informed consent - Locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy - Confirmed EGFR sensitizing mutation (exon 19 deletion or exon 21 L858R ) in medical record - Progressed on previous EGFR TKI treatment, based on physician judgement, with or without additional lines of treatment - Suggested to undergo T790M mutation testing by treating physician, based on physician judgement Exclusion Criteria - Had been treated with osimertinib or any other 3rd generation T790M inhibitors - Enrollment in studies that prohibit participation in this observational study Non-small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung This is a multi-center, observational study of patients with locally advanced/metastatic NSCLC who progressed on previous EGFR TKI treatment. --- L858R ---

Inclusion Criteria - Provision of written informed consent - Locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy - Confirmed EGFR sensitizing mutation (exon 19 deletion or exon 21 L858R ) in medical record - Progressed on previous EGFR TKI treatment, based on physician judgement, with or without additional lines of treatment - Suggested to undergo T790M mutation testing by treating physician, based on physician judgement Exclusion Criteria - Had been treated with osimertinib or any other 3rd generation T790M inhibitors - Enrollment in studies that prohibit participation in this observational study Inclusion Criteria - Provision of written informed consent - Locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy - Confirmed EGFR sensitizing mutation (exon 19 deletion or exon 21 L858R ) in medical record - Progressed on previous EGFR TKI treatment, based on physician judgement, with or without additional lines of treatment - Suggested to undergo T790M mutation testing by treating physician, based on physician judgement Exclusion Criteria - Had been treated with osimertinib or any other 3rd generation T790M inhibitors - Enrollment in studies that prohibit participation in this observational study Non-small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung This is a multi-center, observational study of patients with locally advanced/metastatic NSCLC who progressed on previous EGFR TKI treatment. --- L858R --- --- T790M --- --- T790M --- --- L858R ---

Primary Outcomes

Description: Based on the plasma-tissue testing algorithm in NSCLC patients who progressed on previous EGFR TKI therapy

Measure: EGFR T790M mutation prevalance

Time: 3 years

Secondary Outcomes

Description: Proportion of study subjects who have a valid tissue/cytology T790M testing result after receiving a negative plasma test result for the T790M mutation

Measure: Proportion of Valid Tissue T790M Testing Result

Time: 3 years

Description: Proportions of study subjects who are T790M plasma-negative

Measure: T790M Plasma Outcome

Time: 3 years

Description: Proportion of study subjects who are T790M plasma-negative but T790M tissue/cytology-positive

Measure: False Negative Proportation

Time: 3 years

Description: reasons given for not performing re-biopsy and tissue/cytology testing after obtaining a negative plasma test result

Measure: Reasons for not performing re-biopsy

Time: 3 years

Description: Demographics of T790M-positive subjects and T790M-negative subjects

Measure: Demographics

Time: Baseline

Description: Disease characteristics of T790M-positive subjects and T790M-negative subjects

Measure: Disease Characteristics

Time: 3 years

Description: Number of particapants with complications assoicated with tissue/cytology re-biopsy

Measure: Number of particapants with complications assoicated with re-biopsy

Time: 3 years

Description: Clinical outcomes after osimertinib treatment between study subjects who are T790M plasma-positive

Measure: Clinical Outcomes in T790M plasma-positive subejects

Time: 3 years

Description: Clinical outcomes after osimertinib treatment between study subjects who are urine-positive

Measure: Clinical Outcomes in urine-positive

Time: 3 years

Description: Clinical outcomes after osimertinib treatment between study subjects who are tissue/cytology-positive

Measure: Clinical Outcomes in tissue/cytology-positive

Time: 3 years

Other Outcomes

Description: To analyze the concordance of T790M mutation status as determined by urine, plasma, and tissue/cytology T790M testing

Measure: Concordance

Time: 3 years

80 A Phase I Dose-Escalation Study of Erlotinib in Combination With Pralatrexate in Subjects With Advanced Cancer

The goal of this clinical research study is to find the highest tolerable dose of the combination of erlotinib and pralatrexate that can be given to patients with advanced cancer. The safety of the drug combination will also be studied. Pralatrexate is designed to block the body's ability to make folic acid, a protein that may help cancer tissue to develop and spread. Erlotinib hydrochloride is designed to block proteins that are thought to cause cancer cells to grow. Erlotinib may help slow the growth of tumors.

NCT01532011 Advanced Cancers Solid Tumors Drug: Erlotinib Drug: Pralatrexate
MeSH: Neoplasms
HPO: Neoplasm

For the MTD expansion cohort, patients will be eligible if they meet one of the following criteria: I. Have an epidermal growth factor receptor (EGFR)-sensitive mutation (as G719C in exon 18, E746-A750 in exon 90, L858R in exon 21) and have been previously treated with EGFR inhibitor therapy but have subsequently developed resistance, OR II. --- G719C --- --- L858R ---

Primary Outcomes

Description: MTD defined by dose limiting toxicities (DLTs) that occur in the first cycle. DLT defined as any Grade 3 or 4 non-hematologic toxicity as defined in the NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0. Grade 4 hematologic toxicity lasting 2 weeks or longer despite supportive care. Grade 4 nausea or vomiting > 5 days despite maximum anti-nausea regimens, and any other Grade 3 non-hematologic toxicity, including symptoms/signs of vascular leak or cytokine release syndrome; or any severe or life-threatening complication or abnormality not defined in NCI-CTCAE as attributable to therapy.

Measure: Maximum Tolerated Dose (MTD) of Erlotinib with Pralatrexate

Time: 8 weeks

Secondary Outcomes

Description: Tumor response defined as one or more of the following: (1) stable disease for more than or equal to 4 months, (2) decrease in measurable tumor (sentinel lesions) by more than or equal to 20% by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, (3) decrease in tumor markers by more than or equal to 25% (for example, a >/= 25% decrease in CA125 for patients with ovarian cancer), or (4) a partial response according to the Choi criteria, i.e. decrease in size by 10% or more, or a decrease in tumor density, as measured in Hounsfield units (HU), by more than or equal to 15% (28).

Measure: Tumor Response

Time: 8 weeks

81 A Randomized Phase II Trial of Erlotinib Alone or in Combination With Bevacizumab in Patients With Non-Small Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations

This randomized phase II trial studies how well erlotinib hydrochloride (Tarceva) with or without bevacizumab (Avastin) works in treating patients with stage IV non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, may block tumor growth in different ways by targeting certain cells. Bevacizumab may also stop the growth of NSCLC by blocking the growth of new blood vessels necessary for tumor growth. It is not yet known whether erlotinib hydrochloride is more effective when given alone or with bevacizumab in treating patients with NSCLC.

NCT01532089 EGFR Activating Mutation EGFR Exon 19 Deletion Mutation EGFR NP_005219.2:p.L858R Non-Squamous Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer AJCC v7 Biological: Bevacizumab Drug: Erlotinib Hydrochloride Other: Laboratory Biomarker Analysis
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Tested using Fisher's exact test and multivariately using a logistic regression model with performance status, gender and genetic mutation type and other significant prognostic factors.. Progression free survival of patients with different mutation types (exon deletion 19 versus exon 21 L858R). --- L858R ---

Evaluated using time-dependent receiver operating characteristic curve and area under curve.. Inclusion Criteria: - Histologic documentation of primary lung carcinoma, non-squamous histology with activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R mutation); Note: EGFR mutation testing must be performed at a Clinical Laboratory Improvement Amendments (CLIA) certified lab; either institutional or through a commercial laboratory (e.g. --- L858R ---

Genzyme, Response Genetics, etc); the laboratory report from the commercial laboratories report the specific mutations detected, and the method of detecting the exon 19 and exon 21 L858R point mutations must be available - Stage IV disease according to the 7th Edition of the American Joint Committee on Cancer staging system - Measurable disease - Life expectancy of >= 12 months - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 - Absolute neutrophil count (ANC) >= 1,500/mm^3 obtained =< 14 days prior to randomization - Platelet count >= 100,000/mm^3 obtained =< 14 days prior to randomization - Hemoglobin >= 9.0 g/dL obtained =< 14 days prior to randomization - Total bilirubin =< 1.5 x upper limit of normal (ULN) obtained =< 14 days prior to randomization - Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x ULN in patients without liver or bone metastases; < 5 x ULN in patients with liver or bone metastases obtained =< 14 days prior to randomization - Cockcroft-Gault calculated creatinine clearance of >= 45 ml/min or creatinine =< 1.5 x ULN obtained =< 14 days prior to randomization - Urine dipstick proteinuria < 2+ or urine protein/creatinine (UPC) ratio =< 1.0 obtained =< 14 days prior to randomization - Note: patients discovered to have >= 2 + proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate =< 1 g of protein in 24 hours - Negative pregnancy test done =< 7 days prior to randomization, for women of childbearing potential only - Provide informed written consent - Willing to return to Academic and Community Cancer Research United (ACCRU) enrolling institution for follow-up - Willing to provide tissue and blood samples for correlative research purposes Exclusion Criteria: - Mixed, non-small cell and small cell tumors or mixed adenosquamous carcinomas with a predominant squamous component - Prior chemotherapy or treatment for metastatic non-small cell lung cancer - Any of the following: - Pregnant women - Nursing women - Men or women of childbearing potential who are unwilling to employ adequate contraception - Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens - Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive, per medical doctor (MD) discretion - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations, or any other medical condition that would limit compliance with study requirements - Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm - Other active malignancy =< 3 years prior to randomization; EXCEPTIONS: non melanotic skin cancer or carcinoma-in-situ of the cervix; Note: if there is a history of prior malignancy, they must not be receiving other specific treatment (i.e. --- L858R ---

aortic aneurysm surgical repair or recent peripheral arterial thrombosis) =< 6 months prior to randomization - Radiotherapy to any site for any reason =< 14 days prior to randomization - Receiving any medications or substances that are strong or moderate inhibitors of CYP3A4; use of the following strong or moderate inhibitors are prohibited =< 7 days prior to randomization: - Strong inhibitors of CYP3A4: indinavir (Crixivan), nelfinavir (Viracept), atazanavir (Reyataz), ritonavir (Norvir), clarithromycin (Biaxin, Biaxin XL), itraconazole (Sporanox), ketoconazole (Nizoral), nefazodone (Serzone), saquinavir (Fortovase, Invirase), telithromycin (Ketek) - Moderate inhibitors of CYP3A4: aprepitant (Emend), erythromycin (Erythrocin, E.E.S, Ery-Tab, Eryc, EryPed, PCE, fluconazole (Diflucan), grapefruit juice, verapamil (Calan, Calan SR, Covera-HS, Isoptin SR, Verelan, Verelan PM), diltiazem (Cardizem, Cardizem CD, Cardizem LA, Cardizem SR, Cartia XT, Dilacor XR, Diltia XT, Taztia XT, Tiazac) - Receiving any medications or substances that are strong or moderate inducers of CYP3A4; use of the following inducers are prohibited =< 7 days prior to randomization: efavirenz (Sustiva), nevirapine (Viramune), carbamazepine (Carbatrol, Epitol, Equetro, Tegretol, Tegretol-XR), modafinil (Provigil), phenobarbital (Luminal), phenytoin (Dilantin, Phenytek), pioglitazone (Actos), rifabutin (Mycobutin), rifampin (Rifadin), St. John?s wort Inclusion Criteria: - Histologic documentation of primary lung carcinoma, non-squamous histology with activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R mutation); Note: EGFR mutation testing must be performed at a Clinical Laboratory Improvement Amendments (CLIA) certified lab; either institutional or through a commercial laboratory (e.g. --- L858R ---

To investigate the progression-free survival in patients with exon deletion 19 or exon 21 L858R point mutations. --- L858R ---

Primary Outcomes

Description: Described graphically using the Kaplan and Meier product limit estimator. Comparisons of PFS between arms will be conducted using a stratified log rank test. Cox proportional hazards model will be used to estimate the adjusted hazard ratios and their 95% confidence intervals. Hazard ratio for treatment effect will be estimated for each subgroup of patients that has significant interaction with treatment. The robustness of treatment effects in different patient subgroups will examined in Forest plots.

Measure: Progression free survival (PFS)

Time: Time from randomization to disease progression and death of any cause, whichever comes first, assessed up to 6 years

Secondary Outcomes

Description: Described graphically using the Kaplan and Meier product limit estimator. Comparisons between arms will be conducted using a stratified log rank test. Cox proportional hazards model will be used to estimate the adjusted hazard ratios and their 95% confidence intervals. Hazard ratio for treatment effect will be estimated for each subgroup of patients that has significant interaction with treatment. The robustness of treatment effects in different patient subgroups will examined in Forest plots.

Measure: Overall survival

Time: Time from randomization to death of any causes, assessed up to 6 years

Description: 95% confidence intervals will be estimated. Tested using Fisher's exact test and multivariately using a logistic regression model with performance status, gender and genetic mutation type and other significant prognostic factors.

Measure: Response rate (complete or partial) to each treatment, evaluated using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors guidelines (version 1.1)

Time: Up to 6 years

Description: Tested using Cox proportional hazard model after adjusting for treatment effect. The robustness of treatment effect in different subgroups will be examined in a Forest plot.

Measure: Progression free survival of patients with different mutation types (exon deletion 19 versus exon 21 L858R)

Time: From the date of randomization to the date of disease progression or death of any cause, whichever comes first, assessed up to 6 years

Description: Types and the frequency of treatment-related adverse events will be tabulated for erlotinib hydrochloride.

Measure: Incidence of treatment-related adverse events for erlotinib hydrochloride, tabulated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Time: Up to 42 days after treatment discontinuation

Description: Types and the frequency of treatment-related adverse events will be tabulated for bevacizumab and erlotinib hydrochloride.

Measure: Incidence of treatment-related adverse events for bevacizumab and erlotinib hydrochloride, tabulated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Time: Up to 42 days after treatment discontinuation

Description: Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.

Measure: EGFR mutations detected in plasma deoxyribonucleic acid (DNA)

Time: Up to 6 years

Description: Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.

Measure: EGFR mutations detected in tumor deoxyribonucleic acid (DNA)

Time: Up to 6 years

Description: Tested using Cox proportional hazard model after adjusting for treatment effect. The robustness of treatment effect in different subgroups will be examined in a Forest plot.

Measure: Prevalence of EGFR T790M resistance mutations from pretreatment tumor biopsies using more sensitive mutation detection methods

Time: Baseline

Description: Detected from pre-treatment tumor specimen using allele specific quantitative polymerase chain reaction (PCR). The PFS of patients with EGFR T790M mutations will be estimated and the survival difference will be tested using Cox proportional hazard model after adjusting for treatment effect. The robustness of treatment effect in different subgroups will be examined in a Forest plot.

Measure: EGFR T790M mutations

Time: Up to 6 years

Description: Evaluated using time-dependent receiver operating characteristic curve and area under curve.

Measure: Predictive value of plasma VEGF-A levels on progression free survival in patients treated with erlotinib hydrochloride alone or in combination with bevacizumab

Time: Baseline

82 A Phase I, Open-Label, Non-Randomised, Multicentre Study to Assess the Effect of Rifampicin (a CYP3A4 Inducer) on the Pharmacokinetics of AZD9291 in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent. Part A will assess the effect of rifampicin on the pharmacokinetic (PK) parameters of AZD9291 and metabolites AZ5104 and AZ7550 following multiple oral dosing of both rifampicin and AZD9291 in a fasted state. Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients who complete Part A will be able to enter part B, and continue to receive AZD9291 80 mg once daily until: disease progression; they are no longer deriving clinical benefit; or any other reason.

NCT02197247 Non Small Cell Lung Cancer Procedure: Pharmacokinetic sampling - AZD9291 Drug: Rifampicin Drug: AZD9291 tablet dosing Procedure: Pharmacokinetic sampling - rifampicin Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks (Appendix G). 6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening. --- L858R ---

Primary Outcomes

Description: Rate and extent of absorption of AZD9291 by assessment of maximum plasma concentration at steady state (Css,max). AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).

Measure: Assessment of Maximum Plasma Concentration for AZD9291 After Dosing Alone and in Combination With Rifampicin (Css,Max)

Time: Samples collected on Day 28 following AZD9291 alone and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).

Measure: Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval for AZD9291 After Dosing Alone and in Combination With Rifampicin (AUCtau)

Time: Samples collected on Day 28 following AZD9291 alone and Day 49 following AZD9291 and rifampicin at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Secondary Outcomes

Description: Rate and extent of absorption of AZD9291 by assessment of Css,max. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).

Measure: Assessment of Css,Max for AZD9291 Before and After Rifampicin

Time: Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZ5104 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of Css,Max for AZ5104 (Metabolite)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZ7550 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of Css,Max for AZ7550 (Metabolite)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of Css,max. AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of Css,Max for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).

Measure: Assessment of AUCtau for AZD9291 Before and After Rifampicin

Time: Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZ5104 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of AUCtau for AZ5104 (Metabolite)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZ7550 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of AUCtau for AZ7550 (Metabolite)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of AUCtau. AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of AUCtau for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of time to reach maximum plasma concentration at steady state (tss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of tss,max. AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of Tss,Max for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of Css,Min for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of the apparent plasma clearance following oral administration and multiple dosing (CLss/F). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of CLss/F for AZD9291

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of CLss/F. AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of CLss/F for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for Css,max (MRCss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for AUCtau (MRAUCtau). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

83 Randomized Study of Erlotinib vs Observation in Patients With Completely Resected Epidermal Growth Factor Receptor (EGFR) Mutant Non-Small Cell Lung Cancer (NSCLC)

This phase III ALCHEMIST trial studies how well erlotinib hydrochloride compared to observation works in treating patients with stage IB-IIIA non-small cell lung cancer that has been completely removed by surgery. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02193282 ALK Gene Rearrangement EGFR Exon 19 Deletion Mutation EGFR NP_005219.2:p.L858R Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Other: Clinical Observation Drug: Erlotinib Hydrochloride Other: Laboratory Biomarker Analysis Other: Placebo
MeSH: Carcinoma Carcinoma, Non-Small-Cell Lung
HPO: Carcinoma Non-small cell lung carcinoma

Analysis of the overall adverse event rates, as well as specific events of interest will involve chi-square tests or Fisher's exact tests.. Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN ALK Gene Rearrangement EGFR Exon 19 Deletion Mutation EGFR NP_005219.2:p.L858R Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To assess whether adjuvant therapy with erlotinib (erlotinib hydrochloride) will result in improved overall survival (OS) over observation for patients with completely resected stage IB (>= 4 cm)-IIIA epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) (confirmed centrally) following complete resection and standard post-operative therapy. --- L858R ---

Analysis of the overall adverse event rates, as well as specific events of interest will involve chi-square tests or Fisher's exact tests.. Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN ALK Gene Rearrangement EGFR Exon 19 Deletion Mutation EGFR NP_005219.2:p.L858R Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To assess whether adjuvant therapy with erlotinib (erlotinib hydrochloride) will result in improved overall survival (OS) over observation for patients with completely resected stage IB (>= 4 cm)-IIIA epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) (confirmed centrally) following complete resection and standard post-operative therapy. --- L858R --- --- T790M --- --- L858R ---

Primary Outcomes

Description: Estimated using the method of Kaplan-Meier survival curves and a 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare OS between the two arms. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess whether the distribution of OS times differ with respect to treatment regimen after having adjusted for the stratification factors as well as other potential prognostic and treatment covariates.

Measure: Overall survival (OS)

Time: The time from randomization until death, assessed up to 10 years

Secondary Outcomes

Description: DFS will be defined as the proportion of patients alive and disease free at 2 years from the date of randomization. Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Disease free survival (DFS) rate

Time: Time from randomization until documented disease-recurrence or death, whichever occurs first, assessed at 2 years

Description: Will be defined as the proportion of patients alive at 5 years from date of randomization. Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Overall survival (OS) rate at 5 years

Time: At 5 years

Description: Will be defined as the proportion of patients alive at 10 years from date of randomization. Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test [accounting for all the stratification factors] will be used to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Overall survival (OS) rate at 10 years

Time: At 10 years

Description: Estimated using the method of Kaplan-Meier survival curves (21). A 1-sided stratified log rank test [accounting for all the stratification factors] will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Overall disease free survival (DFS) between the erlotinib hydrochloride and observation arms

Time: Time from randomization until documented disease-recurrence or death, whichever occurs first, assessed up to 10 years

Description: The maximum grade for each type of adverse event will be recorded for each patient and frequency tables will be reviewed to determine the overall patterns. The number and severity of grade 3 + adverse events will be tabulated and summarized. All adverse events analysis will entail comparisons between the arms within Arms A and B, respectively. Analysis of the overall adverse event rates, as well as specific events of interest will involve chi-square tests or Fisher's exact tests.

Measure: Incidence of adverse events associated with each treatment arm

Time: Up to 10 years

84 A Phase I, Open-Label, Non-Randomised, Multicentre Study to Assess the Effect of AZD9291 on the Pharmacokinetics of Simvastatin (a Sensitive CYP3A4 Substrate) in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent. Part A will assess the effect of AZD9291 on the pharmacokinetic (PK) parameters of simvastatin and simvastatin acid, following multiple oral dosing of AZD9291 in a fasted state. Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients from Part A who completed treatment may continue to receive AZD9291 80 mg once daily until: disease progression; they are no longer deriving clinical benefit; or any other reason.

NCT02197234 Non Small Cell Lung Cancer Procedure: Pharmacokinetic sampling - AZD9291 Drug: Simvastatin Drug: AZD9291 tablet dosing Procedure: Pharmacokinetic sampling - simvastatin Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks (Appendix G). 6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening. --- L858R ---

Primary Outcomes

Description: Pharmacokinetics of simvastatin by assessment of maximum plasma simvastatin concentration

Measure: Cmax of Simvastatin

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Pharmacokinetics of simvastatin by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of Simvastatin

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Secondary Outcomes

Description: Pharmacokinetics of simvastatin and simvastatin acid by time to Cmax

Measure: Tmax of Simvastatin and Simvastatin Acid

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Rate and extent of absorption of simvastatin by assessment of apparent clearance following oral administration

Measure: CL/F of Simvastatin

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Pharmacokinetics of simvastatin acid by assessment of maximum plasma simvastatin acid concentration

Measure: Cmax of Simvastatin Acid

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Pharmacokinetics of simvastatin acid by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of Simvastatin Acid

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Pharmacokinetics of simvastatin and simvastatin acid by assessment of area under the plasma concentration time curve from time zero to last quantifiable dose

Measure: AUC(0-t) of Simvastatin and Simvastatin Acid

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

85 A Phase Ib Open-label Clinical Trial of Once Daily Oral Treatment of Afatinib Plus Weekly Intravenous Infusion of Xentuzumab (BI 836845) in Patients With EGFR Mutant Non-small Cell Lung Cancer With Progression Following Prior EGFR Tyrosine Kinase Inhibitors

Part A: To determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of Xentuzumab (BI 836845) in combination with afatinib in patients with non-small cell lung cancer with progression following prior treatment (EGFR TKI or platinum-based chemotherapy). Part B: To evaluate the early anti-tumour activity of Xentuzumab (BI 836845) in combination with afatinib in patients with EGFR mutant non-small cell lung cancer with progression following prior irreversible EGFR TKIs. Part A and B: To evaluate the safety and pharmacokinetics of BI 836845 in combination with afatinib in patients with non-small cell lung cancer

NCT02191891 Carcinoma, Non-Small-Cell Lung Drug: BI 836845 Drug: afatinib
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

Inclusion criteria: - Aged 18 years or older - Pathologically confirmed of advanced and/or metastatic stage IIIb/IV non-small cell carcinoma of lung - Activating EGFR mutation (exon 19 deletion, L858R, G719X, L861X) - Presence of EGFR activating mutation and absence of EGFR T790M in the tumour associated with the latest disease progression. --- L858R ---

AZD9291 or CO-1686) Inclusion criteria: - Aged 18 years or older - Pathologically confirmed of advanced and/or metastatic stage IIIb/IV non-small cell carcinoma of lung - Activating EGFR mutation (exon 19 deletion, L858R, G719X, L861X) - Presence of EGFR activating mutation and absence of EGFR T790M in the tumour associated with the latest disease progression. --- L858R ---

Primary Outcomes

Measure: Maximum tolerated dose (MTD) of BI 836845 in combination with afatinib - part A

Time: up to 12 months

Measure: Dose limiting toxicity (DLT) during the first treatment course - part A

Time: up to 28 days

Measure: Objective response (OR), defined as complete response (CR) or partial response (PR)

Time: up to 12 months

Secondary Outcomes

Measure: Disease control (DC), defined as complete response (CR), partial response (PR) or stable disease (SD)

Time: up to 12 months

Measure: Time to objective response, defined as the duration of time from the date of first treatment administration until objective response

Time: up to 12 months

Measure: Duration of objective response, defined as the duration of time from first objective response to the date of first objective tumour progression or death due to any cause

Time: up to 12 months

86 Phase I and II Study of ASP8273 — An Open-label Study of the Oral Administration of ASP8273 in Patients With Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor (EGFR) Mutations —

Purpose of the study is to determine the following in patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. - the safety and tolerability of ASP8273. - the pharmacokinetics (PK) of ASP8273. - the antitumor activity of ASP8273.

NCT02192697 Non-small Cell Lung Cancer Drug: ASP8273
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

- Patients confirmed to have the del ex19, L858R, G719X, or L861Q mutation among the EGFR activating mutations (patients at the study site who are documented to have any of the above-stated EGFR activating mutations can be enrolled in the study). --- L858R ---

Primary Outcomes

Description: A DLT is defined as any pre-determined toxicity that is related to study drug per the investigator and which occurs during Cycle 0 and Cycle 1 using the Japan Clinical Oncology Group (JCOG) Japanese translation of the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE ver 4.0 - JCOG)

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by Dose Limiting Toxicities (DLTs)

Time: Up to Day 23

Description: The overall response rate, which is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated

Measure: Phase II: Overall response rate (CR+PR) at Week 24

Time: Week 24

Secondary Outcomes

Description: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by adverse events (AEs)

Time: Up to 18 months

Description: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by laboratory tests

Time: Up to 18 months

Description: Vital signs to be measured includes blood pressure, pulse rate and temperature

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by vital signs

Time: Up to 18 months

Description: including the assessment of QT intervals

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by 12-lead ECG

Time: Up to 18 months

Measure: Phase I: Plasma concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Measure: Phase I: Urine concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Description: The overall response rate is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated

Measure: Phase I: Overall response rate (CR+PR)

Time: Up to 18 months

Description: The disease control rate is defined as the proportion of subjects whose best overall response is rated as CR, PR, or stable disease (SD) according to RECIST Version 1.1, will be calculated.

Measure: Phase I: Disease control rate (CR+PR+SD)

Time: Up to 18 months

Measure: Phase II: Plasma concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Measure: Phase II: Urine concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Description: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by adverse events (AEs)

Time: Up to 18 months

Description: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by laboratory tests

Time: Up to 18 months

Description: Vital signs to be measured includes blood pressure, pulse rate and temperature

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by vital signs

Time: Up to 18 months

Description: including the assessment of QT intervals

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by 12-lead ECG

Time: Up to 18 months

Description: The disease control rate is defined as the proportion of subjects whose best overall response is rated as CR, PR, or stable disease (SD) according to RECIST Version 1.1, will be calculated.

Measure: Phase II: Disease control rate

Time: Up to 18 months

Measure: Phase II: Progression-free survival (PFS)

Time: Up to 18 months

Measure: Phase II: Overall survival (OS)

Time: Up to 18 months

Description: The overall response rate, which is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated

Measure: Phase II: Overall response rate (CR+PR)

Time: Up to 18 months

87 A Phase I, Open-Label, Non-Randomised, Multicentre Study to Assess the Effect of AZD9291 on the Pharmacokinetics of Rosuvastatin (a Sensitive BCRP Substrate) in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent. Part A will assess the effect of AZD9291 on the pharmacokinetic (PK) parameters of rosuvastatin, following multiple oral dosing of AZD9291 in the fasted state. Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients from Part A who completed treatment may continue to receive AZD9291 80 mg once daily as a single agent until: disease progression; they are no longer deriving clinical benefit; or any other reason.

NCT02317016 Non Small Cell Lung Cancer Procedure: Pharmacokinetic sampling - AZD9291 Drug: AZD9291 tablet dosing Drug: Rosuvastatin Procedure: Pharmacokinetic sampling - rosuvastatin Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 with no deterioration over the previous 2 weeks (Appendix G). 6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening. --- L858R ---

Primary Outcomes

Description: Rate and extent of absorption of rosuvastatin by assessment of Cmax. Single rosuvastatin doses were first without, then with AZD9291 (Day 1 [Period 1] and Day 32 [Period 3], respectively).

Measure: Assessment of Maximum Plasma Concentration (Cmax) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of AUC from time zero extrapolated to infinity. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of AUC From Time Zero Extrapolated to Infinity for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Secondary Outcomes

Description: Rate and extent of absorption of rosuvastatin by assessment of tmax. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Time to Maximum Plasma Concentration (Tmax) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of AUC0-t. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration at Time "t" (AUC0-t) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of CL/F. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Apparent Plasma Clearance (CL/F) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of Vz/F. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Apparent Volume of Distribution (Vz/F) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of t1/2(lambda_z). Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Terminal Elimination Half-life (t1/2[lambda_z]) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of AUCtau. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval (AUCtau) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of Css,max after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Maximum Plasma Concentration at Steady State (Css,Max) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of tss,max after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Time to Reach Maximum Plasma Concentration at Steady State (Tss,Max) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of Css,min over the dosing interval. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Minimum Plasma Concentration at Steady State (Css,Min) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption for AZD9291 by assessment of CLss/F after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Apparent Plasma Clearance at Steady State (CLss/F) for AZD9291 Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Assessment of MRCss,max for AZ5104 and AZ7550 (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of the Metabolite to Parent Ratios of Css,Max (MRCss,Max) for AZ5104 and AZ7550 Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Assessment of MRAUCtau for AZ5104 and AZ7550 (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of the Metabolite to Parent Ratios of AUCtau (MRAUCtau) for AZ5104 and AZ7550 Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

88 A Phase 2, Multicenter, Randomized, Double-blind Study of Ficlatuzumab Plus Erlotinib Versus Placebo Plus Erlotinib in Subjects Who Have Previously Untreated Metastatic, EGFR-mutated Non-small Cell Lung Cancer (NSCLC) and BDX004 Positive Label

Phase 2 multicenter, controlled, randomized, double-blind study to evaluate the efficacy and safety of ficlatuzumab versus placebo when administered with erlotinib in subjects with previously untreated metastatic EGFR-mutated NSCLC and BDX004 Positive Label.

NCT02318368 Non-small Cell Lung Cancer Drug: Ficlatuzumab Drug: Erlotinib Drug: placebo
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

- An EGFR exon 19 deletion and/or an exon 21 (L858R) substitution mutation. --- L858R ---

Primary Outcomes

Measure: Progression Free Survival is defined as the time from the date of randomization to the date of the first objective documentation of radiographic disease progression or death due to any cause, whichever occurs first.

Time: Approximately 24 months

Secondary Outcomes

Measure: Overall Survival as measured from the date of randomization to the date of death.

Time: Approximately 48 months

Measure: Objective response rate is defined as a CR or PR according to RECIST v.1.1 recorded from randomization until disease progression or death due to any cause.

Time: Approximately 24 months

Measure: Disease control rate is defined as CR, PR, or SD at least 4 cycles (16 weeks) according to the RECIST v.1.1 recorded in the time period between randomization and disease progression or death to any cause.

Time: Approximately 24 months

Measure: Safety and tolerability, as defined by number of AEs.

Time: Approximately 24 months

Measure: PK parameters of ficlatuzumab and erlotinib will be calculated from serum and plasma levels in the blood over time.

Time: Cycle 1 day 1 & day 15, Cycle 2 day 1 & day 15, Cycle 3 day 1 & day 15, Cycle 4 day 1 & day 15, Cycle 5 day 1, Cycle 7 day 1, Cycle 9 day 1, Cycle 11 day 1

89 A Phase 2, Open-Label, Multi-Center Study to Assess Safety and Efficacy of Second/Third-Line Treatment With NAB®-Paclitaxel (ABI-007) In Combination With Epigenetic Modifying Therapy Of CC-486, Or Immunotherapy of Durvalumab (MEDI4736), Or As Monotherapy In Subjects With Advanced Non-Small Cell Lung Cancer (NSCLC): Abound.2L+

This is a Phase 2, open-label, multicenter study to assess the efficacy and safety of second/third-line treatment with nab-paclitaxel in combination with the epigenetic modifying therapy of CC-486 or immunotherapy of durvalumab, and nab-paclitaxel monotherapy in subjects with advanced non-small cell lung cancer (NSCLC).

NCT02250326 Carcinoma, Non-Small-Cell Lung Drug: nab-paclitaxel IV Drug: CC-486 Drug: Duravalumab
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

4. Known activating EGFR mutations (such as exon 19 deletions or L858R). 5. Known activating EML4-ALK mutations. --- L858R ---

Primary Outcomes

Description: Progression-free survival was defined as the time in months from the date of randomization/assignment to the date of disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria documented by computed tomography (CT) scan, not including symptomatic deterioration, or death (any cause) on or prior to the clinical cut-off date, which ever occurred earlier. Participants who did not have disease progression and had not died, regardless of whether they were discontinued from treatment, were censored at the date of last tumor assessment, on or prior to the clinical cut-off date that the participant was progression free. Progressive Disease was defined as at least a 20% increase in the sum of diameters of target lesions from nadir.

Measure: Kaplan Meier Estimate of Progression-Free Survival (PFS) as Assessed by the Investigator

Time: From date of first dose of IP to DP; up to data cut-off date of 30 August (Aug) 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 December (Dec) 2017 for Durva + nab-paclitaxel; participants were followed for PFS for up to 18 months

Secondary Outcomes

Description: Disease control rate was defined as the percentage of participants who had a CR, PR or SD during the course of the study, according to RECIST version 1.1 criteria, as evaluated by the investigator. RECIST Version 1.1 criteria is defined as follows: Complete Response is the disappearance of all target lesions; Partial Response is at least a 30% decrease in the sum of diameters of target lesions from baseline; Stable Disease is neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for progressive disease. Responses were evaluated every 6 weeks.

Measure: Percentage of Participants Who Achieved a Complete Response (CR), Partial Response (PR) or Stable Disease (SD) According to RECIST V 1.1 Criteria

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

Description: Overall Response was defined as percentage of participants who achieved a radiologic confirmed complete response or partial response according to RECIST V 1.1 criteria and compared with baseline among all tumor assessments, where baseline was the last CT obtained prior to or on Day 1 of treatment. Per RECIST V 1.1 criteria, a CR is defined as a disappearance of all target lesions; a PR is defined as having at least a 30% decrease in the sum of diameters of target lesions from baseline. Responses were evaluated every 6 weeks.

Measure: Percentage of Participants Who Achieved a Best Overall Response of Complete Response or Partial Response According to RECIST V 1.1 Criteria

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

Description: Overall survival was defined as the time in months between randomization/treatment assignment and death from any cause. Participants who were still alive as of the clinical cut-off date had their OS censored at the date of last contact or clinical cut-off, whichever was earlier. Participants who were lost to follow-up prior to the end of the study or who were withdrawn from the study were censored at the time of last contact.

Measure: Kaplan Meier Estimate of Overall Survival (OS)

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; participants were followed for overall survival up to 30 months

Description: TEAEs were defined as any adverse event or serious adverse event that occurred or worsened on or after the day of the first dose of the IP through 28 days after the last dose of IP for Arms A and C or up to 90 days after the last dose for Arm B, and those SAEs made known to the investigator at any time thereafter that are suspected of being related to IP. A serious AE (SAE) = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 and the scale: Grade 1 = Mild l intervention/therapy required Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life threatening Grade 5 = Death.

Measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Entire Treatment Period

Time: TEAEs were collected up to 4 weeks after receiving last dose of IP for nab-paclitaxel and CC-486 + nab-paclitaxel, and up to 90 days after the last IP dose for Durva + nab-paclitaxel; TEAEs were collected up to 86.1 weeks

Description: The discontinuation rate was defined as the percentage of participants who had study drug discontinued and was assessed throughout the conduct of the study.

Measure: Percentage of Participants Who Discontinued Study Treatment

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

Description: Dose intensity was the cumulative dose divided by the dosing period in weeks.

Measure: Dose Intensity Per Week of Nab-Paclitaxel

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

Description: Dose intensity was the cumulative dose divided by the dosing period in weeks.

Measure: Dose Intensity Per Week of CC-486

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

Description: Dose intensity was the cumulative dose divided by the dosing period in weeks).

Measure: Dose Intensity Per Week of Durvalumab

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

Description: A dose reduction occurred when the dose assigned at a visit was lower than the dose assigned at the previous visit. Dose reductions were typically caused by clinically significant laboratory abnormalities and/or TEAEs or toxicities.

Measure: Percentage of Participants With Study Drug Dose Reductions

Time: Up to 16 Jan 2017 for CC-486 + nab-paclitaxel and up to 23 Dec 2017 for nab-paclitaxel and Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

90 A Pilot Study Testing the Detection of Oncogenic Tumor Mutations in the Urine and Blood of Lung and Colorectal Cancer Patients

The purpose of this study is to see whether gene mutations can be found in the urine or blood of lung cancer patients and urine of colorectal cancer patients. Gene mutations are when DNA in a gene is damaged in a way that changes the genetic message carried by that gene. Gene mutations can sometimes cause lung cancers. These gene mutations are only found in lung and colorectal cancer cells, not the normal cells in your body. All lung cancer tumors and colorectal cancer tumors are now tested for different gene mutations as their presence affects lung cancer treatment. Tumor samples obtained from a biopsy or surgery are typically tested for these gene mutations.

NCT02186236 Lung Cancer Colorectal Cancer
MeSH: Colorectal Neoplasms
HPO: Neoplasm of the large intestine

- Patients must have had or intend to have EGFR mutation testing (specifically including exon 19 deletions and L858R) performed on their tumor with results available from a CLIA certified laboratory. --- L858R ---

- Patients must have a confirmed EGFR mutant lung cancer (exon 19 deletions and L858R) with molecular testing results available from a CLIA certified laboratory. --- L858R ---

Primary Outcomes

Description: The Trovagene urine-based assay will test to determine the presence of EGFR mutation in cfDNA or RAS/RAF mutation in colorectal cancer

Measure: EGFR detection in urinary cell free DNA [cfDNA]

Time: 2 years

Description: urine assay to identify EGFR mutations as compared to the gold standard of tumor tissue.

Measure: To validate the Trovagene urine assay

Time: 2 years

Secondary Outcomes

Description: The plasma-based assay will test to determine the presence of EGFR mutation in CTC and in cfDNA.

Measure: EGFR detection in plasma circulating tumor cells [CTC] and plasma cfDNA)

Time: 2 years

91 LUX-Lung 7: A Randomised, Open-label Phase IIb Trial of Afatinib Versus Gefitinib as First-line Treatment of Patients With EGFR Mutation Positive Advanced Adenocarcinoma of the Lung

This is a randomised, open-label, phase IIb trial of afatinib to compare to gefitinib in first-line treatment setting with patients who are having epidermal growth factor receptor mutation positive advanced adenocarcinoma of the lung.

NCT01466660 Lung Neoplasms Drug: Afatinib Drug: gefitinib
MeSH: Adenocarcinoma Lung Neoplasms Adenocarcinoma of Lung
HPO: Neoplasm of the lung

2. Documented activating epidermal growth factor receptor mutation (Del19 and/or L858R) with tumour tissues. --- L858R ---

Primary Outcomes

Description: Progression-free survival (PFS) defined as the time from the date of randomisation to the date of disease progression, or to date of death if a patient died earlier. Disease progression was primarily evaluated by an independent central imaging review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.

Measure: Progression-free Survival

Time: From first drug administration until last drug administration, up to 1293 days

Description: Time to Treatment Failure (TTF) which was the time from the date of randomisation to the date of i.e. permanent treatment discontinuation for any reason.

Measure: Time to Treatment Failure (TTF)

Time: From first drug administration until last drug administration, up to 1293 days

Description: Overall survival (OS) which was defined as the time from the date of randomisation to the date of death.

Measure: Overall Survival

Time: From first drug administration until last drug administration, up to 1482 days

Secondary Outcomes

Description: Objective response rate (ORR) which was defined as the number of participants with complete response (CR) or partial response (PR) as assessed by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. divided by the total number of participants who received treatment. Per RECIST v1.1. for target lesions and assessed by CT-scan or Magnetic Resonance Imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions from baseline; Overall Response (OR) = CR + PR

Measure: Objective Response Rate

Time: From first drug administration until last drug administration, up to 1293 days

Description: Number of participants with objective response over time, cumulative number of participants is displayed. Time to objective response was defined as the time from randomisation to the first recorded objective response.

Measure: Time to Objective Response

Time: From first drug administration until last drug administration, up to 1293 days

Description: Duration of objective response defined as the time of first objective response to the time of progression or death, whichever occurred first (or date of censoring for progression free survival (PFS))

Measure: Duration of Objective Response

Time: From first drug administration until last drug administration, up to 1293 days

Description: Disease control which was defined as objective response (complete response or partial response) or stable disease (SD).

Measure: Disease Control

Time: From first drug administration until last drug administration, up to 1293 days

Description: Duration of disease control was measured from randomisation to the time of progressive disease (PD) or death, whichever occurred first (or date of censoring for progression free survival (PFS))

Measure: Duration of Disease Control

Time: From first drug administration until last drug administration, up to 1293 days

Description: Tumour shrinkage assessed by minimum sum of post-baseline target lesion diameters recorded after randomisation. A positive value shows a decrease in tumour size.

Measure: Tumour Shrinkage

Time: From first drug administration until last drug administration, up to 1293 days

Description: Health-related quality of life (HRQoL) measured using European Quality of life - 5 Dimensions (EQ-5D) score for United Kingdom (UK) and Belgium and European European Quality Visual Analogue Scale (EQ-VAS). EQ-5D utility scores range from 0 (worst health) to 1 (full health). EQ-VAS scores range from 0 (worst imaginable health state) to 100 (best imaginable health state). Results display the mean score up to 56 weeks.

Measure: Health-related Quality of Life

Time: Every 8 weeks, up to 56 weeks

92 Phase I Study of INC280 Plus Erlotinib in Patients With C-Met Expressing Non-Small Cell Lung Cancer

This phase I trial studies the side effects and best dose of c-Met inhibitor INCB028060 and erlotinib hydrochloride when given together in treating patients with previously treated non-small cell lung cancer. C-Met inhibitor INCB028060 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT01911507 Recurrent Non-small Cell Lung Cancer Drug: INC280 Drug: erlotinib hydrochloride
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

G719X, exon 19 deletion, L858R, L861Q) - Systemic progression of disease (Response Evaluation Criteria in Solid Tumors [RECIST] or World Health Organization [WHO]) while on continuous treatment with gefitinib or erlotinib - Patients must have measurable disease; disease in previously irradiated sites is considered measurable if there is clear disease progression following radiation therapy - Failed 1-2 prior chemotherapies for advanced disease; prior erlotinib is allowed in the dose finding phase and expansion cohort A (Patients in expansion cohort B must be erlotinib naïve and have v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog [KRAS] wild type tumor) - Patients must be willing to be off therapy for a minimum of two weeks (In expansion cohort A patients on erlotinib do not have to discontinue treatment) - Eastern Cooperative Oncology Group (ECOG) performance status 0-2 - Life expectancy greater than 3 months - Hemoglobin > 9 g/dL (International System [SI] units: 90 g/L) without transfusion support or growth factors within 10 days of starting INC280 - Platelet count >= 75 x 10^9/L - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L without growth factor support - Total bilirubin =< 2 x upper limit of normal (ULN) - Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and/or alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 2.5 x upper limit of normal (ULN) - Serum creatinine =< 2 x ULN - Serum amylase =< ULN - Serum lipase =< ULN - Fasting serum triglyceride level =< 500 mg/dL Exclusion Criteria: - Patients who have had major surgery within 4 weeks of initiation of study medication, excluding the placement of vascular access - Patients with concurrent uncontrolled medical conditions that may interfere with their participation in the study or potentially affect the interpretation of the study data - Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction =< 6 months prior to first study treatment, serious uncontrolled cardiac arrhythmia - Severely impaired lung function - Active (acute or chronic) or uncontrolled infection - Nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy - Liver disease (i.e. --- L858R ---

Primary Outcomes

Description: The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by nadir or maximum values for the laboratory measures), time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize toxicities and side effects by dose and by course. Baseline information (e.g. the extent of prior therapy) and demographic information will be presented.

Measure: Maximum tolerated dose (MTD) of c-Met inhibitor INCB028060 and erlotinib, determined according to incidence of dose-limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V4

Time: Up to 28 days after a full course of therapy

Secondary Outcomes

Description: The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by nadir or maximum values for the laboratory measures), time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by course. Baseline information (e.g. the extent of prior therapy) and demographic information will be presented.

Measure: Toxicities as measured by NCI CTCAE V4

Time: Up to 30 days

Description: Response rate among patients with measurable disease will be summarized by exact binomial confidence intervals.

Measure: Overall response rate among patients with measurable disease, measured by RECIST 1.1

Time: Up to 30 days

Measure: Disease control rate, measured by RECIST 1.1

Time: Up to 30 days

Description: Summarized with Kaplan-Meier plots. Median time to progression will be estimated using standard life table methods.

Measure: Progression-free survival

Time: Duration of time from start of treatment to time of progression or death, assessed up to 30 days

Description: Summarized with Kaplan-Meier plots. Median time to progression will be estimated using standard life table methods.

Measure: Overall survival

Time: Duration of time from the start of treatment to death from any cause, assessed up to 30 days

Measure: Concentrations of c-Met inhibitor INCB028060 in plasma, measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay

Time: Days 15-16 of course 1, days 1 and 15 of course 2, and day 1 of courses 3-4

93 A Phase I/II Study to Assess the Safety,Tolerability, Pharmacokinetics and Anti-tumour Activity of ASK120067 in Patients With Locally Advanced or Metastatic T790M Mutation-positive Non-Small Cell Lung Cancer Who Have Progressed Following Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent

ASK120067 Tablets is a Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor which can efficient suppress the EGFR T790M drug-resistant mutation tumor cell in Xenograft mouse model. This study aims at local advanced or metastatic non-small cell lung cancer patients with T790M drug-resistant mutation.

NCT03502850 Locally Advanced or Metastatic NSCLC Drug: ASK120067
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

Inclusion Criteria: - Patients of either gender, aged from 18 years older to 70. - Histologically or cytologically confirmed metastatic, or unresectable locally advanced, recurrent NSCLC - Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including at least one of G719X, exon 19 deletion, L858R, L861Q mutation) - Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI e.g. --- L858R ---

Total bilirubin > 1.5 times ULN if no liver metastases or > 3 times ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases Creatinine >1.5 times ULN concurrent with creatinine clearance < 50 ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN. - History of hypersensitivity to active or inactive excipients of ASK120067 or drugs with a similar chemical structure or class to ASK120067 - Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements Inclusion Criteria: - Patients of either gender, aged from 18 years older to 70. - Histologically or cytologically confirmed metastatic, or unresectable locally advanced, recurrent NSCLC - Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including at least one of G719X, exon 19 deletion, L858R, L861Q mutation) - Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI e.g. --- L858R ---

Primary Outcomes

Description: Evaluation of objective response rate assessed by RECIST 1.1

Measure: Objective response rate

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Secondary Outcomes

Description: Assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram, ophthalmic examinations and NCI CTCAE v4.03

Measure: Incidence and Severity of Treatment-Emergent Adverse Events

Time: Adverse events will be collected from baseline until 28 days after the last dose

Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate progression free survival

Measure: Progression free survival

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Description: Duration of response assessed by RECIST 1.1

Measure: Duration of response

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Description: Evaluation of Disease control rate assessed by RECIST 1.1

Measure: Disease control rate

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Description: difined as the time from date of first dose until date of death due to any cause

Measure: Overall survival

Time: Time from treatment start to the time of death due to any cause or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Description: Collect plasma concentrations of ASK120067 and 1 metabolites following single dose at designated time points of Day 1 to figure out Cmax

Measure: Maximum Plasma Concentration [Cmax] of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out tmax

Measure: Peak Plasma Time [tmax] of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day1 to figure out AUC

Measure: Area under the plasma concentration versus time curve (AUC) of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out terminal rate constant

Measure: Terminal rate constant of single dose single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out clearance

Measure: Clearance of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out half life

Measure: Half life of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of f ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out volume of distribution

Measure: Volume of distribution of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out mean resistance time

Measure: Mean resistance time of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Cmax of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state Cmax of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Tmax of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state tmax of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Cmin of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state Cmin (Minimum Plasma Concentration) of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: AUC of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state AUC of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Clearance of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state clearance of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Accumulation ratio of ASK120067 and 1 metabolite following multiple doses

Measure: Accumulation ratio of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Time dependency of ASK120067 and 1 metabolite following multiple doses

Measure: Time dependency of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

94 A Randomized, Double-blind, Positive-controlled, Multi-center Phase III Clinical Study of Evaluating Alflutinib Mesylate Versus Gefitinib as First-line Therapy in Patients With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) With EGFR-sensitive Mutations(FlAG)

To assess the efficacy and safety of Alflutinib Mesylate versus Gefitinib in patients with locally advanced or Metastatic Non Small Cell Lung Cancer

NCT03787992 Locally Advanced or Metastatic EGFR Sensitising Mutation Positive Non-small Cell Lung Cancer Drug: Alflutinib Mesylate (AST2818) 80mg//40 mg+ placebo Drug: Placebo Gefitinib 250 mg Drug: Gefitinib 250 mg Drug: Placebo AST2818 80mg//40 mg
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R). --- L858R ---

Primary Outcomes

Description: Progression-free survival was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression and was used to assess the efficacy of single agent alflutinib compared with SoC EGFR-TKI therapy as measured by PFS.

Measure: Median Progression Free Survival (PFS) (Months)

Time: At baseline and every 6 weeks for the first 17 months and then every 12 weeks relative to randomisation until progression ( (approximately 12 months)

Secondary Outcomes

Description: Overall survival was defined as the time from the date of randomisation until death from any cause and was used to further assess the efficacy of alflutinib compared with SoC EGFR-TKI therapy

Measure: Overall Survival (OS)- Number of Participants With an Event

Time: From first dose to end of study or date of death from any cause, whichever comes first, assessed every 6 weeks (approximately 29 months)

Description: Progression-free survival was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression and was used to assess the efficacy of single agent alflutinib compared with SoC EGFR-TKI therapy as measured by PFS.

Measure: Progression Free Survival (PFS) evaluated by investigator

Time: At baseline and every 6 weeks for the first 17 months and then every 12 weeks relative to randomisation until progression (approximately 12 months)

Description: ORR was defined as the number (%) of patients with measurable disease with at least 1 visit response of Complete response (CR) or Partial response (PR) and it was used to further assess the efficacy of alflutinib compared with SoC EGFR-TKI therapy

Measure: Objective Response Rate (ORR)

Time: At baseline and every 6 weeks for the first 17 months and then every 12 weeks relative to randomisation until progression (approximately 12 months)

Description: Duration of response was defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression and was used to further assess the efficacy of alflutinib compared with SoC EGFR-TKI therapy.

Measure: Duration of Response (DoR)

Time: At baseline and every 6 weeks for the first 17 months and then every 12 weeks relative to randomisation until progression (approximately 12 months)

Description: The Depth of response was defined as the relative change in the sum of the longest diameters of Response Evaluation Criteria in Solid Tumors (RECIST) Target lesions (TLs) at the nadir, in the absence of new lesions (NLs) or progression of Non-target lesions (NTLs), compared to baseline and was used to further assess the efficacy of alflutinib compared with SoC EGFR-TKI therapy

Measure: Depth of Response

Time: At baseline and every 6 weeks for the first 17 months and then every 12 weeks relative to randomisation until progression (approximately 12 months)

Description: The EORTC QLQ-LC13 was a lung-cancer-specific module comprising 13 questions to assess lung cancer symptoms (cough, haemoptysis, dyspnoea, and site-specific pain [pain in chest, pain in arm or shoulder, and pain in other parts); treatment related side-effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia); and pain medication. Except for a multi-item scale for dyspnoea, all were single items. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items. Higher scores on the global health status/QoL and functioning scales indicated better health status/QoL and better function. Higher scores on the symptoms scales indicated greater symptom burden. The results of the analyses were presented in terms of a least squares mean together with its associated 95% profile likelihood CI

Measure: Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QLQ) Questionnaires Lung Cancer 13 (QLQ-LC13)

Time: Questionnaires completed at week 1, 4, 7, 9, 12, 15 , 18,21,27,33,39,45and51

Description: he EORTC QLQ-C30 cancer-specific questionnaire consisted of 30 questions, which were combined to produce 5 functional scales (Physical, Role, Cognitive, Emotional, Social); 3 symptom scales (Fatigue, Pain, Nausea/Vomiting); 6 individual items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties); and a global measure of health status/QoL. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, the functional scales, and the global health status/QoL scale in the EORTC QLQ-C30. Higher scores on the global health status and functioning scales indicated better health status/function. Higher scores on the symptoms scales indicated greater symptom burden. The results of the analyses were presented in terms of a least squares mean together with its associated 95% profile likelihood CI.

Measure: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items

Time: Questionnaires completed at week 1, 4, 7, 9, 12, 15 , 18,21,27,33,39,45and51

95 ALCMI-012 A Prospective Biospecimen Collection Study From Patients With EGFR Mutant Tumors

A biospecimen collection study from individuals with EGFR mutant cancers resistant to EGFR TKIs or those harboring an Exon 20 insertion mutation.

NCT03872440 Non Small Cell Lung Cancer
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

1. EGFR T790M patients who have progressed on osimertinib or other third generation (mutant selective) EGFR TKI therapy or 2. Patients must have an EGFR exon 19 deletion or L858R and progressed on first line osimertinib or 3. Patients with an exon EGFR or HER2 20 insertion mutation. --- T790M --- --- L858R ---

No confirmed diagnosis of EGFR exon 19 deletion, L858R or EGFR or HER2 exon 20 mutation. --- L858R ---

Patients whose tumors harbor EGFR mutations other than an exon 19 deletion, L858R or exon 20 EGFR insertion or HER2 exon 20 insertions are not eligible. --- L858R ---

There are several types of EGFR mutations including both the common L858R and exon 19 deletions (accounting for 85%) or the rare exon 20 insertion (accounting for 5-8%) EGFR mutations. --- L858R ---

Osimertinib is an EGFR inhibitor approved for patients newly diagnosed with EGFR exon 19 or L858R mutations and for patients who have been treated with a prior EGFR inhibitor but have developed EGFR T790M as a resistance mechanism. --- L858R ---

Primary Outcomes

Description: Successful generation of at least fifty (50) PDX models with full characterization including whole exome sequencing (WES) and RNA sequencing. These PDX models will be used to inform the study of EGFR-driven cancers at large.

Measure: The primary objective is to develop a unique cohort of PDX models from EGFR mutant cancers as a resource to the research community.

Time: 48 months

96 Open Label, Multicenter, Real World Treatment Study of Single Agent Tagrisso; KOREA PLUS Study (Korea Osimertinib Real World Evidence Study to Assess Safety and Efficacy - PLUS)

This is a local, prospective, non-interventional, regulatory postmarketing surveillance study. The objectives of this study are to assess the safety and efficacy of single agent Tagrisso (Osimertinib, hereinafter "the study drug") in a real world setting according to the approved label in Korea.

NCT03918304 Carcinoma, Non-Small-Cell Lung
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

- Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial - Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung - Primary objective: To assess safety of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea - Secondary objective: To assess efficacy of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea --- L858R ---

- Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial - Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung - Primary objective: To assess safety of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea - Secondary objective: To assess efficacy of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea --- L858R --- --- T790M --- --- L858R ---

- Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial - Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung - Primary objective: To assess safety of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea - Secondary objective: To assess efficacy of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea --- L858R --- --- T790M --- --- L858R --- --- T790M --- --- L858R ---

- Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial - Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung - Primary objective: To assess safety of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea - Secondary objective: To assess efficacy of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea --- L858R --- --- T790M --- --- L858R --- --- T790M --- --- L858R --- --- T790M --- --- L858R ---

Primary Outcomes

Measure: Proportion (%) of patients with at least one event of adverse events (AEs), serious adverse events (SAEs) and AEs of special interest (AESI)

Time: for about 1 year since the first dose of the study drug

Measure: Severity of (S)AEs according to CTCAE

Time: for about 1 year since the first dose of the study drug

Secondary Outcomes

Measure: ORR (Objective response rate), if available

Time: for about 1 year since the first dose of the study drug

97 A Phase III, Randomized, Double-blind, Placebo-controlled, Multi-center Clinical Study to Evaluate the Efficacy and Safety of Toripalimab Injection (JS001) or Placebo Combined With First-line Standard Chemotherapy in Treatment-naive Advanced Non-small Cell Lung Cancer (NSCLC)

This is one randomized, double-blind, placebo-controlled, multi-center, phase III clinical study to evaluate the efficacy and safety of Toripalimab injection (JS001) or placebo combined with standard 1st-line chemotherapy in treatment-naïve advanced non-small cell lung cancer (NSCLC); and evaluate the population with the best predictive biomarkers, i.e., positive diagnosis population. About 450 subjects with advanced non-small cell lung cancer without activated EGFR mutation (exon 19 deletion, or exon 21 L858R, exon 21 L861Q, exon 18 G719X or exon 20 S768I mutations) and ALK fusion will be 2:1 randomized into two groups, JS001 combined with the standard 1st-line chemotherapy will be given in the study group whereas placebo combined with standard 1st-line chemotherapy will be given in the control group. The stratification will be based on the following factors: PD-L1 expression (TC≥1% vs TC<1%); Smoking state (often smoking vs no smoking or infrequent smoking); Pathological type (squamous cell carcinoma vs non-squamous cell carcinoma).

NCT03856411 Treatment-naive Advanced Non-small Cell Lung Cancer Drug: TORIPALIMAB INJECTION (JS001 ) combine with chemotherapy
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

About 450 subjects with advanced non-small cell lung cancer without activated EGFR mutation (exon 19 deletion, or exon 21 L858R, exon 21 L861Q, exon 18 G719X or exon 20 S768I mutations) and ALK fusion will be 2:1 randomized into two groups, JS001 combined with the standard 1st-line chemotherapy will be given in the study group whereas placebo combined with standard 1st-line chemotherapy will be given in the control group. --- L858R ---

Primary Outcomes

Description: Progression free survival (PFS) evaluated by investigators according to the response evaluation criteria in solid tumors (RECIST 1.1)

Measure: PFS

Time: Up to 2 approximately years

Secondary Outcomes

Description: Overall survival (OS)

Measure: OS

Time: Up to 2 approximately years

Description: PFS evaluated by the Blinded Individual Review Committee (BIRC) based on RECIST1.1 criteria

Measure: PFS

Time: Up to 2 approximately years

Description: Objective response rate (ORR) evaluated by investigators and BIRC based on RECIST1.1

Measure: ORR

Time: Up to 2 approximately years

Description: Duration of response (DOR) evaluated by investigators and BIRC based on RECIST1.1

Measure: DOR

Time: Up to 2 approximately years

Description: Disease control rate (DCR) evaluated by investigators and BIRC based on RECIST1.1

Measure: DCR

Time: Up to 2 approximately years

Description: Time to response (TTR) evaluated by investigators and BIRC based on RECIST1.1

Measure: TTR

Time: Up to 2 approximately years

Description: Overall incidence of adverse events (AEs); incidence of grade 3 and above AEs; incidence of serious adverse events (SAEs); incidence of AEs leading to termination of the investigational drug; incidence of AEs interruption of the investigational drug

Measure: Incidence of AEs/SAEs

Time: From date of consent informed until 60 days after the last investigational product administration. Up to 2 approximately years

98 A Randomized Controlled, Double-blind, Multicenter, Phase III Clinical Study to Compare Efficacy and Safety of Abivertinib Maleate Versus First-line Standard Therapy EGFR-TKI in Patients With Advanced NSCLC With Sensitive EGFR Mutation

To compare efficacy and safety of Abivertinib maleate alone versus standard first-line EGFR-TKIs for the treatment of patients with advanced non-small cell lung cancer with sensitive EGFR mutation

NCT03856697 Advanced Non-small Cell Lung Cancer Drug: Abivertinib Maleate Capsules Drug: Placebo Gefitinib Tablets Drug: Gefitinib Tablets Drug: Placebo Abivertinib Maleate Capsules
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

4. Tumor tissue or cytopathological specimens have any of two common sensitive EGFR mutation (Ex19del or L858R) as confirmed by tests with Cobas (Roche) kit in central lab of this study, which can be combined with other EGFR gene mutations. --- L858R ---

Primary Outcomes

Description: Progression-free survival (PFS) of Abivertinib maleate alone versus standard first-line EGFR-TKI for the treatment of treatment-naïve patients with advanced non-small cell lung cancer with sensitive EGFR mutation (Investigator's evaluation according to RECIST1.1 criteria)

Measure: Assess the efficacy of Abivertinib: Progression Free Survival (PFS)

Time: From baseline, then every 6 weeks, until disease progression or discontinuation from study. From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months

Secondary Outcomes

Description: Objective Response Rate (ORR) of Abivertinib maleate alone versus standard first-line EGFR-TKI for the treatment of treatment-naïve patients with advanced non-small cell lung cancer with sensitive EGFR mutation

Measure: Objective Response Rate (ORR)

Time: At baseline and every 6 weeks until the date of first documented progression or date of death from any cause ( approximately 12 months)

Description: Disease Control Rate (DCR) of Abivertinib maleate alone versus standard first-line EGFR-TKI for the treatment of treatment-naïve patients with advanced non-small cell lung cancer with sensitive EGFR mutation

Measure: Disease Control Rate (DCR)

Time: At baseline and every 6 weeks until the date of first documented progression or date of death from any cause ( approximately 12 months)

Description: Duration of Response (DoR) of Abivertinib maleate alone versus standard first-line EGFR-TKI for the treatment of treatment-naïve patients with advanced non-small cell lung cancer with sensitive EGFR mutation

Measure: Duration of Response (DoR)

Time: At baseline and every 6 weeks until the date of first documented progression or date of death from any cause ( approximately 12 months)

Description: Overall Survival (OS) of Abivertinib maleate alone versus standard first-line EGFR-TKI for the treatment of treatment-naïve patients with advanced non-small cell lung cancer with sensitive EGFR mutation

Measure: Overall Survival (OS)

Time: From first dose to end of study or date of death from any cause, whichever comes first, assessed every 6 weeks (approximately 36 months)

Description: Number and severity of AEs/SAEs of Abivertinib maleate alone versus standard first-line EGFR-TKI for the treatment of treatment-naïve patients with advanced non-small cell lung cancer with sensitive EGFR mutation

Measure: Safety and Resistance: Number and severity of AEs/SAEs

Time: From screening to the end of survival follow-up, which is assessed through study completion until 30 days after discontinuation

Description: The mean, standard deviation, maximum, minimum, and median of drug exposures in the two groups are described

Measure: Safety and Resistance: Drug exposure

Time: Continuously throughout the study until 30days after discontinuation

Description: A general physical examination includes: general status, skin, head and neck (includes: eyes, ears, nose, throat), respiratory system, cardiovascular system, abdomen,superficial lymph nodes, thyroid, musculoskeletal system (including spine and limbs), and nervous system, and any other physical signs of clinical significance. During the treatment, physical examination of the potentially affected organs will be performed.

Measure: Safety and Resistance: General physical examination status

Time: Continuously throughout the study until 30days after discontinuation

Description: Descriptive statistical analysis of clinical diagnosis results of ECG examination and changes compared with baseline are performed at planned time points, and abnormal ECG examination results are listed.

Measure: Safety and Resistance: Electrocardiogram(ECG test)

Time: Continuously throughout the study until 30days after discontinuation

Description: ECOG (Eastern Clinical Oncology Group) Performance Status Grading Criteria: Range from 0-5, 0 considered to be the best outcome and 5 to be the worst outcome

Measure: Safety and Resistance: Eastern Clinical Oncology Group Scores

Time: Continuously throughout the study until 30days after discontinuation

Description: Quality of life questionnaire of Abivertinib maleate alone versus standard which includes 5 functional domains, 3 symptom domains, 1 overall health status/quality of life domain and 6 single entries. Standardized scores of the domains/single entries in the questionnaire are used to statistically describe the absolute values and changes from baseline at each evaluation time point; t test is used to compare changes from baseline in overall quality of life score at each evaluation time point in both groups; analysis of variance is used to compare changes in overall health status score at each evaluation time point between the two groups. first-line EGFR-TKI for the treatment of treatment-naïve patients with advanced non-small cell lung cancer with sensitive EGFR mutation

Measure: Questionnaire: Health-related quality of life (HRQoL)

Time: At baseline and every 6 weeks until the date of first documented progression or date of death from any cause ( approximately 12 months)

99 A Randomized, Open-label, Phase III Study of Single Agent Nazartinib Versus Investigator's Choice (Erlotinib or Gefitinib) as First-Line Treatment in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Harboring EGFR Activating Mutations

This is a phase III, open label, randomized controlled multi-center global study designed to evaluate the safety and efficacy of single agent nazartinib (EGF816) compared with investigator's choice (erlotinib or gefitinib) in patients with locally advanced or metastatic NSCLC who are treatment naïve and whose tumors harbor EGFR activating mutations (L858R or ex19del).

NCT03529084 Carcinoma, Non-small Cell Lung Drug: EFG816 Drug: erlotinib or gefitinib
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

Phase III Study of Nazartinib (EGF816) Versus Erlotinib/Gefitinib in First-line Locally Advanced / Metastatic NSCLC With EGFR Activating Mutations This is a phase III, open label, randomized controlled multi-center global study designed to evaluate the safety and efficacy of single agent nazartinib (EGF816) compared with investigator's choice (erlotinib or gefitinib) in patients with locally advanced or metastatic NSCLC who are treatment naïve and whose tumors harbor EGFR activating mutations (L858R or ex19del). --- L858R ---

- Histologically documented locally advanced or metastatic, stage IIIB/ IIIC or stage IV NSCLC with documented EGFR activating mutation (L858R or ex19del) - Provision of a tumor tissue sample to allow for retrospective analysis of EGFR mutation status - No prior treatment with any systemic antineoplastic therapy in the advanced setting - Recovered from all toxicities related to prior treatment - Presence of at least one measurable lesion according to RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance ≤1 - Meet the following laboratory values at the screening visit: - Absolute Neutrophil Count ≥1.5 x 109/L - Platelets ≥75 x 109/L - Hemoglobin (Hgb) ≥9 g/dL - Creatinine Clearance ≥ 45 mL/min using Cockcroft-Gault formula - Total bilirubin ≤1.5 x ULN - Aspartate transaminase (AST) ≤ 3.0 x ULN, except for patients with liver metastasis, who may only be included if AST ≤5.0 x ULN - Alanine transaminase (ALT) ≤ 3.0 x ULN, except for patients with liver metastasis, who may only be included if ALT ≤5.0 x ULN Exclusion Criteria: - Prior treatment with EGFR-TKI. --- L858R ---

Any other known EGFR activating mutations other than L858R or ex19del. --- L858R ---

Patients whose tumors harbor other EGFR mutations concurrent with L858R or ex19del EGFR mutations are eligible. --- L858R ---

Primary Outcomes

Description: PFS using central BIRC assessment according to RECIST 1.1, is defined as the time from the date of randomization to the date of the first documented progression (as assessed by BIRC per RECIST 1.1) or death due to any cause, whichever occurs first.

Measure: Progression Free Survival (PFS) by Blinded independent review committee (BIRC)

Time: Approximately 3 years

Secondary Outcomes

Description: Overall survival is defined as the time from date of randomization to date of death due to any cause.

Measure: Overall Survival

Time: Approximately 6 years

Description: PFS by Investigator assessment according to RECIST 1.1, is defined as the time from the date of randomization to the date of the first documented progression (as assessed by Investigator per RECIST 1.1) or death due to any cause, whichever occurs first.

Measure: PFS by investigator

Time: Approximately 3 years

Description: PFS after next-line of treatment (PFS2) using investigator assessment according to RECIST 1.1 is defined as time from date of randomization to the first documented disease progression (clinical or radiologic) as per investigator assessment on next-line therapy or death from any cause, whichever occurs first.

Measure: PFS after next-line of treatment (PFS2) using investigator assessment according to RECIST 1.1

Time: Approximately 4 years

Description: Time to progression in CNS, defined as time from date of randomization to the date of first documented progression of brain metastases as assessed by central neuro-radiologist BIRC per modified RECIST 1.1 for patients with at least one non-measurable and/or measurable lesion in the brain at baseline.

Measure: Time to progression in Central Nervous System (CNS) per central neuro-radiologist BIRC

Time: Approximately 3 years

Description: ORR in accordance with RECIST 1.1. ORR is defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR)

Measure: Overall response rate (ORR) by central BIRC

Time: Approximately 3 years

Description: DOR is defined as the time from date of first documented response (CR and PR) to the date of the first documented progression or death due to underlying cancer, whichever occurs first.

Measure: Duration of response (DOR) by central BIRC

Time: Approximately 3 years

Description: DCR is defined as the percentage of participants with BOR of CR, PR, or stable disease (SD).

Measure: Disease control rate (DCR) by central BIRC

Time: Approximately 3 years

Description: TTR is defined as the time from the date of randomization to the first documented response CR or PR.

Measure: Time to response (TTR) by central BIRC

Time: Approximately 3 years

Description: CNS ORR in patients with brain metastases who have measurable disease in the brain at baseline review per modified RECIST 1.1

Measure: CNS ORR per central neuro-radiologist BIRC

Time: Approximately 3 years

Description: CNS DoR in patients with brain metastases who have measurable disease in the brain at baseline per modified RECIST 1.1

Measure: CNS DoR per central neuro-radiologist BIRC

Time: Approximately 3 years

Description: Peak plasma concentration (Cmax) of EGF816 and its metabolite (LMI258)

Measure: Charactise Plasma PK (Cmax) of EGF816

Time: Day 1 of Cycles 1 to 6 inclusive (21 day cycle)

Description: Area under the plasma concentration versus time curve (AUC) of EGF816 and its metabolite (LMI258)

Measure: Charactise Plasma PK (AUC) of EGF816

Time: Day 1 of Cycles 1 to 6 inclusive (21 day cycle)

Description: Elimination half life (t1/2) of EGF816 and its metabolite (LMI258)

Measure: Charactise Plasma PK (t1/2) of EGF816

Time: Day 1 of Cycles 1 to 6 inclusive (21 day cycle)

Description: HRQoL as measured by European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality of life score

Measure: Patient Reported Outcome: Health Related Quality of Life (HRQoL) as measured by QLQ-C30 Questionnaire

Time: Approximately 4 years

Description: HRQoL as measured by European Organization for Research and Treatment of Cancer (EORTC) QLQ-LC13 quality of life score

Measure: Patient Reported Outcome: Health Related Quality of Life (HRQoL) as measured by QLQ-LC13 Questionnaire

Time: Approximately 4 years

Description: Global health status/quality of life score of the EQ-5D-5L

Measure: Patient Reported Outcome: Health Related Quality of Life (HRQoL) as measured by EuroQoL-5 Dimension-5 (EQ-5D-5L) Questionnaire

Time: Approximately 4 years

100 A Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter, International Study of Osimertinib as Maintenance Therapy in Patients With Locally Advanced, Unresectable EGFR Mutation-positive Non-Small Cell Lung Cancer (Stage III) Whose Disease Has Not Progressed Following Definitive Platinum-based Chemoradiation Therapy (LAURA).

A global study to assess the efficacy and safety of osimertinib following chemoradiation in patients with stage III unresectable Epidermal Growth Factor Receptor Mutation Positive non-small cell lung cancer

NCT03521154 Non Small Cell Lung Cancer (Stage III) Drug: Osimertinib 80mg/40mg Drug: Placebo Osimertinib 80mg/40mg
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

PFS in patients with EGFR Ex19del or L858R mutation. --- L858R ---

PFS in patients with EGFR mutations Ex19del or L858R detectable in plasma-derived ctDNA. --- L858R ---

3. The tumor harbours one of the two common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations, assessed by cobas® EGFR Mutation Test v2 (Roche Diagnostics) in a CLIA certified (USA sites) or an accredited local laboratory (sites outside of the USA) or by central testing. --- L858R ---

Contraindication to MRI, including but not limited to, claustrophobia, pace makers, metal implants, intracranial surgical clips and metal foreign bodies Non Small Cell Lung Cancer (Stage III) Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a phase 3 double-blind, randomized, placebo-controlled, study to assess the efficacy and safety of osimertinib following chemoradiation in patients with stage III unresectable EGFR mutation-positive NSCLC, including the most common EGFR sensitising mutations (Ex19Del and L858R), either alone or in combination with other EGFR mutations. --- L858R ---

Primary Outcomes

Description: Defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression, based on blinded independent central review assessment according to RECIST 1.1

Measure: Progression-free survival (PFS)

Time: Approximately 13 months

Secondary Outcomes

Description: Defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression.' based on blinded independent central review assessment according to RECIST 1.1

Measure: PFS in patients with EGFR Ex19del or L858R mutation

Time: Approximately 13 months

Description: Defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression.' based on blinded independent central review assessment according to RECIST 1.1

Measure: PFS in patients with EGFR mutations Ex19del or L858R detectable in plasma-derived ctDNA

Time: Approximately 13 months

Description: Defined as earlier event of CNS progression or death based on blinded independent central review assessment according to RECIST 1.1

Measure: Time to CNS PFS

Time: MRI Brain Scan- Approximately 13 months

Description: Defined as the time from randomization until death from any cause

Measure: Overall survival (OS)

Time: Approximately 45 months

Description: Defined as the number (%) of patients with measurable disease with at least 1 visit response of CR (Complete response) or PR (Partial response) based on blinded independent central review assessment according to RECIST 1.1

Measure: Objective response rate (ORR)

Time: Approximately 13 months

Description: Defined as the time from the date of first documented response (i.e., subsequently confirmed) until the date of documented progression or death in the absence of disease progression based on blinded independent central review assessment according to RECIST 1.1

Measure: Duration of response (DoR)

Time: Approximately 13 months

Description: Defined as Disease control rate is defined as the percentage of subjects who have a best overall response of CR or PR or SD based on blinded independent central review assessment according to RECIST 1.1

Measure: Disease control rate (DCR)

Time: Approximately 13 months

Description: Defined as the relative change in the sum of the longest diameters of RECIST target lesions at the nadir in the absence of new lesions or progression of non-target lesions compared to baseline based on blinded independent central review assessment according to RECIST 1.1

Measure: Tumor shrinkage

Time: Approximately 13 months

Description: Defined as the time from the date of randomization until the first date of distant metastasis or date of death in the absence of distant metastasis based on blinded independent central review assessment according to RECIST 1.1

Measure: Time to death or distant metastases (TTDM)

Time: Approximately 13 months

Description: Defined as the time from randomization to the earlier of the date of study treatment discontinuation (regardless of the reason for study treatment discontinuation) or death

Measure: Time to treatment discontinuation

Time: Approximately 13 months

Description: Time from randomisation to second progression (PFS2) is defined as the time from the date of randomisation to the earliest of the progression event subsequent to that used for the primary variable PFS or date of death after starting subsequent anti-cancer treatment.

Measure: Second progression free survival on a subsequent treatment (PFS2)

Time: Assessed by investigator in accordance with clinical practice-approximately 21 months

Description: Defined as the time from the date of randomization to the earlier of the date of anti-cancer therapy start date following study drug discontinuation or death

Measure: Time to first subsequent therapy (TFST)

Time: Approximately 13 months

Description: Defined as the time from the date of randomization to the earlier of the date of second subsequent anti-cancer therapy start date following study drug discontinuation or death.

Measure: Time to second subsequent therapy (TSST)

Time: Approximately 21 months

Description: Change in symptoms from baseline

Measure: Patients reported disease-related symptoms and HRQoL by EORTC QLQ-LC13 and EORTC QLQ-30 questionnaires

Time: Approximately 21 months

Description: AEs graded by CTCAE version 5.0

Measure: Incidence of Adverse Events (AEs)

Time: Approximately 14 months

Description: The pharmacokinetics exposure parameters derived from plasma concentrations of osimertinib and AZD5104

Measure: Plasma concentrations of osimertinib and AZD5104

Time: Trough concentrations at Week 4,12 and 24

101 A Randomized Phase II Trial of Nivolumab, Cabozantinib Plus Nivolumab, and Cabozantinib Plus Nivolumab Plus Ipilimumab in Patients With Previously Treated Non-Squamous NSCLC

This partially randomized phase II trial studies how well nivolumab, cabozantinib s-malate, and ipilimumab work in treating patients with stage IV non-small cell lung cancer that has come back. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving nivolumab, cabozantinib s-malate, and ipilimumab may work better than cabozantinib s-malate alone in treating patients with stage IV non-small cell lung cancer.

NCT03468985 c-MET Gene Amplification MET Exon 14 Mutation Metastatic Lung Non-Squamous Non-Small Cell Carcinoma Recurrent Lung Non-Squamous Non-Small Cell Carcinoma RET/PTC Rearrangement ROS1 Gene Rearrangement Stage IV Lung Non-Small Cell Cancer AJCC v7 Drug: Cabozantinib Drug: Cabozantinib S-malate Biological: Ipilimumab Other: Laboratory Biomarker Analysis Biological: Nivolumab Other: Questionnaire Administration
MeSH: Carcinoma
HPO: Carcinoma

Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.. Inclusion Criteria: - ELIGIBILITY CRITERIA FOR STEP 0 - Patients with tumors with the following molecular alterations must submit testing results via Medidata Rave to determine eligibility to Arm T; the study chair, co-chair, biology co-chair, or a delegate must review the molecular testing and agree that the testing meets one of the molecular eligibility criteria below: - ROS1 gene rearrangement by fluorescence in situ hybridization (FISH) or deoxyribonucleic acid (DNA) analysis (may have progressed on prior crizotinib therapy) - MET exon 14 splice mutations on DNA analysis (may have progressed on prior crizotinib therapy) - MET high amplification by FISH or DNA analysis or other MET mutations predicted to be sensitive to MET inhibitor (no prior targeted therapy allowed) - RET gene rearrangement by FISH or DNA analysis (no prior targeted therapy allowed) - Institutions will be notified of the patient's eligibility status for Arm T within two (2) business days of submission of the molecular testing reports - If patients do not have tumors with the above molecular alterations noted proceed directly to step 1 - ELIGIBILITY CRITERIA FOR STEP 1 - For patients with known molecular alterations, institution has been notified that patient is deemed eligible for Arm T per review of molecular testing reports - Pathologically confirmed non-squamous non-small cell lung carcinoma (NSCLC) - Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th edition of the lung cancer tumor, node, and metastasis (TNM) classification system - Predominant non-squamous histology (patients with NSCLC not otherwise specified [NOS] are eligible); mixed tumors will be categorized by the predominant cell type; if small cell elements are present the patient is ineligible - Tumors must be tested and known negative for EGFR tyrosine kinase inhibitor (TKI) sensitizing mutations (EGFR exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements by routine Clinical Laboratory Improvement Act (CLIA)-certified clinical testing methods; negative circulating tumor DNA results alone are not acceptable; prior testing for tumor PD-L1 status is not required - Patients must have progressed radiographically following first line platinum-based chemotherapy, no additional lines of therapy are permitted - NOTE: Prior adjuvant chemotherapy for early stage disease does not count as one line of therapy if 12 months or greater elapsed between completion of adjuvant therapy and initiation of first-line systemic therapy; if less than 12 months elapsed, adjuvant chemotherapy counts as one line of therapy - Exception for targeted therapy sub-study (Arm T): At least one line of prior chemotherapy or targeted therapy is required, but there is no limit on number of prior treatments - Patients must have measurable disease as defined by RECIST v. 1.1 criteria; baseline measurements and evaluation of ALL sites of disease must be obtained within 4 weeks prior to registration - No prior anti-MET therapy such as crizotinib or cabozantinib, or PD-1/PD-L1 immune checkpoint inhibitor therapy (such as nivolumab, pembrolizumab, atezolizumab) or CTLA4 inhibitor therapy (such as ipilimumab); no prior allergic reaction to small molecule tyrosine kinase inhibitors or monoclonal antibodies - Exception for targeted therapy sub-study (Arm T): Prior crizotinib may be allowed depending on the gene alteration - Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the following times prior to registration: - Chemotherapy/ targeted oral therapy administered in a daily or weekly schedule must be completed >= 1 week prior to registration; - Any chemotherapy administered in an every 2 week or greater schedule must be completed >= 2 weeks prior to registration - Additionally, patients should be recovered to equal to or less than grade 1 toxicities related to any prior treatment, unless adverse event (AE)(s) are clinically nonsignificant and/or stable on supportive therapy - No prior radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks prior to registration - Patients with no known brain metastasis must have baseline brain imaging within 12 weeks prior to study registration not demonstrating brain metastases OR - Patients with known brain metastases must have baseline brain imaging within 4 weeks prior to study registration and meet all of the following criteria: - Have completed treatment to all symptomatic brain metastases (with whole brain radiation or radiosurgery) >= 4 weeks prior to registration, or have undergone complete neurosurgical resection >= 3 months prior to registration - Be clinically stable from brain metastases at time of screening, if no treatment was administered - Known leptomeningeal disease is not allowed - Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - NOTE: Participants with impaired decision-making capacity (IDMC) should not be allowed to participate in this study due to its complexity - Patients must have anticipated life expectancy greater than 3 months - Absolute neutrophil count >= 1,500/mm^3 (within 2 weeks prior to registration) - Platelets >= 100,000/mm^3 (within 2 weeks prior to registration) - Hemoglobin >= 9 g/dL (within 2 weeks prior to registration) - Subject has prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) test =< 1.3 x the laboratory upper limit of normal (ULN) (within 2 weeks prior to registration) - Total bilirubin =< 1.5 x ULN (within 2 weeks prior to registration) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x ULN (within 2 weeks prior to registration) - Serum albumin >= 2.8 g/dL (within 2 weeks prior to registration) - Serum calcium (absolute or albumin corrected), magnesium and potassium >= lower limit of normal (LLN) (within 2 weeks prior to registration) - NOTE: serum calcium, magnesium and potassium can be replaced if values are below LLN - Creatinine =< 1.5 x ULN or calculated (Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min/1.73 --- L858R ---

- Serious non-healing wound/ulcer/bone fracture within 28 days prior to registration - History of organ transplant - Concurrent symptomatic untreated hypothyroidism within 7 days prior to registration - History of surgery as follows: - Major surgery (as an example, surgery requiring anesthesia and a > 24 hour hospital stay) within 3 months prior to registration, with wound healing at least 28 days prior to registration - Minor surgery within 28 days prior to registration with complete wound healing at least 10 days prior to registration - Minor procedures within 7 days prior to registration such as thoracentesis, paracentesis, or 18 g or smaller needle biopsy of tumor - Patients with clinically relevant ongoing complications from prior surgery are not eligible - Patients must have corrected QT interval calculated by the Fridericia formula (QTcF) =< 500 ms within 28 days before registration - Patients must be able to swallow tablets - No currently active other malignancies which require systemic treatment - No patients that have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses =< 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted - No patients with known active autoimmune disease or known history of autoimmune disease for which recurrence may affect vital organ function or require immune suppressive treatment including systemic corticosteroids; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, autoimmune hepatitis; patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease; patients with vitiligo, endocrine deficiencies including type I diabetes mellitus or thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible - No ongoing major illness or psychosocial issues that would limit compliance with the protocol - Women must not be pregnant or breast-feeding due to contraindications with the study agents - All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy - A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) - Women of childbearing potential (WOCBP) and males who are sexually active with WOCBP must use an accepted and effective method of contraception or abstain from sexual intercourse for at least one week prior to the start of treatment, and continue for 5 months after the last dose of protocol treatment for women of childbearing potential and 7 months after the last dose of protocol treatment for males who are sexually active with WOCBP - Patients with known human immunodeficiency virus (HIV) disease taking antiretroviral therapy are excluded because there are no safety data with the combination of antiretroviral therapy and cabozantinib or ipilimumab or nivolumab with ipilimumab - Patients with known chronic active hepatitis B (defined as a positive hepatitis B surface antigen and/or hepatitis B viral load in the last Inclusion Criteria: - ELIGIBILITY CRITERIA FOR STEP 0 - Patients with tumors with the following molecular alterations must submit testing results via Medidata Rave to determine eligibility to Arm T; the study chair, co-chair, biology co-chair, or a delegate must review the molecular testing and agree that the testing meets one of the molecular eligibility criteria below: - ROS1 gene rearrangement by fluorescence in situ hybridization (FISH) or deoxyribonucleic acid (DNA) analysis (may have progressed on prior crizotinib therapy) - MET exon 14 splice mutations on DNA analysis (may have progressed on prior crizotinib therapy) - MET high amplification by FISH or DNA analysis or other MET mutations predicted to be sensitive to MET inhibitor (no prior targeted therapy allowed) - RET gene rearrangement by FISH or DNA analysis (no prior targeted therapy allowed) - Institutions will be notified of the patient's eligibility status for Arm T within two (2) business days of submission of the molecular testing reports - If patients do not have tumors with the above molecular alterations noted proceed directly to step 1 - ELIGIBILITY CRITERIA FOR STEP 1 - For patients with known molecular alterations, institution has been notified that patient is deemed eligible for Arm T per review of molecular testing reports - Pathologically confirmed non-squamous non-small cell lung carcinoma (NSCLC) - Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th edition of the lung cancer tumor, node, and metastasis (TNM) classification system - Predominant non-squamous histology (patients with NSCLC not otherwise specified [NOS] are eligible); mixed tumors will be categorized by the predominant cell type; if small cell elements are present the patient is ineligible - Tumors must be tested and known negative for EGFR tyrosine kinase inhibitor (TKI) sensitizing mutations (EGFR exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements by routine Clinical Laboratory Improvement Act (CLIA)-certified clinical testing methods; negative circulating tumor DNA results alone are not acceptable; prior testing for tumor PD-L1 status is not required - Patients must have progressed radiographically following first line platinum-based chemotherapy, no additional lines of therapy are permitted - NOTE: Prior adjuvant chemotherapy for early stage disease does not count as one line of therapy if 12 months or greater elapsed between completion of adjuvant therapy and initiation of first-line systemic therapy; if less than 12 months elapsed, adjuvant chemotherapy counts as one line of therapy - Exception for targeted therapy sub-study (Arm T): At least one line of prior chemotherapy or targeted therapy is required, but there is no limit on number of prior treatments - Patients must have measurable disease as defined by RECIST v. 1.1 criteria; baseline measurements and evaluation of ALL sites of disease must be obtained within 4 weeks prior to registration - No prior anti-MET therapy such as crizotinib or cabozantinib, or PD-1/PD-L1 immune checkpoint inhibitor therapy (such as nivolumab, pembrolizumab, atezolizumab) or CTLA4 inhibitor therapy (such as ipilimumab); no prior allergic reaction to small molecule tyrosine kinase inhibitors or monoclonal antibodies - Exception for targeted therapy sub-study (Arm T): Prior crizotinib may be allowed depending on the gene alteration - Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the following times prior to registration: - Chemotherapy/ targeted oral therapy administered in a daily or weekly schedule must be completed >= 1 week prior to registration; - Any chemotherapy administered in an every 2 week or greater schedule must be completed >= 2 weeks prior to registration - Additionally, patients should be recovered to equal to or less than grade 1 toxicities related to any prior treatment, unless adverse event (AE)(s) are clinically nonsignificant and/or stable on supportive therapy - No prior radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks prior to registration - Patients with no known brain metastasis must have baseline brain imaging within 12 weeks prior to study registration not demonstrating brain metastases OR - Patients with known brain metastases must have baseline brain imaging within 4 weeks prior to study registration and meet all of the following criteria: - Have completed treatment to all symptomatic brain metastases (with whole brain radiation or radiosurgery) >= 4 weeks prior to registration, or have undergone complete neurosurgical resection >= 3 months prior to registration - Be clinically stable from brain metastases at time of screening, if no treatment was administered - Known leptomeningeal disease is not allowed - Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - NOTE: Participants with impaired decision-making capacity (IDMC) should not be allowed to participate in this study due to its complexity - Patients must have anticipated life expectancy greater than 3 months - Absolute neutrophil count >= 1,500/mm^3 (within 2 weeks prior to registration) - Platelets >= 100,000/mm^3 (within 2 weeks prior to registration) - Hemoglobin >= 9 g/dL (within 2 weeks prior to registration) - Subject has prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) test =< 1.3 x the laboratory upper limit of normal (ULN) (within 2 weeks prior to registration) - Total bilirubin =< 1.5 x ULN (within 2 weeks prior to registration) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x ULN (within 2 weeks prior to registration) - Serum albumin >= 2.8 g/dL (within 2 weeks prior to registration) - Serum calcium (absolute or albumin corrected), magnesium and potassium >= lower limit of normal (LLN) (within 2 weeks prior to registration) - NOTE: serum calcium, magnesium and potassium can be replaced if values are below LLN - Creatinine =< 1.5 x ULN or calculated (Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min/1.73 --- L858R ---

Primary Outcomes

Description: Will be estimated using the Kaplan-Meier method and Cox proportional hazards models will be used to estimate the treatment hazard ratios. The primary comparison of PFS will use a logrank test stratified on the randomization stratification factors with a one-sided type I error rate of 10%. Other comparisons of groups will be made using the logrank test and Cox modeling.

Measure: Progression-free survival (PFS)

Time: From randomization to documented disease progression or death from any cause, whichever occurs first, assessed up to 5 years

Secondary Outcomes

Description: Will be estimated using the Kaplan-Meier method and Cox proportional hazards models will be used to estimate the treatment hazard ratios.

Measure: Overall survival

Time: From randomization to death from any cause, assessed up to 5 years

Description: According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Response rates (complete response and partial response) will be compared using Fischer's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes.

Measure: Best objective response evaluated

Time: Up to 5 years

Description: Evaluated according to Common Terminology Criteria for Adverse Events version 5 criteria. Toxicity will be compared using Fischer's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes.

Measure: Incidence of toxicity

Time: Up to 5 years

Other Outcomes

Description: As measured by RECIST 1.1 criteria.

Measure: Time to tumor response

Time: Up to 5 years

Measure: Comparison of RECIST 1.1 imaging response assessment measurements

Time: Up to 5 years

Description: A combined analysis of the data from the selected Eastern Cooperative Oncology Group (ECOG) and the American College of Radiology Imaging Network (ACRIN) trials is planned. Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.

Measure: Effects of tobacco on provider-reported cancer-treatment toxicity (adverse events (both clinical and hematologic) and dose modifications

Time: Up to 5 years

Description: A combined analysis of the data from the selected ECOG-ACRIN trials is planned. Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.

Measure: Effects of tobacco on patient-reported physical symptoms and psychological symptoms

Time: Up to 5 years

Description: A combined analysis of the data from the selected ECOG-ACRIN trials is planned. Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.

Measure: Assessment of quitting behaviors, behavioral counseling/support and cessation medication utilization

Time: Up to 5 years

Description: A combined analysis of the data from the selected ECOG-ACRIN trials is planned. Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.

Measure: Effects of tobacco use and exposure on treatment duration, relative dose intensity, and therapeutic benefit

Time: Up to 5 years

102 An Open-label PET Study to Determine Brain Exposure of Osimertinib After IV Microdose Administration of [11C]Osimertinib and Therapeutic Oral Doses of Osimertinib to Patients With EGFR Mutated NSCLC With Brain Metastases

This is an open-label, single centre, Phase I study to determine the brain exposure of [11C]osimertinib in patients with EGFRm NSCLC with brain metastases.

NCT03463525 Non-small Cell Lung Cancer Drug: Osimertinib Drug: [11C]osimertinib
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

For TKI-naïve patients, confirmation of EGFR mutation known to be associated with EGFR-TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) as assessed by local and/or central laboratory via tissue/cytology is required. --- L858R ---

Primary Outcomes

Description: Measurement of the brain standard uptake value (SUV) seen on PET scan at baseline.

Measure: Brain Exposure to [11C]osimertinib in Tumour Region of Interest

Time: PET Scan on Day 1

Description: Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken at baseline.

Measure: Pharmacokinetics of [11C]osimertinib

Time: Blood samples collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken at baseline.

Measure: Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC)

Time: Measurement collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken at baseline.

Measure: Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax)

Time: Blood samples collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Measurement of the brain standard uptake value (SUV) seen on PET scan after a single dose of oral osimertinib.

Measure: Brain Exposure to [11C]osimertinib in Tumour Region of Interest

Time: PET Scan on Day 2

Description: Measurement of the brain standard uptake value (SUV) seen on PET scan after at least 21days of continuous oral osimertinib dosing.

Measure: Brain Exposure to [11C]osimertinib in Tumour Region of Interest

Time: PET Scan on Day 29

Description: Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib

Time: Blood samples collected on Day 292, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib

Time: Blood samples collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax)

Time: Blood samples collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax)

Time: Blood samples collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC)

Time: Measurement collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC)

Time: Measurement collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Secondary Outcomes

Description: Pharmacokinetics of osimertinib and its metabolite by assessment of AUC metabolite to parent ratio, derived from the curves taken during the treatment period.

Measure: Pharmacokinetics of Osimertinib and its Metabolite by Assessment of AUC Metabolite to Parent Ratio

Time: Blood samples collected on Day 2 at pre-administration, 1, 2,4 and 6 hours post dose.

Description: Pharmacokinetics of osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of Osimertinib by Assessment of Maximum Plasma Concentration (Cmax)

Time: Blood samples collected on Day 2 at pre-administration, 1, 2,4 and 6 hours post dose.

Description: Pharmacokinetics of osimertinib by assessment of area under the concentration-time curve from time zero to the last measurable time point.

Measure: Pharmacokinetics of Osimertinib by Assessment of Area Under the Concentration-time Curve

Time: Blood samples collected on Day 2 at pre-administration, 1, 2,4 and 6 hours post dose.

Description: Pharmacokinetics of osimertinib by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of Osimertinib by Assessment of Time to Cmax (Tmax)

Time: Blood samples collected on Day 2 at pre-administration, 1, 2,4 and 6 hours post dose.

Description: Pharmacokinetics of osimertinib and its metabolite by assessment of AUC metabolite to parent ratio, derived from the curves taken during the treatment period.

Measure: Pharmacokinetics of Osimertinib and its Metabolite by Assessment of AUC Metabolite to Parent Ratio

Time: Blood samples collected on Day 29 at pre-administration, 1,2,4 and 6 hours post dose.

Description: Pharmacokinetics of osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of Osimertinib by Assessment of Maximum Plasma Concentration (Cmax)

Time: Blood samples collected on Day 29 at pre-administration, 1,2,4 and 6 hours post dose.

Description: Pharmacokinetics of osimertinib by assessment of area under the concentration-time curve from time zero to the last measurable time point.

Measure: Pharmacokinetics of Osimertinib by Assessment of Area Under the Concentration-time Curve

Time: Blood samples collected on Day 29 at pre-administration, 1,2,4 and 6 hours post dose.

Description: Pharmacokinetics of osimertinib by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of Osimertinib by Assessment of Time to Cmax (Tmax)

Time: Blood samples collected on Day 29 at pre-administration, 1,2,4 and 6 hours post dose.

Other Outcomes

Description: Collection and assessment of adverse events graded using CTCAE (version 4.03).

Measure: Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] with IV [11C]osimertinib administration

Time: From study Day 1 and until 30 days after the study drug is discontinued.

Description: Collection and assessment of adverse events using CTCAE (version 4.03)

Measure: Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] with continuous oral osimertinib

Time: From study Day 1 and until 30 days after the study drug is discontinued.

103 A Randomized Phase 3 Trial Comparing Continuation Nivolumab-Ipilimumab Doublet Immunotherapy Until Progression Versus Observation in Treatment-naive Patients With PDL1-positive Stage IV Non-Small Cell Lung Cancer (NSCLC) After Nivolumab-Ipilimumab Induction Treatment

Non Small Cell lung cancer (NSCLC) remains the first cause of death by cancer in the World. For the patients presenting a NSCLC stage IV, the median of survival is about 15 months today. The chemotherapy with platinum is the standard treatment for these patients but immunotherapy showed these efficacy in 1st line for patients PD-L1 positive. On the other hand, the duration of treatment by immunotherapy is not clear. Indeed, prolonged responses and long survivals have been described in patients having interrupted the treatment. In the melanoma, a treatment of 6 months of ipilimumab demonstrated its efficacy. The objective of the study is to demonstrate that a treatment of 6 months followed by an observation (stop and go) is not less effective than a treatment given until progression or toxicity. This strategy would allow to decrease the accumulated toxicities, to improve the quality of life of the patients and to decrease the costs.

NCT03469960 Non-Small Cell Lung Cancer Metastatic Drug: Ipilimumab Drug: Nivolumab
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Exclusion Criteria: 1. Small cell lung cancer or tumors with mixt histology including a SCLC component 2. Known EGFR activating tumor mutation (deletion LREA in exon 19, L858R ou L861X mutations in exon 21, G719A/S mutation in exon 18) or HER exon 20 insertion (either tissue or plasma cfDNA mutation). --- L858R ---

Primary Outcomes

Description: Time between the date of randomization and the first date of documented progression, as determined by BICR (Blinded Independent Central Review), or death due to any cause, whichever occurs first.

Measure: Progression Free Survival (PFS1)

Time: 24 months after randomization of the last subject

Secondary Outcomes

Description: Time between the start date of the second line and the second date of documented progression, as determined by BICR, or death due to any cause, whichever occurs first.

Measure: Progression Free Survival (PFS2)

Time: 24 months after randomization of the last subject

Description: Time until definitive deterioration (TUDD) from the randomization time in the experimental arm B.

Measure: Quality of life

Time: 24 months after randomization of the last subject

Measure: Overall survival (OS)

Time: 6, 12 and 18 months after randomization

Description: PD-L1-stained % of tumor cells will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS

Measure: Biological correlative exploratory studies (PD-L1)

Time: 6 months

Description: PD-L1 H-score will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS

Measure: Biological correlative exploratory studies (PD-L1 H score)

Time: 6 months

Description: CD3/CD8 tumor infiltration will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS

Measure: Biological correlative exploratory studies (CD3/CD8)

Time: 6 months

Description: neutrophil tumor infiltration will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS

Measure: Biological correlative exploratory studies (neutrophil)

Time: 6 months

Description: plasma concentration of different cytokines at baseline or at the randomization point, will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS

Measure: Biological correlative exploratory studies (cytokines)

Time: 6 months

Description: plasma concentration of different chemokines at baseline or at the randomization point, will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS

Measure: Biological correlative exploratory studies (chemokines)

Time: 6 months

104 Third-line Treatment of Gefitinib in NSCLC Patients Who Had Received First-line Gefitinib With EGFR 19del/L858R Mutation and Tumor Progression After the Second-line Chemotherapy: a Single-arm, Prospective and Multi-center Study

The purpose of this study is to evaluate the disease control rate (DCR) of gefitinib as third-line retreatment in stage IIIB/IV NSCLC with EGFR 19del/L858R positive mutation patients who had benefited from first-line gefitinib treatment with EGFR 19del/L858R positive mutation and tumor progression after the second-line chemotherapy

NCT01933347 Non Small Cell Lung Cancer Drug: Gefitinib
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

Third-line Treatment of Gefitinib in NSCLC Patients Who Had Received First-line Gefitinib With EGFR 19del/L858R Mutation and Tumor Progression After the Second-line Chemotherapy: a Single-arm, Prospective and Multi-center Study. --- L858R ---

Third-line Treatment of Gefitinib in NSCLC Patients The purpose of this study is to evaluate the disease control rate (DCR) of gefitinib as third-line retreatment in stage IIIB/IV NSCLC with EGFR 19del/L858R positive mutation patients who had benefited from first-line gefitinib treatment with EGFR 19del/L858R positive mutation and tumor progression after the second-line chemotherapy Disease Control Rate (DCR). --- L858R ---

Third-line Treatment of Gefitinib in NSCLC Patients The purpose of this study is to evaluate the disease control rate (DCR) of gefitinib as third-line retreatment in stage IIIB/IV NSCLC with EGFR 19del/L858R positive mutation patients who had benefited from first-line gefitinib treatment with EGFR 19del/L858R positive mutation and tumor progression after the second-line chemotherapy Disease Control Rate (DCR). --- L858R --- --- L858R ---

2. Male or female aged 18 years or older; 3. Subjects were diagnosed with stage IIIB or IV NSCLC before starting the first dose of gefitinib third-line treatment; 4. EGFR exon 19 deletion or exon 21 L858R substitution mutation confirmed; 5. ECOG performance status 0-2; 6. Life expectancy of at least 12 weeks or longer; 7. Has at least one measureable lesion by RECIST 1.1; 8. NSCLC of enrolled subjects previously progressed after first-line gefitinib treatment (PFS ≥ 6 months) and progressed again after second-line chemotherapy (not limited for chemotherapy regimen, ≥ 4 cycles of chemotherapy). --- L858R ---

Non Small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung - Primary Study Objective: To evaluate the disease control rate (DCR) of gefitinib as third-line retreatment in stage IIIB/IV NSCLC with EGFR 19del/L858R positive mutation patients who had benefited from first-line gefitinib treatment with EGFR 19del/L858R positive mutation and tumor progression after the second-line chemotherapy - Secondary Study Objectives: To evaluate objective response rate (ORR), progressive-free survival (PFS), overall survival(OS) and quality of life (QoL) of gefitinib as third-line retreatment in NSCLC patients To evaluate the safety of gefitinib as third-line treatment in NSCLC patients - Exploratory analyses: To dynamically monitor EGFR mutation status and explore the relationship with clinical outcome --- L858R ---

Non Small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung - Primary Study Objective: To evaluate the disease control rate (DCR) of gefitinib as third-line retreatment in stage IIIB/IV NSCLC with EGFR 19del/L858R positive mutation patients who had benefited from first-line gefitinib treatment with EGFR 19del/L858R positive mutation and tumor progression after the second-line chemotherapy - Secondary Study Objectives: To evaluate objective response rate (ORR), progressive-free survival (PFS), overall survival(OS) and quality of life (QoL) of gefitinib as third-line retreatment in NSCLC patients To evaluate the safety of gefitinib as third-line treatment in NSCLC patients - Exploratory analyses: To dynamically monitor EGFR mutation status and explore the relationship with clinical outcome --- L858R --- --- L858R ---

Primary Outcomes

Measure: Disease Control Rate (DCR)

Time: week 8

Secondary Outcomes

Measure: objective response rate (ORR), progressive-free survival (PFS), overall survival(OS)

Time: until the death of last subject or 2 years after enrollment

105 A Phase 2A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Immune Response, Safety and Efficacy of HS-110 in Combination With Erlotinib vs. Erlotinib as a Single Agent in Patients With Advanced, Non-EGFR Mutated Non-Small Cell Lung Cancer (NSCLC)

This study will enroll patients with locally advanced or metastatic non-EGFR mutated Non-Small Cell Lung Cancer (NSCLC) lung cancer after failure of at least one but no more than two prior approved treatment regimens. Patients will be randomized to receive one of two doses of vaccine or placebo to be dosed twice weekly for 18 weeks (36 doses total) and patients will also receive erlotinib 150mg taken orally once daily for the duration of the trial. The study will examine the immune effects, safety and efficacy of two different doses of HS110 vaccine in combination with erlotinib versus erlotinib alone.

NCT01504542 Non-small Cell Lung Cancer Biological: HS110 vaccine Biological: Placebo Biological: HS110 vaccine
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This multicenter, randomized, double-blind, placebo-controlled study will enroll patients with advanced NSCLC (squamous cell or non-squamous cell) without EGFR mutations (either L858R or 746-750 deletions) who have had progression or recurrence of their disease following at least one but no more than two prior regimens (adjuvant therapy excluded) of approved therapy that did not include immunomodulating or anti-EGFR targeted therapy for their disease. --- L858R ---

Primary Outcomes

Description: Immune response will be evalulated by ELISPOT assays and change will be assessed from baseline.

Measure: Immunologic Response (defined as production of IFNƴ from CD8+ T cells as evaluated by ELISPOT assay)

Time: Week 18

Secondary Outcomes

Description: Incidence and severity of adverse events, changes in laboratory measures, physical exams and evaluation of autoimmune phenomena.

Measure: Safety of the combination of HS110 vaccine and erlotinib

Time: Up to 1 year

Description: Patients will have a CT scan performed at baseline, Week 12 and Week 22 or at the end of study visit in the case of early termination from study. Investigators will assess the disease response using irRC for overall response, CR, PR, SD or PD.

Measure: Tumor assessment by immunologic response criteria (irRC)

Time: Baseline, Week 12 and Week 22

Description: Analysis via a semiautomated, epithelial cell adhesion molecule-based immunomagnetic technique.

Measure: Exploratory Immunologic endpoint - evaluation of circulating tumor cells

Time: Baseline, Week 1, Week 2, Week 3, Week 4, Week 6, Week 9, Week 12 and Week 18

Description: Analysis of cell surfance molecules by flow cytometry

Measure: Exploratory immunologic endpoint - immune function

Time: Baseline, Week 1, Week 2, Week 3, Week 4, Week 6, Week 9, Week 12 and Week 18

Description: Examination of protein expression utilizing western blot, immunohistochemical staining, enzyme linked immunosorbent assay (ELISA) or mass spectrometry

Measure: Exploratory immunologic endpoint - proteomic profile

Time: Baseline, Week 1, Week 2, Week 3, Week 4, Week 6, Week 9, Week 12 and Week 18

106 A Randomized, Open-Label, Multicenter, Phase 3 Trial Comparing Veliparib Plus Carboplatin and Paclitaxel Versus Investigator's Choice of Standard Chemotherapy in Subjects Receiving First Cytotoxic Chemotherapy for Metastatic or Advanced Non-Squamous Non-Small Cell Lung Cancer (NSCLC) and Who Are Current or Former Smokers

This is a 2-arm, Phase 3 study to evaluate the safety and efficacy of veliparib plus carboplatin and paclitaxel versus the Investigator's choice of standard chemotherapy in Lung Subtype Panel (LSP) positive subjects with metastatic or advanced non-squamous non-small cell lung cancer.

NCT02264990 Non-squamous Non-small Cell Lung Cancer Drug: Paclitaxel Drug: Pemetrexed Drug: Carboplatin Drug: Cisplatin Drug: Veliparib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

- Subject has peripheral neuropathy ≥ grade 2. - Subject has squamous NSCLC, or an untreated known EGFR mutation of exon 19 deletion or L858R mutation in exon 21, or a known ALK gene rearrangement. --- L858R ---

Primary Outcomes

Description: Overall survival is defined as the number of days from the date that the participant was randomized to the date of the participant's death.

Measure: Overall Survival (OS) in the LSP (Lung Subtype Panel) positive subgroup

Time: Up to 3 years from first dose of study drug.

Secondary Outcomes

Description: Objective response rate is defined as the proportion of participants with complete or partial response as determined by the investigator per Response Evaluation Criteria In Solid Tumors (version 1.1).

Measure: Objective Response Rate (ORR) in the LSP (Lung Subtype Panel) positive subgroup and all participants

Time: Up to 3 years from first dose of study drug

Description: Progression-free survival is defined as the number of days from participant randomization to the date the participant experiences an event of disease progression (PD) or death (all causes of mortality), if PD is not reached.

Measure: Progression Free Survival (PFS) in the LSP (Lung Subtype Panel) positive subgroup and all participants

Time: Up to 5 years from first dose of study drug

Description: Overall survival is defined as the number of days from the date that the participant was randomized to the date of the participant's death.

Measure: Overall Survival (OS) in all participants

Time: Up to 5 years from first dose of study drug.

Other Outcomes

Description: Participants will answer the European Quality of Life-5 Dimensions-5 Levels Questionnaire (EQ-5D-5L) and the Functional Assessment of Cancer Therapy (FACT) Lung Symptom Index-17 questionnaire.

Measure: Change in Quality of Life in the LSP (Lung Subtype Panel) positive subgroup and in all participants

Time: From Screening (prior to dosing) up to 2 years

Description: The duration of overall response for a participant is defined as the number of days from when the criteria is met for a complete or partial response (whichever occurs first), to the date that progressive disease (PD) is objectively documented.

Measure: Duration of overall response (DOR) in the LSP (Lung Subtype Panel) positive subgroup and in all participants

Time: Up to 3 years from randomization.

Measure: Change in Eastern Cooperative Oncology Group (ECOG) Performance Status in the LSP (Lung Subtype Panel) positive subgroup and in all participants

Time: From Screening (prior to dosing) up to 2 years

107 An epidemiOlogy Study to deteRmine the Prevalence of EGFR muTations in RUSsian Patients With Advanced NSCLC (ORTUS)

This is a multicentre, non-interventional, prospective study to be carried out in representative oncology departments / institutions in order to determine the prevalence of EGFR mutations in treatment-naive Russian patients with cytologically verified advanced NSCLC in Russia.

NCT02321046 Non-Small Cell Lung Cancer
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

EGFR mutations (EGFR del746-750, EGFR L858R, EGFR T790M) rate in cytology and plasma samples prior to treatment. --- L858R ---

Primary Outcomes

Measure: EGFR mutations (EGFR del746-750, EGFR L858R, EGFR T790M) rate in cytology and plasma samples prior to treatment

Time: up to 18 months

Secondary Outcomes

Measure: Patient characteristics: Gender. Age. Race, ethnicity. Smoking habits. Family history of NSCLC.

Time: up to 18 months

Description: Date of the cytological verification of the NSCLC diagnosis. Disease stage and TNM classification. Morphological classification. Extent of the disease. Performance Status ECOG, including at diagnosis

Measure: Disease information/diagnostic procedures

Time: up to 18 months

Measure: EGFR mutations profile in cytology and/or histology (depending on the availablility of samples) and plasma samples at the time of every progression or in 1.5 year follow up in case of no progression

Time: up to 18 months

Description: 1st line and subsequent lines of therapy treatment, therapy regimen, medicines used for therapy (drugs by INN), for EGFRm+ patients - number of cycles of antitumor therapy, onset date, end date of each line

Measure: Characteristics of the 1st line and subsequent lines of antitumor therapy

Time: up to 18 months

Description: Treatment response/ progression of disease on every line of antitumor therapy: progressive disease, partial response, stable disease and complete response according to RECIST 1.1 evaluation and/or any other clinical assessment. Death: Disease-related or for other reasons

Measure: Clinical outcome/Patient response (for EGFRm+ patients who entered observation phase)

Time: up to 18 months

108 A Phase Ib/II, Multicenter, Open-label Study of EGF816 in Combination With INC280 in Adult Patients With EGFR Mutated Non-small Cell Lung Cancer.

The study is designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of EGF816 in combination with INC280 and to estimate the preliminary anti-tumor activity of EGF816 in combination with INC280 in patients with advanced non-small cell lung cancer (NSCLC) with documented EGFR mutation.

NCT02335944 Non Small Cell Lung Cancer Drug: INC280 Drug: EGF816
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Inclusion criteria: - Histologically documented, locally advanced or recurrent (stage IIIB who are not eligible for combined modality treatment) or metastatic (Stage IV) NSCLC - Locally documented EGFR mutation L858R and/or ex19del, or a characterized de novo EGFR T790M mutation (or other rare activating mutations that confer sensitivity to 1st and 2nd generation EGFR inhibitors (e.g. --- L858R ---

Primary Outcomes

Measure: Phase Ib: Incidence of dose limiting toxicities (DLTs) and Estimation of the Maximum tolerated dose (MTD) or Recommended Phase II dose (RP2D)

Time: First 28 days of treatment

Description: ORR is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) determined by Blinded Independent Review Committee (BIRC) assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Phase II Groups 1, 2 and 3: Overall Response Rate per RECIST 1.1

Time: At least 24 weeks

Description: Frequency of treatment-emergent adverse events

Measure: Phase II Group 4 Incidence and severity of AEs/SAEs, dose interruptions, reductions and dose intensity

Time: At least 24 weeks

Secondary Outcomes

Description: Assessment of the safety of EGF816 in combination with INC280 will be performed continuously during the treatment phase and 30 days after discontinuation of the study treatment

Measure: Safety of INC280 and EGF816: Incidence and severity of AEs and SAEs, including changes in hematology and chemistry values, vital signs and ECGs (Phase I/II)

Time: At least 24 weeks

Description: Assessment of the tolerability of EGF816 in combination with INC280 will be performed continuously during the treatment phase and 30 days after discontinuation of the study treatment

Measure: Frequency of dose interruption, frequency of reduction and dose intensity (Phase I/II)

Time: At least 24 weeks

Description: ORR is defined as proportion of patients with best overall response of (PR+CR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Overall Response Rate (Phase Ib and Phase II Group 4)

Time: At least 24 weeks

Description: DCR is defined as the proportion of patients with best overall response of CR, PR, or SD determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Disease Control Rate (Phase I/II)

Time: At least 24 weeks

Description: Progression-free survival (PFS). PFS is defined as time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1

Measure: Progression Free Survival (Phase I/II)

Time: At least 24 weeks

Description: DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1

Measure: Duration of Response (Phase I/II)

Time: At least 24 weeks

Description: OS is defined as the time from first dose of the study treatment to the date of death due to any cause.

Measure: Overall Survival (Phase I/II)

Time: At least 24 weeks

Measure: Plasma concentration versus time profiles

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Area under the plasma concentration versus time curve (AUC) of EGF816

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Area under the plasma concentration versus time curve (AUC) of INC280

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Peak plasma concentration (Cmax) of INC280

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Peak plasma concentration (Cmax) of EGF816

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Elimination half life (t1/2) of INC280

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Elimination half life (t1/2) of EGF816

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Description: TTR is defined as the time from the date of the first dose to the date of first documented response (CR or PR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Time to Response (Phase I/II)

Time: At least 24 weeks

109 Gefitinib Alone or With Concomitant Whole Brain Radiotherapy for Patients Harboring an EGFR Mutation With Multiple Brain Metastases From Non-Small-cell Lung Cancer: a Phase II/III Randomized Controlled Trial

1. Compare the effect and safety of gefitinib alone with gefitinib plus concomitant WBRT(whole-brain radiotherapy ) in treatment of NSCLC patients harboring an EGFR mutation with multiple BM. 2. Verify the failure pattern of NSCLC patients harboring an EGFR mutation with multiple BM. 3. Explore the rescuable therapy after progression of disease.

NCT02338011 Non-Small Cell Lung Cancer Brain Metastases EGFR Gene Mutation Drug: Gefitinib Radiation: WBRT
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Brain Neoplasms
HPO: Brain neoplasm Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - years of age or older - ECOG score ≤ 2 - Recursive Partitioning Analysis(RPA) Class I-II; - The pathological diagnosis of primary non-small cell lung cancer and detection of pulmonary primary ARMs; - Sequencing EGFR mutation(primary lesion or metastases,exon 19 deletions or exon 21 L858R (EGFR mutation in exon 21, L858R point mutation) mutations; - Enhanced MRI showed brain metastases ≥ 4; - 1 or 2 line treatment revealed failure; - No use of EGFR-TKIs(Tyrosine kinase inhibitors) previously; - No treatment for BM previously,including WBRT, SRS, surgery or experimental therapy; - Expected survival period over 3 months; - Two weeks before randomization, organs function in patients with meet the following criteria: - bone marrow:HB(hemoglobin) ≥ 90g/L, neutrophil≥ 1.5 × 109/L and platelet ≥ 100 × 109/L; - liver function:total bilirubin ≤ 1.5 times the upper limit of normal, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times the upper limit of normal; - renal function:more than 1.5 times the upper limit of normal serum creatinine or creatinine clearance rate ≥ 60 ml/min; - Urine dipstick testing the proteinuria < 1+; if the urine dipstick test value, 1+, is 24 hours total urine protein must < 500mg; - blood glucose:normal range,DM(diabetes mellitus) patients are under treatment and have a stable state; - Can understand and consent Exclusion Criteria: - Patients have been treated with brain radiation or surgery of BM; - Prior of EGFR-TKIs; - Mixed with small cell lung cancer patients with components; - Wild-type of EGFR; - Unable to tolerate MRI scanning; - Post 2 line treated patients; - Brain meninges metastases or incorporate with brain meninges metastases; - 5 years before other cancers except NSCLC treatment in patients with the start of the study (except for simple operation resection and there are at least 5 consecutive years disease free survival, has been cured of cervical carcinoma in situ, has cured the base cell cancer and bladder epithelial tumor); - Before entering the group 4 weeks received any other investigational drugs; - Incorporate with local symptoms(hemiplegic paralysis, anepia, nystagmus, ataxia.et); --- L858R ---

Inclusion Criteria: - years of age or older - ECOG score ≤ 2 - Recursive Partitioning Analysis(RPA) Class I-II; - The pathological diagnosis of primary non-small cell lung cancer and detection of pulmonary primary ARMs; - Sequencing EGFR mutation(primary lesion or metastases,exon 19 deletions or exon 21 L858R (EGFR mutation in exon 21, L858R point mutation) mutations; - Enhanced MRI showed brain metastases ≥ 4; - 1 or 2 line treatment revealed failure; - No use of EGFR-TKIs(Tyrosine kinase inhibitors) previously; - No treatment for BM previously,including WBRT, SRS, surgery or experimental therapy; - Expected survival period over 3 months; - Two weeks before randomization, organs function in patients with meet the following criteria: - bone marrow:HB(hemoglobin) ≥ 90g/L, neutrophil≥ 1.5 × 109/L and platelet ≥ 100 × 109/L; - liver function:total bilirubin ≤ 1.5 times the upper limit of normal, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times the upper limit of normal; - renal function:more than 1.5 times the upper limit of normal serum creatinine or creatinine clearance rate ≥ 60 ml/min; - Urine dipstick testing the proteinuria < 1+; if the urine dipstick test value, 1+, is 24 hours total urine protein must < 500mg; - blood glucose:normal range,DM(diabetes mellitus) patients are under treatment and have a stable state; - Can understand and consent Exclusion Criteria: - Patients have been treated with brain radiation or surgery of BM; - Prior of EGFR-TKIs; - Mixed with small cell lung cancer patients with components; - Wild-type of EGFR; - Unable to tolerate MRI scanning; - Post 2 line treated patients; - Brain meninges metastases or incorporate with brain meninges metastases; - 5 years before other cancers except NSCLC treatment in patients with the start of the study (except for simple operation resection and there are at least 5 consecutive years disease free survival, has been cured of cervical carcinoma in situ, has cured the base cell cancer and bladder epithelial tumor); - Before entering the group 4 weeks received any other investigational drugs; - Incorporate with local symptoms(hemiplegic paralysis, anepia, nystagmus, ataxia.et); --- L858R --- --- L858R ---

Primary Outcomes

Description: Compare the progression free survival(PFS) and safety in two arms,including intracranial PFS、extracranial PFS and overall PFS.

Measure: Time to progression

Time: 12-14 months

Secondary Outcomes

Measure: Overall survival

Time: 3 years

Description: intracranial or extracranial site

Measure: Disease Progression Classification

Time: 3 years

Description: measured by ECGO(Eastern Cooperative Oncology Group) PS (Performance Status)

Measure: Health-related quality of life

Time: 3 years

Description: measured by scale of MMSE( Mini Mental Status Examination)

Measure: Mental Status

Time: 3 years

110 Phase II Trial of Afatinib in Combination With Weekly Paclitaxel in the Second Line Treatment of HER2 Amplified Advanced Gastric, Gastroesophageal Junction and Esophageal Cancer

The investigators are doing this research program to find out if the investigational drug, afatinib which is a medication known to block the function of the ErbB2 protein might help standard chemotherapy, in particular paclitaxel, work better. Afatinib (GILOTRIF) is a highly potent, irreversible inhibitor of the EGFR and HER2. On July 12, 2013 the United States Food and Drug Administration (US FDA) approved afatinib for the first-line treatment of patients with metastatic non-small cell lung cancer whose tumors had specific EGFR gene mutations (exon 19 deletions or exon 21 i.e. L858R substitution mutations) as detected by an FDA approved test. Paclitaxel is a standard, anti-cancer medicine that has been approved by the US Food and Drug Administration (FDA) for the treatment of lung cancer. The combination of Afatinib and Paclitaxel are considered investigational when used in this research program. An investigational drug is a drug that is not approved by the FDA for its indication.

NCT02274012 HER-2 Positive Gastric Cancer Gastrooesophageal Cancer Esophageal Cancer Drug: Afatinib Drug: Paclitaxel
MeSH: Esophageal Neoplasms
HPO: Esophageal neoplasm

L858R substitution mutations) as detected by an FDA approved test. --- L858R ---

Primary Outcomes

Measure: Change of tumor burden (in centimeters) for participants during protocol therapy

Time: Change from Baseline Tumor burden, measured every 8 weeks, up to approximately 4 years

Secondary Outcomes

Description: Safety of BIBW 2992 will be evaluated as indicated by intensity and incidence of adverse events, graded according to US National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) Version 4.0. Safety endpoints include: events leading to dose reduction events leading to permanent treatment discontinuation the overall incidence and CTC criteria grade of adverse events, as well as relatedness of adverse events to treatment causes of death

Measure: Number of participants with adverse events.

Time: up to approximately 36 months

Description: CTC number changes from cycle 1, day 1 to cycle 2/3, day 1 will be correlated with response rate, progression-free survival as well as skin toxicity.

Measure: Total number of circulating tumor cell (CTC) numbers.

Time: up to approximately 36 months

Measure: Clinical benefit in progression free survival.

Time: every 3 months up to approximately 4 years

Measure: Clinical benefit in overall survival.

Time: every 3 months up to approximately 4 years

Description: Diagnostic tumor specimens will be retrieved for all subjects participating in the protocol. These specimens will be used for confirmation of ErbB2 status as well as correlative analyses of clinical response.

Measure: ErbB2 levels benefit during therapy.

Time: up to approximately 4 years

111 A Prospective Study of Plasma Genotyping as a Noninvasive Biomarker for Genotype-directed Cancer Care

Tumor genotyping has become an essential biomarker for the care of advanced lung cancer and melanoma, and is currently used to identify patients for treatment with targeted kinase inhibitors like erlotinib and vemurafenib. However, tumor genotyping can be slow and cumbersome, and is limited by availability of tumor biopsy tissue for testing. The aim of this study is to prospectively evaluate a blood-based genotyping tool that can quantify the presence of oncogenic mutations (EGFR, KRAS, BRAF) in patients with lung cancer and melanoma. This assay is being studied both as a diagnostic tool for classifying patient genotype, and a serial measurement tool for quantification of response and progression on therapy.

NCT02279004 NSCLC Melanoma
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

We will determine the accuracy of plasma NGS in performing noninvasive genotyping compared to tumor NGS and paired ddPCR.. Inclusion Criteria To participate in this study a participant must meet the eligibility of one of the following cohorts: Cohort 1: Cancers beginning initial treatment - One of the following diagnoses: - Cohort 1A (CLOSED): ---Advanced non-squamous NSCLC (including adenosquamous) - Cohort 1B: - Stage II-III non-squamous NSCLC (including adenosquamous) - Stage IIIB-IV melanoma - Patient must be planned to begin initial therapy, or completely resected before or after receiving adjuvant therapy - For patients with NSCLC, EGFR and KRAS genotype may be known or unknown - For patients with melanoma, BRAF and NRAS genotype may be known or unknown - For patients without tumor genotyping, there must be a plan for genotyping including either: - Archived tumor tissue available and planned for genotyping - A biopsy at some future time is anticipated and will be available for genotyping Cohort 2: Cancers with acquired resistance to targeted therapy - One of the following diagnoses: - Cohort 2A (CLOSED): ---Advanced NSCLC harboring a known EGFR mutation - Cohort 2B: - Advanced NSCLC harboring a targetable genotype other than EGFR - Advanced melanoma harboring a known tumor genotype - Clinical determination of progression targeted therapy, as evidence by plans to start a new systemic treatment regimen, or obtain a biopsy to plan a new treatment regimen - New systemic treatment regimen planned OR - Re-biopsy for resistance genotyping planned - Note, date of targeted therapy start and clinical progression must be provided Cohort 3: Cancers with a known genotype starting palliative systemic therapy Cohort 3A (CLOSED): - Advanced NSCLC harboring one of the following mutations: - EGFR exon 19 deletion - EGFR L858R - EGFR T790M - KRAS G12X - BRAF V600E - Patients must be initiating palliative systemic therapy, either on or off a clinical trial Cohort 4: Paired plasma NGS and ddPCR - Cohort 4A (CLOSED): - Advanced NSCLC, newly diagnosed or with progression following treatment. --- L858R ---

T790M, etc) Exclusion Criteria - Participants who are unable to provide informed consent - Participants who are 18 years of age or younger - Participants who are unable to comply with the study procedures Inclusion Criteria To participate in this study a participant must meet the eligibility of one of the following cohorts: Cohort 1: Cancers beginning initial treatment - One of the following diagnoses: - Cohort 1A (CLOSED): ---Advanced non-squamous NSCLC (including adenosquamous) - Cohort 1B: - Stage II-III non-squamous NSCLC (including adenosquamous) - Stage IIIB-IV melanoma - Patient must be planned to begin initial therapy, or completely resected before or after receiving adjuvant therapy - For patients with NSCLC, EGFR and KRAS genotype may be known or unknown - For patients with melanoma, BRAF and NRAS genotype may be known or unknown - For patients without tumor genotyping, there must be a plan for genotyping including either: - Archived tumor tissue available and planned for genotyping - A biopsy at some future time is anticipated and will be available for genotyping Cohort 2: Cancers with acquired resistance to targeted therapy - One of the following diagnoses: - Cohort 2A (CLOSED): ---Advanced NSCLC harboring a known EGFR mutation - Cohort 2B: - Advanced NSCLC harboring a targetable genotype other than EGFR - Advanced melanoma harboring a known tumor genotype - Clinical determination of progression targeted therapy, as evidence by plans to start a new systemic treatment regimen, or obtain a biopsy to plan a new treatment regimen - New systemic treatment regimen planned OR - Re-biopsy for resistance genotyping planned - Note, date of targeted therapy start and clinical progression must be provided Cohort 3: Cancers with a known genotype starting palliative systemic therapy Cohort 3A (CLOSED): - Advanced NSCLC harboring one of the following mutations: - EGFR exon 19 deletion - EGFR L858R - EGFR T790M - KRAS G12X - BRAF V600E - Patients must be initiating palliative systemic therapy, either on or off a clinical trial Cohort 4: Paired plasma NGS and ddPCR - Cohort 4A (CLOSED): - Advanced NSCLC, newly diagnosed or with progression following treatment. --- T790M --- --- L858R ---

Primary Outcomes

Description: We will determine the accuracy of a droplet digital PCR (ddPCR)-based plasma genotyping assay in performing noninvasive tumor genotyping.

Measure: Accuracy of Plasma Genotyping Assay

Time: 2 years

Secondary Outcomes

Description: The amount of time required to perform this noninvasive genotyping assay.

Measure: Turnaround Time of Plasma Genotyping Assay

Time: 2 years

Description: The ability of serial quantitative ddPCR-based plasma genotyping to predict early treatment failure in patients initiating a new line of therapy.

Measure: Early Treatment Failure

Time: 2 years

Description: We will determine the accuracy of plasma NGS in performing noninvasive genotyping compared to tumor NGS and paired ddPCR.

Measure: Accuracy of Plasma NGS

Time: 2 years

112 Phase I/II Clinical Trial Combining TUSC2-nanoparticles and Erlotinib in Stage IV Lung Cancer

The goal of phase 1 of this clinical research study is to find the highest dose of DOTAP:Chol-TUSC2 that can be safely given in combination with Tarceva (erlotinib hydrochloride) to patients with NSCLC. The goal of phase 2 of this clinical research study is to learn if the combination of DOTAP:Chol-TUSC2 and erlotinib hydrochloride can help to control NSCLC. The safety of this drug combination will also be studied in both phases. DOTAP:Chol-TUSC2 (previously FUS1) is a drug that helps transfer a gene called TUSC2 into cancer cells. Researchers think that cells without this gene may be involved in the development of lung cancer tumors. They want to find out if replacing the gene in these cells may keep the tissue from forming cancer cells. Erlotinib hydrochloride is designed to block a protein on tumor cells that may control tumor growth and survival. This may stop tumors from growing.

NCT01455389 Lung Cancer Drug: DOTAP:Chol-TUSC2 Drug: Erlotinib Drug: Dexamethasone Drug: Diphenhydramine
MeSH: Lung Neoplasms
HPO: Neoplasm of the lung

Subjects must have specimens adequate for analysis of EGFR mutations (and other clinically relevant biomarkers) 4. All subjects with an activating EGFR mutation (exon 19 deletion or exon 21 L858R mutation) are eligible IF they have progressed following treatment with a first, second, or third generation EGFR inhibitor. --- L858R ---

Primary Outcomes

Description: MTD defined as dose level at which less than 2 participants experience dose-limiting toxicity (DLT). Toxicity graded according to National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 4. DLT will be grade > 3 toxicity occurring during the first cycle of therapy (i.e., within the first 3 weeks).

Measure: Maximum Tolerated Dose (MTD) Level for Drug Treatment Combination

Time: First 21 day cycle

Secondary Outcomes

Description: Responses determined by RECIST criteria. Responses will include only complete response (CR) + partial response (PR). Participants considered as non-responders when tumor progression by RECIST is observed. Measurable disease is defined as tumor masses with identifiable diameters measurable in two dimensions by computed tomography. Best overall response is best response designation recorded from the start of treatment until disease progression. Complete and partial responses have to be confirmed by two evaluations of the disease taken at least four weeks apart.

Measure: Response Rate

Time: After two, 21 day cycles

113 Multicenter, Randomized, Phase Ib/IIb Study to Evaluate the Efficacy and Tolerability of Gefitinib in Combination With Olaparib (AZD2281) Versus Gefitinib Alone, in Patients With EGFR Mutation Positive Advanced Non-small-cell Lung Cancer

This is a study of gefitinib plus olaparib gefitinib in combination with olaparib (AZD2281) versus gefitinib alone, in patients with Epidermal Growth Factor Receptor (EGFR) mutation positive advanced non-small-cell lung cancer.

NCT01513174 Non Small Cell Lung Cancer Drug: Gefitinib Drug: Gefitinib plus olaparib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

4. Tumor tissue available (according to the criterion of the specimen-processing laboratory) for EGFR mutation assessment: to be included in the study patients should present at least one EGFR mutation (exon 19 deletion or L858R with or without T790M). --- L858R ---

Primary Outcomes

Measure: MTD (Maximum Tolerated Dose) defined as the highest dose level at which < 2 out of 6 patients experience a DLT

Time: 5 weeks

Secondary Outcomes

Measure: Progression-free survival

Time: An expected average of 2 years

Measure: Overall response rate

Time: An expected average of 2 years

Measure: Overall survival

Time: An expected average of 2 years

Measure: Peak Plasma Concentration

Time: Predose, half an hour, 1, 2, 4, 6 and 12 hours post-dose

114 A Phase Ib Study of Afatinib Plus Nimotuzumab in Non-small Cell Lung Cancer Patients Who Progressed With Reversible EGFR TKI

To find the optimal dose of afatinib and nimotuzumab in patients who acquired resistance to gefitinib or erlotinib.

NCT01861223 NSCLC Drug: afatinib (30 or 40mg) + nimotuzumab (100 or 200mg)

Inclusion Criteria: - Histologically confirmed diagnosis of stage IIIB or IV NSCLC - Presence of EGFR sensitizing mutations (L858R mutation in exon 21 or exon 19 deletion) or response by RECIST on prior gefitinib or erlotinib or stable disease on prior gefitinib or erlotinib for at least 6 months - Disease progression on treatemtn with gefitinib or erlotinib within 30 days - Biopsy on disease progression - Age ≥20 years - ECOG performance status of 0, 1, or 2 - Measurable disease by the criteria of RECIST 1.1 - Adequate organ function as evidenced by the following; Absolute neutrophil count > 1.5 x 109/L; platelets > 100 x 109/L; total bilirubin ≤1.5 UNL; AST and/or ALT < 5 UNL; creatinine clearance ≥ 45 mL/min Exclusion Criteria: - Known interstitial lung disease - Prior treatment with EGFR targeting antibodies or BIBW 2992 - Prior three or more lines of chemotherapy for advanced NSCLC - Significant bowel disease impairing drug absorption - Uncontrolled systemic illness such as DM, CHF, unstable angina, hypertension or arrhythmia - Have symptomatic, untreated, or uncontrolled central nervous system (CNS) metastases. --- L858R ---

Primary Outcomes

Description: To establish maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) for BIBW 2992 and nimotuzumab in patients with acquired resistance to erlotinib or gefitinib

Measure: Maximal tolerated dose

Time: 4 weeks

115 A Randomized Open-Label Phase II Trial of Pemetrexed and a Platinum (Carboplatin or Cisplatin) With or Without Erlotinib in Patients With Non-Small Cell Lung Cancer Harboring Activating Epidermal Growth Factor Receptor Mutations and Acquired Resistance to First-Line EGFR TKIs, Erlotinib or Gefitinib

This randomized phase II trial studies how well pemetrexed disodium and carboplatin or cisplatin with or without erlotinib hydrochloride work in treating patients with epidermal growth factor receptor (EGFR) mutant positive stage IV non-small cell lung cancer and acquired resistance to first-line therapy with erlotinib hydrochloride or gefitinib. In patients that develop resistance to first-line therapy with EGFR tyrosine kinase inhibitors (TKIs) the drug is usually stopped and the patient is switched to chemotherapy. Drugs used in chemotherapy, such as pemetrexed disodium, carboplatin, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether pemetrexed disodium and carboplatin or cisplatin is more effective with or without erlotinib hydrochloride in treating patients with EGFR mutant non-small cell lung cancer and acquired resistance to EGFR TKIs.

NCT01928160 Recurrent Non-small Cell Lung Cancer Stage IV Non-small Cell Lung Cancer Drug: pemetrexed disodium Drug: carboplatin Drug: cisplatin Drug: erlotinib hydrochloride Other: laboratory biomarker analysis
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

- Age > 18 years - Able and willing to comply with the protocol - Histologically- or cytologically-confirmed Stage IV NSCLC with an EGFR exon-19 deletion or L858R mutation - Must have received at least 6 months of first-line therapy with erlotinib or gefitinib - Clinical evidence of progression on first-line EGFR TKI therapy - Adequate hematological function within 7 days of study treatment initiation: 1. Absolute neutrophil count (ANC) > 1.5 x 109/L AND 2. Platelet count > 100 x 109/L AND 3. Hemoglobin > 9 g/dL (may be transfused to maintain or exceed this level) - Adequate liver function within 7 days of study treatment initiation: 1. --- L858R ---

Primary Outcomes

Description: The Kaplan-Meier approach will be used to estimate the time-to-PFS distribution (and median PFS times) for each treatment arm. The stratified log-rank test will be used to compare the PFS distributions between the two treatment arms. The stratified Cox-regression model will be used to estimate the hazard ratio (erlotinib plus chemotherapy vs chemotherapy alone) and corresponding 80% confidence interval (CI).

Measure: Progression free survival using the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1

Time: From randomization to the first occurrence of disease progression or death from any cause, whichever occurs earlier, assessed up to 1 year

Secondary Outcomes

Description: The Kaplan-Meier approach will be used. The stratified log-rank test will be used to compare the Overall Survival (OS) distributions between the two treatment arms. The stratified Cox-regression model will be used to estimate the hazard ratio (erlotinib plus chemotherapy vs chemotherapy alone) and corresponding 80% confidence interval (CI).

Measure: Overall survival

Time: From the date of randomization to the date of death from any cause, assessed up to 1 year

Description: An estimate of the objective response rate and its 95% CI (Blyth-Still-Casella) will be calculated for each treatment arm. The Mantel-Haenszel chi-squared test stratified according to the factors specified by EGFR activating mutation type (exon 19 deletion vs. exon 21 single point mutation), time to progression on first-line EGFR TKI (≤ 1 year vs. > 1 year), and ECOG performance status (0 vs. 1) will be used to compare the response rates between the two treatment arms. An unadjusted Fisher's exact test result will also be provided.

Measure: Objective response rate defined as partial response (PR) and complete response (CR) using RECIST version 1.1

Time: Up to 1 year

Description: Safety will be assessed through summaries of Adverse Events (AEs), Serious Adverse Events (SAEs), deaths, grade 3 or 4 AEs, AEs with incidence rates greater than 10% (all grades), AE of grade 3 or 4 with incidence rates greater 2%, and changes in laboratory test results. Verbatim descriptions of AEs will be mapped to Medical Dictionary for Regulatory Activities (MedDRA) thesaurus terms

Measure: Number of patients with each worst grade toxicity grades 3-5 based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4

Time: Up to 45 days post-treatment

116 A Randomized, Open-Label, Multi Center, Phase III Study to Assess the Efficacy and Safety of HS-10296 Versus Gefitinib as First-Line Treatment in Patients With EGFR Mutation Positive, Locally Advanced or Metastatic NSCLC

This is a randomized, open-Label, multicenter, Phase III study.

NCT03849768 Non Small Cell Lung Cancer Drug: HS-10296 Drug: Gefitinib
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

4. The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either or in combination with other EGFR mutations assessed by central testing using tumour tissue sample or blood sample. --- L858R ---

Primary Outcomes

Description: To assess the efficacy of HS-10296 compared with gefitinib as first line therapy to EGFRm+, locally advanced or metastatic NSCLC patients by assessment of progression free survival (PFS) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).

Measure: Assess the efficacy of HS-10296: progression free survival (PFS)

Time: From baseline, then every 6 weeks, until disease progression or discontinuation from study. From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months.

Secondary Outcomes

Description: Overall survival (OS)

Measure: Assess the anti-tumor activity: OS

Time: Start of study drug to Survival Endpoint through study completion, an average of 3 years.

Description: Objective response rate (ORR)

Measure: Assess the anti-tumor activity: ORR

Time: From baseline, then every 6 weeks, until disease progression or discontinuation from study. ORR is defined as the percentage of patients who have at least 1 response of CR or PR prior to any evidence of progression assessed up to 24 months.

Description: Duration of response (DoR)

Measure: Assess the anti-tumor activity: DoR

Time: DoR is defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression assessed up to 24 months.

Description: Disease control rate (DCR)

Measure: Assess the anti-tumor activity: DCR

Time: From baseline, then every 6 weeks, until disease progression or discontinuation from study. The DCR is defined as the proportion of patients with a best overall response of CR, PR, or SD assessed up to 24 months.

Description: Depth of response (DepOR)

Measure: Assess the anti-tumor activity: DepOR

Time: From baseline, then every 6 weeks, until disease progression or discontinuation from study. DepOR is defined as the sum of the lengths of the longest diameters of the RECIST 1.1 target lesions up to 24 months.

Description: Number of adverse events (AEs)/serious adverse events (SAEs)

Measure: Assess the safety of HS-10296: Number of AEs/SAEs

Time: Continuously throughout the study until 28 days after HS-10296 discontinuation

Description: Incidence and severity of AEs/SAEs assessed by CTCAE v4.03

Measure: Assess the safety of HS-10296: Incidence and severity of AEs/SAEs

Time: Continuously throughout the study until 28 days after HS-10296 discontinuation

Description: Dose interruptions

Measure: Assess the safety of HS-10296: Number of Participants with Dose interruptions

Time: Continuously throughout the study until 28 days after HS-10296 discontinuation.

Description: Dose reductions

Measure: Assess the safety of HS-10296: Number of Participants with Dose reductions

Time: Continuously throughout the study until 28 days after HS-10296 discontinuation.

117 An Open-Label Randomized Phase II Study of Combining Osimertinib With and Without Ramucirumab in Tyrosine Kinase Inhibitor (TKI)-naïve Epidermal Growth Factor Receptor (EGFR)-Mutant Locally Advanced or Metastatic NSCLC

The primary objective of the study is to evaluate the efficacy of osimertinib plus ramucirumab versus osimertinib alone using progression free survival (PFS). Events associated with PFS include: disease progression per RECIST 1.1 and death due to any cause. A total of 150 patients will be enrolled and randomized in a 2:1 fashion (osimertinib plus ramucirumab vs. osimertinib) to the two treatment arms according to the following stratification factors: types of epidermal growth factor receptor (EGFR) mutations and presence of brain metastasis.

NCT03909334 Non Small Cell Lung Cancer EGFR Gene Mutation Advanced Cancer Metastatic Cancer Drug: Osimertinib Drug: Ramucirumab
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis
HPO: Neoplasm of the lung Non-small cell lung carcinoma

- NSCLC which harbors EGFR L858R mutation. --- L858R ---

Primary Outcomes

Description: Progression free survival (PFS) time will be calculated from the date of randomization to disease progression or death from any cause, whichever occurs the first.

Measure: Progression Free Survival (PFS)

Time: 3 years

Secondary Outcomes

Description: Objective Response Rate (ORR) is defined as the number (%) of subjects with measurable disease with at least one visit response of complete response (CR) or partial response (PR). Data obtained up until progression, or last evaluable assessment in the absence of progression, will be included in the assessment of ORR.

Measure: Objective Response Rate (ORR)

Time: 1 year

Description: Disease control rate (DCR) is defined as the percentage of subjects who have a best overall response of CR or PR or stable disease (SD).

Measure: Disease control rate (DCR)

Time: 2 years

Description: Overall survival (OS) time is defined from the date of randomization to death date. A patient is censored at the last follow-up date if death has not been observed.

Measure: Overall survival (OS)

Time: 3 years

Description: Toxicities will be measured in frequency and severity using CTCAE v5

Measure: Assess frequency and severity of adverse events

Time: 2 years

118 A Single Arm Phase II Study Osimertinib in Patients With Stage 4 Non-small Cell Lung Cancer With Uncommon EGFR Mutations

This is a research study to find out if a drug called, osimertinib, is safe and effective in treating advanced Non-Small Cell Lung Cancer (NSCLC) by targeting the treatment of epidermal growth factor receptor (EGFR) mutation exon 18 G719X, exon 20 S7681, or exon 21 L861Q. Patients on the study will not have had previous tyrosine kinase inhibitor (TKI) treatment.

NCT03434418 Non Small Cell Lung Cancer Drug: osimertinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

- Malabsorption syndrome, refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib - Detection of concurrent EGFR mutation with exon 20 T790M, exon 19 deletion, exon 21 L858R mutation or exon 20 insertion. --- T790M --- --- L858R ---

Primary Outcomes

Description: RECIST 1.1 will be used to measure confirmed partial or complete responses to the study drug.

Measure: Objective response rate as assessed by the investigator using Response Evaluation Criteria In Solid Tumors RECIST 1.1 (brand name)

Time: Up to 3 years

Secondary Outcomes

Description: Progression will be defined as time from starting study therapy to disease progression or death (whichever occurs first)

Measure: Progression free survival as measured by Response Evaluation Criteria In Solid Tumors RECIST 1.1 (brand name) as assessed by the investigator.

Time: Up to 5 years

Description: Evaluation of safety using the National Cancer Institute (NCI) CTCAE version 4.03

Measure: AEs as measured by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03

Time: Up to 3 years

Description: Overall survival as defined as time from starting study therapy until death from any causes.

Measure: Overall survival as noted by follow-up via composite of telephone or medical record review.

Time: Up to 5 years

119 A Phase II Study to Evaluate Neoadjuvant Osimertinib Therapy in Patients With Surgically Resectable, EGFR-Mutant Non-Small Cell Lung Cancer

This phase II trial studies how well osimertinib works in treating participants with stage I-IIIA Epithelial Growth Factor Receptor (EGFR) -mutant non-small cell lung cancer before surgery. Osimertinib may stop the growth of tumor cells by blocking mutant EGFR signaling in cancer cells.

NCT03433469 Stage I Non-Small Cell Lung Cancer Stage IA Non-Small Cell Lung Cancer Stage IB Non-Small Cell Lung Cancer Stage II Non-Small Cell Lung Cancer Stage IIA Non-Small Cell Lung Cancer Stage IIB Non-Small Cell Lung Cancer Stage IIIA Non-Small Cell Lung Cancer Other: Laboratory Biomarker Analysis Drug: Osimertinib Procedure: Therapeutic Conventional Surgery
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Histologically or cytologically confirmed non-small cell lung cancer, performed on a biopsy that occurred within the last 60 days - Documented activating EGFR mutation (Exon 19 deletion, T790M, or L858R) on tumor samples by Food and Drug Administration (FDA)-approved test - Positron emission tomography (PET)-computed tomography (CT) within the last 60 days showing radiographic stage I to IIIa lung cancer (mediastinal staging biopsy is allowed but not required) - Brain magnetic resonance imaging (MRI) (or CT if contraindication to MRI) within the last 60 days showing no evidence of metastatic disease - Documentation that the patient is a candidate for surgical resection of their lung cancer by an American Board of Thoracic Surgery certified surgeon - Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria - The patient must have a tumor size >=1 centimeter (cm) in its longest diameter. --- T790M --- --- L858R ---

malabsorption syndrome, history of biliary tract disease), including refractory nausea or vomiting, or chronic GI disease which may affect absorption or tolerance to oral medications - History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib - Involvement in the planning and/or conduct of the study (applies to both investigator staff and/or staff at the study site) - Participation in another clinical study with an investigational product during the last 2 months or within five half-lives of the compound, whichever is longer - Uncontrolled medical, psychological, familial, sociological, or geographical conditions that interfere with the patient?s safety, ability to provide informed consent, or ability to comply with the protocol Inclusion Criteria: - Histologically or cytologically confirmed non-small cell lung cancer, performed on a biopsy that occurred within the last 60 days - Documented activating EGFR mutation (Exon 19 deletion, T790M, or L858R) on tumor samples by Food and Drug Administration (FDA)-approved test - Positron emission tomography (PET)-computed tomography (CT) within the last 60 days showing radiographic stage I to IIIa lung cancer (mediastinal staging biopsy is allowed but not required) - Brain magnetic resonance imaging (MRI) (or CT if contraindication to MRI) within the last 60 days showing no evidence of metastatic disease - Documentation that the patient is a candidate for surgical resection of their lung cancer by an American Board of Thoracic Surgery certified surgeon - Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria - The patient must have a tumor size >=1 centimeter (cm) in its longest diameter. --- T790M --- --- L858R ---

Primary Outcomes

Description: Tumors that exhibit =< 10% viable tumor will meet the criteria for a major pathological response. The major pathological response rate will be reported with 95% confidence intervals.

Measure: Major pathological response rate (MPR) defined as =< 10% viable tumor present histologically in the resected tumor specimen

Time: Up to 1 year

Secondary Outcomes

Description: The Kaplan-Meier analysis will be used to calculate the mean DFS with 95% confidence interval.

Measure: 1 year disease-free survival (DFS)

Time: From date of surgical resection to documented radiographic relapse/progression or death due to any cause, assessed up to 1 year

Description: The Kaplan-Meier analysis will be used to calculate the mean OS with 95% confidence interval.

Measure: 1 year overall survival (OS)

Time: From surgical resection to death due to any cause, assessed up to 1 year

Description: Depth of response will be summarized using descriptive statistics and correlated with patient outcomes using hazard ratios via the Cox proportional hazards model.

Measure: Depth of response (DpR) defined as the percentage change in tumor burden by RECIST criteria at best response versus baseline imaging

Time: Baseline up to 1 year

Description: The frequency and percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be determined. The ORR will be reported with 95% confidence intervals.

Measure: Objective Response Rate (ORR) determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria by investigator's assessment

Time: From start of treatment until time of surgery

Measure: Pathologic complete response rate (pCR) defined as absence of (0%) viable tumor present histologically in the resected tumor specimen

Time: Up to 1 year

Description: Rate of conversion from operable to non-operative will be recorded as rate of patients initially assessed as surgically resectable, who are subsequently unable to undergo surgical resection due to either treatment-related adverse events (AEs) or disease progression.

Measure: Rate of inability to undergo surgical resection

Time: Up to 1 year

Description: Rate of surgical complications occurring prior to the end of treatment visit will be recorded.

Measure: Rate of surgical complications occurring prior to the end of treatment visit

Time: Up to 1 year

Description: AE terms recorded on the case report forms (CRFs) will be mapped to preferred terms using the Medical Dictionary for Regulatory Activities (MedDRA). Seriousness, severity grade and relationship to study treatment will be assessed by the investigator. Severity grade will be defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Measure: Treatment-emergent adverse events (AEs), laboratory abnormalities and electrocardiogram (ECG) abnormalities

Time: Up to 1 year

Other Outcomes

Description: Rates of adverse pathologic features including rates of positive margins, lymphovascular invasion (LVI), and pathologic upstaging (e.g. by T or N status) as compared to clinical staging based on pre-operative scans, for comparison to historical controls will be recorded.

Measure: Adverse pathologic outcomes

Time: Up to 1 year

Description: Descriptive statistics and graphical methods will be used to analyze the data.

Measure: Changes in circulating tumor deoxyribonucleic acid (ctDNA)

Time: Baseline up to 1 year

Measure: Changes in immune cell infiltration

Time: Baseline up to 1 year

Description: Performance of RNA sequencing and whole exome sequencing analysis on isolated cancer cell populations from pre-treatment tumor biopsy specimens, as well as tumor tissue acquired at the time of surgical resection. Changes of expression levels to baseline will described by calculating z-score

Measure: Calculation of z-score to describe genomic and transcriptional changes within cancer cell populations after treatment

Time: Baseline up to 1 year

Description: Peripheral blood and plasma samples will be stored for the assessment of variant allele frequencies

Measure: Concentration of ctDNA in peripheral blood samples

Time: Up to 1 year

120 Trial of Afatinib (BIBW 2992) in Suspected or Confirmed Mutant EGFR Lung Cancer Patients Unfit for Chemotherapy

The purpose of this study is to examine the efficacy and safety of using afatinib (BIBW 2992) to treat non-small cell lung cancer patients considered unfit for chemotherapy and have either suspected or confirmed Epidermal Growth Factor Receptor (EGFR) mutation.

NCT01415011 Carcinoma, Non-Small-Cell Lung Drug: Afatinib (BIBW 2992)
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

L858R, exon 19 deletions, exon 20 insertions, T790M, list is not exhaustive), and WHO PS 0-3 Or No tissue suitable for EGFR genotyping, failed genotype, or EGFR genotyping unavailable, and NSCLC Adenocarcinoma sub-type, and Eligible smoking history: Never smoker (<100 cigarettes in lifetime), or Former smoker (stopped >1year ago and ≤10 pack-years) and WHO PS 0-2 - Unsuitable for or patient declining chemotherapy due to significant co-morbidity - Measurable disease according to RECIST version 1.1 - Adequate haematopoietic, hepatic and renal function defined as follows: Absolute neutrophil count (ANC) ≤1.5 x 109/L and platelet count ≤100 x 109/L - Bilirubin ≤1.5 x ULN, ALT (SGPT) ≤3 x ULN (or ≤ 5 x ULN in cases of liver metastases) - Serum creatinine clearance ≥45 ml/min - Palliative radiotherapy allowed unless to a solitary target lesion - Age 18 or over (no upper age limit) - Written informed consent that is consistent with ICH-GCP guidelines Exclusion Criteria: - Previous treatment with afatinib (BIBW 2992), or any EGFR-directed inhibitor - Any concurrent anticancer systemic therapy - Prior chemotherapy for relapsed and/or metastatic NSCLC - Neoadjuvant/adjuvant chemotherapy is permitted if at least 12 months has elapsed between the end of chemotherapy and registration - Suitable for radical radiotherapy - Palliative radiotherapy within 2 weeks prior to registration - Palliative radiotherapy to a solitary target lesion - Surgery (other than biopsy) within 4 weeks prior to registration - Inability to take oral medication, requirement for intravenous feeding, active peptic ulcer, prior surgical procedures affecting absorption, any medical co- morbidity affecting gastrointestinal absorption - Patients with current or pre-existing interstitial lung disease - Active or uncontrolled infections or serious illnesses or medical conditions that could interfere with the patient's participation in the trial - Significant or recent acute gastrointestinal abnormalities with diarrhoea as a major symptom e.g., Crohn's disease, mal-absorption, or CTCAE version 4.0 Grade ≥3 diarrhoea of any etiology at baseline - Active brain metastases (defined as stable for <4 weeks and/or symptomatic and/or requiring treatment with anticonvulsants and/or leptomeningeal disease). --- L858R ---

Primary Outcomes

Description: Progression free survival will be determined by measurement of tumour size using RECIST version 1.1 at progression or date of patient death.

Measure: Progression free survival

Time: At 6 months

Secondary Outcomes

Measure: Overall response

Time: CT scan of chest & abdomen 4 weeks after registartion, then every 8 calender weeks until disease progression. CT scans every 12 weeks if patient is still on BIBW 2992 after 1 year of treatment.

Measure: Overall survival

Time: This will be measured in days, from the first day of treatment to the day of death.

Measure: Change in performance status

Time: At 1 month

Description: For each type of adverse event, the maximum toxicity grade will be obtained for each patient using CTCAE version 4.0 to closely monitor tolerability to BIBW 2992. Focus will be on those with a grade 3 or 4 BIBW 2992 related toxicities. The proportion of patients with any grade 3 or 4 event will also be examined.

Measure: Safety

Time: To be assessed at every timepoint i.e. baseline, fortnightly for the first 2 cycles and then monthly for 12 months and 2 monthly thereafter

Measure: Progression free survival in patients aged 70 and over

Time: At progression or patient death

Measure: Treatment compliance

Time: Compliance will be examined based on the time between starting treatment and stopping it completely

121 Pilot Study to Identify the Mechanism of De Novo Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) in NSCLC With EGFR Mutation.

This study is based on the following hypothesis "De novo resistance to EGFR-TKI in EGFR mutation positive patients is related with mutations in EGFR downstream genes". Investigators will prospectively collect genomic DNA and clinical data regarding treatment outcomes to EGFR-TKI in NSCLC patients with activating EGFR mutations. Investigators will sequence candidate mutations of EGFR downstream genes and analyze c-met gene amplification and protein expression in PTEN, HGF, and IGFR. To identify genetic mutations, amplification, and protein over expression as predictive markers of treatment outcomes, investigators analyzed the association of treatment outcomes with the presence of genetic alteration or protein over expression. Investigators will attempt to identify biomarkers that are able to predict de novo resistance to EGFR-TKI in EGFR mutated NSCLC.

NCT01697163 NSCLC

Inclusion Criteria: 1. Pathologically proven unresectable NSCLC 2. 20 years of age or older 3. Planned treatment with Iressa® 4. Patients with activating EGFR mutation (del 19, L858R) 5. Available detailed smoking history 6. Available tissue samples (archival tissue) for mutational or molecular analysis (representative paraffin block or unstained sections from tumor diagnostic specimen are mandatory) 7. Available blood sample 8. --- L858R ---

Primary Outcomes

Description: The primary objective is to compare hazard rates of PFS in patients treated with Iressa between with and without any molecular aberrancy in EGFR-downstream genes/proteins.

Measure: hazard rates of PFS

Time: 1year

Other Outcomes

Description: Overall survival (OS) of EGFR-TKI according to each biomarker (i.e. PIK3CA, AKT, PTEN, and STK11 mutation and HGF, c-met, and IGFR amplification) Disease control rate (DCR) of EGFR-TKI according to each biomarker (i.e. PIK3CA, AKT, PTEN, and STK11 mutation and HGF, c-met, and IGFR amplification) Progression-free survival (PFS) of EGFR-TKI according to each biomarker (i.e. PIK3CA, AKT, PTEN, and STK11 mutation and HGF, c-met, and IGFR amplification)

Measure: OS

Time: 2years

122 A Study to Evaluate the Efficacy of Rh-Endostatin (Endostar®) in Combination With Icotinib for Advanced Non-Small Cell Lung Cancer With EGFR Mutations

This single-arm pilot study tries to invesitgate how well giving icotinib with rh-endostatin (Endostar®) works in treating patients with advanced stage non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutations. Icotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Anti-angiogeneiss drug, such as rh-endostatin, can block tumor growth by inhibiting the ability of tumors to grow new blood vessels and spread. It is not yet known whether icotinib is more effective when given with rh-endostatin in NSCLC patients with EGFR activating mutations.

NCT02375022 Lung Cancer Drug: Endostar and icotinib
MeSH: Lung Neoplasms
HPO: Neoplasm of the lung

Inclusion Criteria: - Histologic documentation of non small cell lung cancer, with activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R mutation). --- L858R ---

- Other active malignancy Inclusion Criteria: - Histologic documentation of non small cell lung cancer, with activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R mutation). --- L858R ---

EGFR mutation status: activating mutation (defined as deletion 19 or exon 21 L858R mutation). --- L858R ---

Primary Outcomes

Measure: Objective response rate

Time: 6 months

Secondary Outcomes

Measure: Progression free survival

Time: 12 months

Description: Number of Participants with Adverse Events as a Measure of Safety and Tolerability

Measure: Safety: Number of Participants with Adverse Events

Time: 12 months

123 A Phase Ib, Open-label, Multi-centre Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-tumour Activity of Volitinib in Combination With Gefitinib (Iressa®) in Patients With Epidermal Growth Factor Receptor-mutated Non-small Cell Lung Cancer Who Have Progressed on Epidermal Growth Factor Receptor Inhibitor Treatment

This is a Phase 1b, open-label, multicentre study of AZD6094 in combination with gefitinib in patients with epidermal growth factor receptor (EGFR) mutation positive (m+) and progressed on EGFR Tyrosine kinase inhibitor (TKI) treatment.

NCT02374645 Non-Small Cell Lung Cancer Drug: Volitinib Drug: gefitinib Drug: Volitinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

3. Histologically or cytologically confirmed locally advanced or metastatic NSCLC patients who are harbouring an EGFR mutation known to be associated with EGFR-TKI sensitivity (including exon 19 deletion, L858R, L861Q, G719X). --- L858R ---

Primary Outcomes

Measure: Number of adverse events and serious adverse events

Time: From ICF signed to within 28 days after the last dose

Secondary Outcomes

Measure: The Pharmacokinetics (PK) profiles of AZD6094

Time: Cycle 1 Day1 and Day 15

Measure: Progression-free survival (PFS)

Time: from enrolled until progression or death due to any cause, assessed up to 2 year

Measure: Disease control rate(DCR)

Time: 12 weeks and 24 weeks

124 T-STAR - T790M Mutation Positive 2nd Line STandard of cAre Registry

The aim of the study is to collect real world information on patients with locally advanced or metastatic non small cell lung cancer (NSCLC) who progressed after first line treatment with an approved Tyrosine-Kinase Inhibitor (TKI), who are known to be T790M positive and have been prescribed second line platinum-based chemotherapy (Pemetrexed + Cisplatin /Carboplatin).

NCT02368990 Non Small Cell Lung Cancer
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

- Confirmation prior to enrolment into the study that the tumour harbours the following EGFR mutations known to be associated with EGFR-targeted TKI sensitivity: Ex19Del, L858R, L861Q, and G719X. --- L858R ---

There are Epidermal Growth Factor Receptor (EGFR) mutations known to be associated with EGFR-targeted TKI sensitivity ( Ex19Del, L858R, L861Q, and G719X). --- L858R ---

Primary Outcomes

Description: This will be assessed as the time from the start date of 2nd line chemotherapy until death due to any cause or censoring (at end of 24 months).To assess efficacy of permetrexed + cisplatinum/carboplatin as the 2nd line of treatment of NSCLC.

Measure: Overall Survival

Time: 24 months from last subject in

Secondary Outcomes

Description: This will be assessed as the time from start of 2nd line therapy until the date of disease progression or death (by any cause in the absence of progression). To assess efficacy of 2nd line treatment and beyond.

Measure: Response to Therapy as assessed by the physician

Time: 24 months from last subject in

Description: This will be assessed as the time from start date of line of therapy to end date of line of therapy or death date. To describe treatment patterns for 2nd line and beyond.

Measure: Time on treatment by line of therapy and between therapies

Time: 24 months from last subject in

Description: This will be assessed as the number and Time from the dates of admission and exit of attendance. To describe Healthcare resource utilization for 2nd line treatment and beyond.

Measure: Admission of planned/unplanned hospitalizations, emergency department visits and outpatient/physician visits

Time: 24 months from last subject in

Description: For each of the symptoms in EORTC QLQ-LC13 and EORTC QLQ-C30, Time from inclusion until the date of first clinically meaningful symptom deterioration or death by any cause in the absence of a clinically meaningful symptom deterioration. To assess the impact of 2nd and subsequent lines of therapy on patients' disease-related symptoms and health related quality of life.

Measure: Time to symptom deterioration

Time: 24 months from last subject in

Description: This will be assessed as the number of patients with two consecutive assessments, which showed a clinically meaningful improvement in that symptom from baseline. To assess the impact of 2nd and subsequent lines of therapies on patients' disease-related symptoms and health related quality of life.

Measure: Symptom Improvement Rate

Time: 24 months from last subject in

Description: This will be assessed as the time from the date of complete or partial response until the first date of recurrence or progression. To assess the efficacy of 2nd line treatment and beyond.

Measure: Duration of Response as defined by the physician

Time: 24 months from last subject in

Description: This will be assessed as the time from start of 2nd line therapy until the date of disease progression or death by any cause. This will be done to assess efficacy of pemetrexed + cisplatin/carboplatin as the 2nd line treatment of NSCLC.

Measure: Progression Free Survival

Time: 24 months from last subject in

125 A Phase I/Ib Trial of MK-3475 (Pembrolizumab) and Afatinib in EGFR-Mutant Non-small Cell Lung Cancer With Resistance to Erlotinib

This phase I/Ib trial studies the side effects and best dose of pembrolizumab when given together with afatinib dimaleate in treating patients with non-small cell lung cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment, or has come back and does not respond to erlotinib hydrochloride. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and afatinib dimaleate together may be an effective treatment for non-small cell lung cancer.

NCT02364609 Recurrent Non-Small Cell Lung Carcinoma Stage IIIA Non-Small Cell Lung Cancer Stage IIIB Non-Small Cell Lung Cancer Stage IV Non-Small Cell Lung Cancer Drug: Afatinib Dimaleate Biological: Pembrolizumab
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Standard descriptive methods will be used to summarize the baseline levels and changes in baseline levels will allow to examine whether observed patterns are consistent with hypothesized patterns.. Inclusion Criteria: - Incurable, advanced or metastatic/recurrent non-small cell lung cancer with EGFR activating mutations (exon 19 del, exon 21 L858R, L861Q, G718X); who have radiologic and/or clinically progressive disease on erlotinib at any point during the patient's cancer treatment as determined by the Investigator - Be willing and able to provide written informed consent for the trial - Have a life expectancy of at least 3 months - Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Adequate archival tissue for determination of EGFR-mutation status and PD-L1 status with a leftover cell block (or equivalent) for additional immune correlates from a tumor lesion biopsied in the last 60 days that has not been previously irradiated occurring: 1) after progression on erlotinib and no intervening systemic treatment between biopsy and initiation of MK-3475 and afatinib or amenable to repeat biopsy - Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance scale - Be willing to consent for biopsy at baseline (if inadequate archival tissue per inclusion criteria above) and an on treatment biopsy; have a tumor in a location that in the opinion of the investigator that is amenable to biopsy or have provided tissue for PD-L1 and other biomarker analysis from a newly obtained (within 60 days) formalin fixed tumor tissue from a recent biopsy of a tumor lesion not previously irradiated; no systemic antineoplastic therapy may be administered between the PD- L1 biopsy and initiating study medication; fine needle aspirates are not acceptable; needle or excisional biopsies, or resected tissue is required; the tissue sample must be received by the central vendor (Labcorp) and evaluated for adequacy prior to starting therapy - There is no limit to the number of prior treatments for this phase I trial - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 100,000/mcL - Hemoglobin >= 9 g/dL or >= 5.6 mmol/L - Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 x upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN - Creatinine clearance should be calculated per institutional standard - Serum total bilirubin =< 1.5 x ULN - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR < 5 x ULN for subjects with liver metastases - International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants; activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants - Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required - Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year - Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy Exclusion Criteria: - Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment - Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment - Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier; denosumab is allowed as long as not < 1 week prior to study day 1 and not administered on day of MK-3475 infusion - Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent - Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study - Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy - Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy - Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment - Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study - Has evidence of interstitial lung disease or active, non-infectious pneumonitis that required oral or intravenous glucocorticoids to assist with management; lymphangitic spread of the non-small cell lung cancer (NSCLC) is not exclusionary - Has an active infection requiring intravenous systemic therapy - Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator - Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial - History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia as determined by the investigator; myocardial infarction within 6 months prior to enrollment - Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment - Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, anti-PD-L2, anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) - Known hypersensitivity to afatinib or the excipients of any of the trial drugs - Prior participation in an afatinib clinical study, even if not assigned to afatinib treatment - Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) - Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) - Has received a live vaccine within 30 days prior to the first dose of trial treatment - The presence of poorly controlled gastrointestinal disorders that could affect the absorption of the afatinib (e.g. --- L858R ---

Crohn's disease, ulcerative colitis, chronic diarrhea, malabsorption) - Subjects that require treatment with a strong inhibitor of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) will be excluded; they may be included if there is an alternate treatment available (not a strong CYP3A4 inhibitor) and they are willing to switch prior to enrollment; if a subject opts to change from a strong CYP 3A4 inhibitor to a weaker CYP 3A4 inhibitor, the subject must stop the strong CYP 3A4 inhibitor 7 days before study drug administration - Receiving drugs known to be strong inducers or inhibitors of permeability (P)-glycoprotein that are known to interact with afatinib including, but not limited to: ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product; the subject must stop the strong inducer or inhibitor of P-glycoprotein 7 days before or 5 half lives before study drug administration (whichever timepoint is longer) - Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study - Hormonal treatment within 2 weeks prior to start of study treatment - Radiotherapy within 4 weeks prior to enrollment, except as follows: - Palliative radiation to target organs other than chest may be allowed up to 2 weeks prior to enrollment, and - Single dose palliative treatment for symptomatic metastasis outside above allowance to be discussed with sponsor-investigator prior to enrolling - Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of study Inclusion Criteria: - Incurable, advanced or metastatic/recurrent non-small cell lung cancer with EGFR activating mutations (exon 19 del, exon 21 L858R, L861Q, G718X); who have radiologic and/or clinically progressive disease on erlotinib at any point during the patient's cancer treatment as determined by the Investigator - Be willing and able to provide written informed consent for the trial - Have a life expectancy of at least 3 months - Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Adequate archival tissue for determination of EGFR-mutation status and PD-L1 status with a leftover cell block (or equivalent) for additional immune correlates from a tumor lesion biopsied in the last 60 days that has not been previously irradiated occurring: 1) after progression on erlotinib and no intervening systemic treatment between biopsy and initiation of MK-3475 and afatinib or amenable to repeat biopsy - Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance scale - Be willing to consent for biopsy at baseline (if inadequate archival tissue per inclusion criteria above) and an on treatment biopsy; have a tumor in a location that in the opinion of the investigator that is amenable to biopsy or have provided tissue for PD-L1 and other biomarker analysis from a newly obtained (within 60 days) formalin fixed tumor tissue from a recent biopsy of a tumor lesion not previously irradiated; no systemic antineoplastic therapy may be administered between the PD- L1 biopsy and initiating study medication; fine needle aspirates are not acceptable; needle or excisional biopsies, or resected tissue is required; the tissue sample must be received by the central vendor (Labcorp) and evaluated for adequacy prior to starting therapy - There is no limit to the number of prior treatments for this phase I trial - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 100,000/mcL - Hemoglobin >= 9 g/dL or >= 5.6 mmol/L - Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 x upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN - Creatinine clearance should be calculated per institutional standard - Serum total bilirubin =< 1.5 x ULN - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR < 5 x ULN for subjects with liver metastases - International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants; activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants - Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required - Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year - Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy Exclusion Criteria: - Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment - Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment - Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier; denosumab is allowed as long as not < 1 week prior to study day 1 and not administered on day of MK-3475 infusion - Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent - Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study - Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy - Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy - Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment - Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study - Has evidence of interstitial lung disease or active, non-infectious pneumonitis that required oral or intravenous glucocorticoids to assist with management; lymphangitic spread of the non-small cell lung cancer (NSCLC) is not exclusionary - Has an active infection requiring intravenous systemic therapy - Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator - Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial - History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia as determined by the investigator; myocardial infarction within 6 months prior to enrollment - Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment - Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, anti-PD-L2, anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) - Known hypersensitivity to afatinib or the excipients of any of the trial drugs - Prior participation in an afatinib clinical study, even if not assigned to afatinib treatment - Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) - Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) - Has received a live vaccine within 30 days prior to the first dose of trial treatment - The presence of poorly controlled gastrointestinal disorders that could affect the absorption of the afatinib (e.g. --- L858R ---

Primary Outcomes

Description: Descriptive summaries will be provided for number and proportion with specific type and grade of toxicities.

Measure: Maximum tolerated dose (MTD) recommended dose of pembrolizumab in combination with lead in pembrolizumab and afatinib dimaleate

Time: Day 21

Description: Will be determined by the overall assessment of the MTD and toxicities observed in the dose de-escalation portion of this study.

Measure: Recommended phase II dose

Time: Day 21

Secondary Outcomes

Description: Descriptive summaries will be provided for numbers and proportion of patients responding.

Measure: Overall response rate per RECIST 1.1

Time: Up to 3 years

Description: Kaplan-Meier plot and life-table summary will be used.

Measure: Progression free survival

Time: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 3 years

Other Outcomes

Description: Standard descriptive methods will be used to summarize the baseline levels and changes in baseline levels will allow to examine whether observed patterns are consistent with hypothesized patterns.

Measure: Changes in plasma EGFR-mutant DNA levels

Time: Baseline to up to 3 years

Description: Descriptive associations with response rate and PFS will be performed. Standard descriptive methods will be used to summarize the baseline levels and changes in baseline levels will allow to examine whether observed patterns are consistent with hypothesized patterns.

Measure: Changes in PDL1 expression by immunohistochemistry

Time: Baseline to up to 3 years

126 A PHASE 3 RANDOMIZED, DOUBLE-BLIND STUDY OF PF- 06439535 PLUS PACLITAXEL-CARBOPLATIN AND BEVACIZUMAB PLUS PACLITAXEL -CARBOPLATIN FOR THE FIRST-LINE TREATMENT OF PATIENTS WITH ADVANCED NON-SQUAMOUS NON-SMALL CELL LUNG CANCER.

This is a multinational, double-blind, randomized, parallel-group Phase 3 clinical trial evaluating the efficacy and safety of bevacizumab-Pfizer plus paclitaxel and carboplatin versus bevacizumab-EU plus paclitaxel and carboplatin in first-line treatment for patients with advanced (unresectable, locally advanced, recurrent or metastatic) non-squamous NSCLC.

NCT02364999 Non-Small Cell Lung Cancer Drug: Bevacizumab-Pfizer Drug: Bevacizumab-EU Drug: Paclitaxel Drug: Carboplatin
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

- Known sensitizing EGFR mutations (for example, deletion 19 or L858R) or EML4-ALK translocation positive mutations. --- L858R ---

Primary Outcomes

Description: ORR refers to percentage of participants who achieved complete response (CR) or partial response (PR) by Week 19 of the study in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 which was subsequently confirmed by Week 25. A participant achieved CR if both target and non-target lesions achieved CR, no new lesions; achieved PR if target lesions achieved CR or PR, non-target lesions were assessed as non-CR/non-PD (progressive disease), indeterminate or missing, and no new lesions. For target lesions, CR: complete disappearance of all target lesions except nodal disease (target nodes must decrease to normal size); PR: >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. For non-target lesions, CR: disappearance of all non-target lesions and normalization of tumor marker levels and all lymph nodes must be normal in size; non-CR/non-PD: persistence of any non-target lesions and/or tumor marker level above the normal limits.

Measure: Objective Response Rate (ORR) by Week 19

Time: 25 weeks

Secondary Outcomes

Description: AE was defined as any untoward medical occurrence in a clinical investigation participant administered a product or medical device, regardless of the causal relationship to study treatment. Treatment-emergent AEs (TEAEs) were defined as AEs which occurred for the first time during the effective duration of treatment or AEs that increased in severity during treatment. Serious AEs (SAEs) were defined as any untoward medical occurrence at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or caused prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduction normal life functions). AEs included SAEs and non-serious AEs. Causality to study treatment was determined by the investigator. Severity was graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Measure: Number of Participants With Treatment-Emergent Adverse Events

Time: 55 weeks

Description: Laboratory evaluation included hematology (hemoglobin, white blood cells, platelets and absolute neutrophil count), blood chemistry (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, serum or plasma creatinine, sodium, potassium, total calcium, magnesium, blood urea nitrogen or urea, and albumin ), coagulation (international normalized ratio for prothrombin time and activated partial thromboplastin time) and urinalysis (dipstick followed by a quantitative urine protein analysis for results of 2+ or greater).

Measure: Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality)

Time: 55 weeks

Description: DOR was defined as the time from date of the first documentation of objective tumor response (CR or PR) to the first documentation of PD or to death due to any cause in the absence of documented PD. DOR was based on the Brookmeyer and Crowley method.

Measure: Duration of Response (DOR)

Time: 55 weeks

Description: This outcome measure refers to the possibility of being progression free at 55 weeks since start of study treatment, estimated from the Kaplan-Meier curve using the product-limit method.

Measure: Progression Free Survival Rate at 55 Weeks

Time: 55 weeks

Description: This outcome measure refers to the possibility of being alive at 55 weeks since start of study treatment, estimated from the Kaplan-Meier curve using the product-limit method.

Measure: Survival Rate at 55 Weeks

Time: 55 weeks

Measure: Serum Concentration of Bevacizumab up to 1 Year

Time: Pre-dose from Cycle 1 to Cycle 17, 2.5 hours post-dose in Cycle 1, and 1.5 hours post-dose in Cycle 5

Description: ADA assay was performed using a sensitive, specific, and semi-quantitative electrochemiluminescent (ECL) method, which used biotinylated- and ruthenium-labeled PF-06439535 as reagents. Samples with ADA titer greater than or equal to (>=) 2.29 were considered positive.

Measure: Number of Participants With Anti-Drug Antibody (ADA)

Time: 55 weeks

Description: Only samples that were confirmed positive for ADA were further tested for NAb. The NAb analysis was conducted using a single validated quasi-quantitative enzyme-linked immunosorbent assay (ELISA) that utilized PF-06439535 as a reagent. Samples with NAb titer >=1.70 were considered positive.

Measure: Number of Participants With Neutralizing Antibody (NAb)

Time: 55 weeks

127 A Phase I, Open-label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumour Activity of AZD3759 or AZD9291 in Patients With EGFR Mutation Positive Advanced Stage Non Small Cell Lung Cancer (NSCLC)

This is the first time in patient study to assess the safety, tolerability and preliminary efficacy of AZD3759 in patients with advanced Non Small Cell Lung Cancer (NSCLC) In this study, patients with Leptomeningeal Metastasis and Brain Metastasis may also be enrolled to assess the anti-tumour efficacy, safety, pharmacokinetics and potential biological activity of AZD9291

NCT02228369 EGFR Mutation Positive Advanced Non Small Cell Lung Cancer Drug: AZD3759 Drug: AZD9291
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

3. Histologically or cytologically confirmed diagnosis of NSCLC with single activating EGFR mutations (L858R or Exon19Del). --- L858R ---

Primary Outcomes

Description: Adverse events will be collected from Informed consent until the end of the follow-up period which is defined as 28 days (+7 days) after study treatment is discontinued.Physical exam (screening, single dosing day, Day 1 of every 3-week cycle of multiple dosing and treatment discontinuation). ECG and vital signs (screening, Day 1 and 2 of Cycle 0 for AZD3759 cohorts, Day 8 of Cycle 1 for AZD3759 cohorts, Day 1 of every 3-week cycle, treatment discontinuation, and if occurrence of any cardiac adverse event). Lab variables (screening, first dosing day, Day 1, 8 and 15 of multiple dosing, Day 1 of every 3-week cycle and treatment discontinuation). Eye exam (at screening and study drug discontinuation and upon occurrence of any visual AE). Echocardiogram or multigated radionuclide angiography (at screening,whenever necessary as clinically indicated throughout the study for AZD3759 cohorts.

Measure: Safety and Tolerability (The number of patients with each AE by system organ class, preferred term and CTCAE grade)

Time: From Informed consent until the end of the follow-up period which is defined as 28 days (+7 days) after study treatment is discontinued.

Secondary Outcomes

Description: The parent drug and N-demethylated metabolite in plasma samples will be analyzed: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, hour in Day 1; 24hour in Day 2 and 48hour in Day 3. AUC: Area Under Curve

Measure: Plasma concentration of AZD3759 and metabolite and pharmacokinetics parameters after single dose of AZD3759(Cmax, tmax, terminal rate constant, half life, AUC, clearance, volume of distribution, mean residence time)

Time: Cycle 0 Day 1 to 3 in Part A patients.

Description: The parent drug and N-demethylated metabolite in plasma samples from all patients will be analyzed: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12hour on Cycle 1 Day 8 and Cycle 3 Day 1 . The parent drug and N-demethylated metabolite in urine samples from Part A patients will be analyzed: 0-12h at Cycle 1 Day 8. The parent drug and N-demethylated metabolite in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 1 Day 8 in brain metastasis patients; pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in leptomeningeal metastasis patients. AUCss: Area Under Curve Steady State CLss: Clearance Steady State

Measure: Plasma,urine,cerebrospinal fluid concentration of AZD3759 and metabolite and pharmacokinetics parameters after multiple dosing(Cmax,ss, tmax,ss, Cmin,ss, AUCss, CLss/F).

Time: Blood samples: Cycle 1 Day 8 and Cycle 3 Day 1 in all patients. Urine samples: 0-12h at Cycle 1 Day 8 in Part A. CSF samples: pre-dose of Cycle 1 Day 8 in BM; Pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in LM

Description: The parent drug and N-demethylated metabolite in plasma samples from all patients will be analyzed: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12hour on Cycle 1 Day 8 and Cycle 3 Day 1. The parent drug and N-demethylated metabolite in urine samples from Part A patients will be analyzed: 0-12h at Cycle 1 Day 8. The parent drug and N-demethylated metabolite in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 1 Day 8 in brain metastasis patients; pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in leptomeningeal metastasis patients.

Measure: Plasma,urine, cerebrospinal fluid concentration of AZD3759 and metabolite and pharmacokinetics parameters after multiple dosing (extent of accumulation, renal clearance, time dependency of pharmacokinetics and amount of drug excreted)

Time: Blood samples: Cycle 1 Day 8 and Cycle 3 Day 1 in all patients. Urine samples: 0-12h at Cycle 1 Day 8 in Part A patients. CSF samples: pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in Part B patients .

Description: The parent drug and metabolites in plasma samples from all patients treated with AZD9291 will be analyzed: pre-dose of Cycle 1 Day 1, 8, 15; pre-dose, 1, 1.5, 2, 4, 6, 8, 10, 12, 24hour on Cycle 2 Day 1. The parent drug and metabolites in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 2 Day 1 in brain metastasis patients; pre-dose of Cycle 2 Day 1 and Cycle 3 Day 1 in leptomeningeal metastasis patients . AUCss: Area Under Curve Steady State CLss: Clearance Steady State

Measure: Plasma, cerebrospinal fluid concentration of AZD9291 and metabolite and pharmacokinetics parameters after multiple dose of AZD9291(Cmax,ss, tmax,ss, Cmin,ss, AUCss, CLss/F).

Time: Blood samples: Cycle 1 Day 1, 8, 15 and Cycle 2 Day 1. Cerebrospinal fluid samples: pre-dose of Cycle 2 Day 1 and pre-dose of Cycle 3 Day 1.

Description: The parent drug and metabolites in plasma samples from all patients treated with AZD9291 will be analyzed: pre-dose of Cycle 1 Day 1, 8, 15; pre-dose, 1, 1.5, 2, 4, 6, 8, 10, 12, 24hour on Cycle 2 Day 1. The parent drug and metabolites in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 2 Day 1 in brain metastasis patients; pre-dose of Cycle 2 Day 1 and Cycle 3 Day 1 in leptomeningeal metastasis patients . AUCss: Area Under Curve Steady State CLss: Clearance Steady State

Measure: Plasma, cerebrospinal fluid concentration of AZD9291 and metabolites and pharmacokinetics parameters after multiple dosing (extent of accumulation, renal clearance, time dependency of pharmacokinetics and amount of drug excreted)

Time: Blood samples: Cycle 1 Day 1, 8, 15 and Cycle 2 Day 1. Cerebrospinal fluid samples: pre-dose of Cycle 2 Day 1 and pre-dose of Cycle 3 Day 1.

Description: After 28-day follow-up visit, patients will be followed for overall survival via telephone every 6 weeks until death, lost to follow-up or consent withdrawal

Measure: Overall survival follow up for all expansion patients

Time: Every 6 weeks after the 28- day safety follow-up visit

Description: Blood collection at pre-dose of Cycle 0 Day 1 and Cycle 1 Day 15 to evaluate if AZD3759 affects 4b-hydroxy cholesterol which is an endogenous marker of CYP enzyme induction

Measure: 4b-hydroxy cholesterol in Part B patients with BM

Time: pre-dose of Cycle 0 Day 1 and Cycle 1 Day 15

Description: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hour of Cycle 0 Day 1and Day 4; 24 hour of Cycle 0 Day 2 and Day 4.A Mixed Effects model with treatment (fed/fasted) and period as fixed effects and patient as a random effect will be used to compare AUC/Cmax in the fed state with AUC/Cmax in the fasted state.

Measure: The effect of food on the pharmacokinetics of a single dose of AZD3759 in plasma

Time: Cycle 0 Day 1 to Day 4 in Part B patients with BM

Description: Cerebrospinal fluid collection at screening and every 6 weeks until progression to evaluate the cerebrospinal fluid response rate which is defined as the percentage of leptomeningeal metastasis patients who have at least one cerebrospinal fluid response (100% clearance of tumour cells from cerebrospinal

Measure: Cerebrospinal fluid response rate for patients with LM and/or BM

Time: Screening and every 6 weeks (relative to first dose of multiple dosing) until progression, expected average 6 months

Description: Quality of life questionnaire-Brain Cancer 20 questionnaire completed by patients at screening, Day 1 of every 3-week cycle and treatment discontinuation. Use relevant symptom questions to evaluate improvement of central nervous system symptoms.

Measure: Changes from baseline in central nervous system symptoms (analyzed from QLQ-BN20) in patients with LM treated with AZD3759 /AZD9291

Time: Screening, Day 1 of every 3-week cycle and treatment discontinuation, expected average 6 months.

Description: Neurological exam will be performed: screening, single dosing day, Day 1 of every 3-week cycle of multiple dosing and treatment discontinuation

Measure: Changes from baseline in neurological exam in patients with LM treated with AZD3759 /AZD9291

Time: Screening, Day 1 of every 3-week cycle and treatment discontinuation, expected average 6 months.

Description: ORR assessed through the number of patients who achieve a disease response (i.e. complete response or partial response) assessed according to modified RECIST 1.1 criteria for central nervous system disease, extracranial disease and overall disease

Measure: Measurement of Objective Response Rate (ORR)

Time: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.

Description: DCR assessed through the number of patients who achieve a best response of confirmed CR, confirmed PR or responding, or stable disease according to modified RECIST 1.1 criteria for central nervous system disease, extracranial disease, leptomeningeal disease and overall disease

Measure: Measurement of Disease Control Rate (DCR)

Time: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.

Description: RR assessed through the number of patients who have at least one confirmed response of Complete Response or Responding prior to any evidence of progression according to modified RECIST 1.1 criteria for leptomeningeal disease

Measure: Measurement of Response Rate (RR)

Time: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.

Description: PFS assessed through change in tumour size (as well as assessment of non-target lesions and appearance of any new lesions) according to modified RECIST 1.1 criteria for Part B patients with brain metastasis and patients with leptomeningeal metastasis

Measure: Measurement of Progression Free Survival (PFS)

Time: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.

Description: Best LM assessment via LANO criteria through the number of patients with LM present at baseline, without a requirement for confirmation. LANO assessments will be mapped to RECIST-like scores and performed via central imaging reading.

Measure: Best Leptomeningeal Metastasis (LM) assessment for AZD9291 LM patients

Time: Screening within 28days

128 A Prospective, Open-labelled, Randomized, Multicenter Phase II Study to Evaluate Efficacy and Safety of Erlotinib vs NP Chemotherapy as Adjuvant Therapy in Post Radical Operation NSCLC Patients With EGFR19 or 21 Exon Mutation

This study is to compare 2-year Disease Free Survival Rate (DFSR) in post radical operation IIIA Non-Small Cell Lung Cancer (NSCLC) patients with Epidermal Growth Factor Receptor (EGFR) 19 or 21 exon mutation treated Erlotinib vs NP chemotherapy as adjuvant therapy.

NCT01683175 Non-small Cell Lung Cancer Stage III Drug: Erlotinib Drug: cis-platinum Drug: Vinorelbine
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

Inclusion Criteria: - IIIA NSCLC patients according to TMN-staging of Lung Staging Standard version 7 2009, confirmed by histopathology or cytology after radical operation, and having EGFR exon 19 deletion mutation or exon 21 L858R single base substitution; - Accept study adjuvant therapy within 6 weeks post radical operation; - ECOP PS 0-1; Life expectancy ≥12 weeks; - Hematology: absolute neutrophil count (ANC) ≥1.5×10^9/L; platelet count ≥100×10^9/L; hemoglobin concentration ≥ 9.0 g/dL (permit to maintain hematologic criteria by blood transfusion); - Liver Function: TBil ≤1.5xULN; ALT and AST ≤2.5xULN; - Renal Function: Cr ≤1.25xULN, and Ccr ≥60ml/min; - Female patients of childbearing potential must have a negative serum or urine pregnancy test within 7 days before study treatment; - Signed inform consent form by patient or his/her legal representative; - Comply with study protocol and procedure, and be able to take oral medication; Aged ≥18 years and ≦75 years; - Eligible patients of reproductive potential (both sexes) must agree to use a reliable method of birth control before enrollment, during the study period and for at least 30 days after their last dose of study therapy; Exclusion Criteria: - Having treated by Her-Target therapy, i.e. erlotinib, gefitinib, cetuximab, trastuzumab; - Having treated by any systemic anti-tumor therapy of NSCLC, including cytotoxic therapy, target medication treatment (i.e. --- L858R ---

Primary Outcomes

Description: 2-year disease free survival rate is defined as the estimation percentage of disease free survival patients with study treatment at 2-year.

Measure: 2-year disease free survival rate (DFSR)

Time: 2 years

Secondary Outcomes

Description: Disease free survival is defined as the time from randomization to disease recurrence or death which comes first.

Measure: disease free survival

Time: 5 years

Description: Overall survival is defined as the time from randomization to death.

Measure: overall survival (OS)

Time: 5 years

Description: The score of Functional Assessment of Cancer Therapy - Lung (FACT-L) subscale and Lung Cancer Symptom Scale (LCSS)

Measure: Quality of Life

Time: 5 years

Description: frequency of Adverse Event

Measure: Adverse Event (AE)

Time: 5 years

Description: Frequency of Serious Adverse Event (SAE)

Measure: Serious Adverse Event (SAE)

Time: 5 years

129 A Randomized, Open-label Trial of Gefitinib Versus Combination of Vinorelbine Plus Platinum as Adjuvant Treatment in Pathological Stage II-IIIA(N1-N2) Non-small Cell Lung Cancer With EGFR Mutation

Activating somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor (EGFR) have been characterized in a subset of patients with advanced NSCLC.The EGFR mutation rate was 30% in Chinese Non-small Cell Lung Cancer(NSCLC). Patients harboring these mutations in their tumors show excellent response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This randomized phase III trial is studying gefitinib to see how well it works compared to cisplatin-based chemotherapy in treating patients who have undergone surgery for stage II-IIIA(N1-N2) NSCLC with EGFR activating mutation in Asian population.

NCT01405079 Non-small Cell Lung Cancer Drug: Gefitinib Drug: Vinorelbine+Cisplatin
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

- Target population is completely resected pathological stage II-IIIA(N1-N2) NSCLC with EGFR exon 19 deletions and exon 21 L858R activating mutation. --- L858R ---

Primary Outcomes

Description: To evaluate the disease free survival of gefitinib versus combination of vinorelbine plus platinum as adjuvant treatment for pathological stage II-IIIA(N1-N2) NSCLC with EGFR mutation.Disease free survival (DFS)- defined as the time from randomization to the first documented disease progression or death, whichever occurs first.

Measure: Disease free survival

Time: Pts after surgery will receive long-term follow-up including chest CT scan, abdominal ultrasound every 3 months, brain MRI every 6 months, bone scan every 12 months for up to 3 years. The survival after 3 years will be followed up with telephone.

Secondary Outcomes

Description: To evaluate the overall survival of gefitinib versus combination of vinorelbine plus platinum as adjuvant treatment for stage II-IIIA(N1-N2) NSCLC with EGFR mutation.

Measure: Overall survival

Time: Pts after surgery will receive long-term follow-up including chest CT scan, abdominal ultrasound every 3 months, brain MRI every 6 months, bone scan every 12 months for up to 3 years. The survival after 3 years will be followed up with telephone.

Description: To compare the randomized treatment arms in terms of 3 yeas DFS rate, 5 years DFS rate, 5 years OS rate.

Measure: 3 yeas DFS rate, 5 years DFS rate, 5 years OS rate

Time: Pts after surgery will receive long-term follow-up including chest CT scan, abdominal ultrasound every 3 months, brain MRI every 6 months, bone scan every 12 months for up to 3 years. The survival after 3 years will be followed up with telephone.

Description: The safety and tolerability profile of gefitinib at a 250 mg daily dose relative to that of Chemotherapy.

Measure: Number of Participants with Adverse Events

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months.Vinorelbine 25 mg/m2 intravenous infusion on day 1 and day 8, Cisplatin 75 mg/m2 on day 1 for 4 cycles.

Description: Quality of life as measured by the total score and Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy - Lung Cancer (FACT-L) questionnaire.

Measure: Quality of life

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months.Vinorelbine 25 mg/m2 intravenous infusion on day 1 and day 8, Cisplatin 75 mg/m2 on day 1 for 4 cycles.

130 An Open Label, Multicenter, Phase II Single-arm Trial of AZD9291 in Non-small Cell Lung Cancer (NSCLC) Patients With Uncommon Epidermal Growth Factor Receptor Mutations

EGFR (ErbB1) mutations define a lung cancer subtype with exquisite sensitivity to EGFR tyrosine kinase inhibitors (TKIs). While in-frame deletion in exon 19 (Del19) and a point mutation (L858R) in exon 21 are the two most common sensitizing EGFR mutations in NSCLC, approximately 10% of EGFR mutation-positive tumors harbor uncommon mutations. These mutations represent a heterogeneous group of rare molecular alterations (or combinations) within exons 18-21, whose oncogenicity and sensitivity to EGFR TKIs may vary and has not been prospectively studied. Recently, a retrospective analysis reported that overall response rate of EGFR TKI (gefitinib or erlotinib) treatment was about 10% or less in Korean NSCLC patients with uncommon EGFR mutation other than del19, L858R and T790M [11]. In preclinical data, the potency of AZD9291 against uncommon EGFR mutants other than exon 20 insertion mutation was fairly good. Based on the result, in this study, we try to evaluate the efficacy of AZD9291, the potent irreversible inhibitor, in NSCLC patients with harboring uncommon EGFR mutations.

NCT03424759 Non Small Cell Lung Cancer Drug: AZD9291
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

While in-frame deletion in exon 19 (Del19) and a point mutation (L858R) in exon 21 are the two most common sensitizing EGFR mutations in NSCLC, approximately 10% of EGFR mutation-positive tumors harbor uncommon mutations. --- L858R ---

Recently, a retrospective analysis reported that overall response rate of EGFR TKI (gefitinib or erlotinib) treatment was about 10% or less in Korean NSCLC patients with uncommon EGFR mutation other than del19, L858R and T790M [11]. --- L858R ---

Inclusion Criteria: - Histologically confirmed metastatic or recurrent stage IV NSCLC with activating EGFR mutation other than deletion in exon 19, L858R, T790M and insertion in exon 20 - metastatic or recurrent NSCLC - Be 19years of age on day of signing informed consent - ECOG performance status of 0 to 2 - At least one measurable lesion by RECIST 1.1(The part of radiation treatment in the palliative setting is excluded.) --- L858R ---

- Untreated asymptomatic brain metastasis or symptomatic brain metastasis treated with local treatment such as operation, whole brain radiotherapy, or gamma-knife surgery - At least 2 weeks later after whole brain radiotherapy or at least 4 weeks later after palliative thoracic radiotherapy - Adequate organ function as evidenced by the following; Absolute neutrophil count > 1.5 x 109/L; Hb > 9.0g/dL; platelets > 100 x 109/L; total bilirubin ≤1.5 UNL; AST and/or ALT < 2.5 ULN if no demonstrable liver metastases or < 5 UNL in the presence of liver metastases, CCr ≥ 50mL/min - Written informed consent form Exclusion Criteria: - Prior treatment with EGFR TKI - Major surgery undertaken less than 4 weeks before the study - Localized palliative radiotherapy unless completed more than 2 weeks before the study - Uncontrolled systemic illness such as DM, CHF, unstable angina, hypertension or arrhythmia - Pregnant or nursing women (Women of reproductive potential have to agree to use an adequate contraceptive method) - Uncontrolled symptomatic brain metastasis - Prior history of malignancy within 5 years from study entry except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer, or well-treated thyroid cancer - Concomitant use of CYP3A4 inducers/inhibitors - Prolonged QT interval in ECG (QTc >450 msec) - Prior history of interstitial lung disease Inclusion Criteria: - Histologically confirmed metastatic or recurrent stage IV NSCLC with activating EGFR mutation other than deletion in exon 19, L858R, T790M and insertion in exon 20 - metastatic or recurrent NSCLC - Be 19years of age on day of signing informed consent - ECOG performance status of 0 to 2 - At least one measurable lesion by RECIST 1.1(The part of radiation treatment in the palliative setting is excluded.) --- L858R ---

Recently, a retrospective analysis reported that overall response rate of EGFR TKI (gefitinib or erlotinib) treatment was about 10% or less in Korean NSCLC patients with uncommon EGFR mutation other than del19, L858R and T790M (9). --- L858R ---

Primary Outcomes

Description: 30%

Measure: Objective response rate

Time: through study completion, an average of 2 years

131 A Phase IIb, Open-label, Single-arm Study to Assess the Safety and Efficacy of BPI-7711 Capsule in Patients With Metastatic or Recurrent Non-small Cell Lung Cancer With EGFR Mutation and T790M Mutation Positive.

A phase IIb, open-label, single-arm study to assess the safety and efficacy of BPI-7711 capsule in patients with metastatic or recurrent non-small cell lung cancer with EGFR mutation and T790M mutation positive.

NCT03812809 NSCLC Drug: BPI-7711
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

- Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). --- L858R ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by MRI or CT. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: ORR according to RECIST 1.1 by an Independent Central Review (ICR)

Time: up to 52 weeks

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by MRI or CT. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: ORR according to RECIST 1.1 by investigators

Time: up to 52 weeks

Description: DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.

Measure: Disease control rate (DCR) according to RECIST 1.1

Time: up to 104 weeks

Description: PFS is the time from date of first dose until the date of PD (by independent review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from BPI-7711 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Measure: Progression free survival(PFS) according to RECIST 1.1

Time: up to 104 weeks

132 A Phase I/II Study of AZD9291(Osimertinib) and CB-839 HCl in Patients With EGFR Mutant Non-Small Cell Lung Cancer

This phase I/II trial studies the side effects and best dose of glutaminase inhibitor CB-839 hydrochloride, and to see how well it works when given together with osimertinib in treating patients with stage IV non-small cell lung cancer and a mutation in the EGFR gene. Glutaminase inhibitor CB-839 hydrochloride and osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT03831932 Advanced Lung Carcinoma EGFR Activating Mutation EGFR Exon 19 Deletion Mutation EGFR NP_005219.2:p.L858R EGFR T790M Mutation Negative Lung Non-Small Cell Carcinoma Metastatic Lung Carcinoma Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8 Drug: Glutaminase Inhibitor CB-839 Drug: Glutaminase Inhibitor CB-839 Hydrochloride Drug: Osimertinib
MeSH: Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

The changes in the FDG-PET/computed tomography (CT) parameter measurements from baseline to after treatment will be compared between responders and non-responders using two sample t-test or Wilcoxon test, whichever is appropriate.. Inclusion Criteria: - Histologically confirmed, stage IV NSCLC, with advanced or metastatic disease - Activating mutation present in the EGFR gene (L858R or exon 19 deletion, alone or in combination with other EGFR mutations) as per local assessment of a tissue biopsy specimen. --- L858R ---

Screening for chronic conditions is not required - Patients with symptomatic CNS metastases who are neurologically unstable - Patients who are at risk for impaired absorption of oral medication including, but not limited to, refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of CB-839 HCl (telaglenastat) and AZD9291 - Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements - Involvement in the planning and/or conduct of the study (applies to both investigator staff and/or staff at the study site) - PHASE 2: Prior chemotherapy for NSCLC is not permitted Inclusion Criteria: - Histologically confirmed, stage IV NSCLC, with advanced or metastatic disease - Activating mutation present in the EGFR gene (L858R or exon 19 deletion, alone or in combination with other EGFR mutations) as per local assessment of a tissue biopsy specimen. --- L858R ---

Primary Outcomes

Measure: Recommended phase II dose (RP2D) (Phase I)

Time: Up to 28 days

Description: Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. Will be calculated as the proportion of patients who achieve a response to therapy divided by the total number of evaluable patients. An evaluable patient is defined as an eligible patient who has received at least one dose of therapy. All evaluable patients will be included in calculating the ORR for the study along with corresponding 95% binomial confidence intervals (CIs) (assuming that the number of patients who respond is binomially distributed).

Measure: Objective response rate (ORR) (Phase II)

Time: Up to 30 days after completion of therapy

Secondary Outcomes

Description: Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Frequency and severity of adverse events and tolerability of the regimen will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.

Measure: Dose limiting toxicities (DLT) (Phase I)

Time: Up to 28 days

Description: Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.

Measure: Progression-free survival (PFS) (Phase II)

Time: From initiation of therapy to documented progression or death without progression, assessed up to 30 days after completion of therapy

Description: Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.

Measure: Overall survival (OS) (Phase II)

Time: From initiation of therapy to death from any cause, assessed up to 30 days after completion of therapy

Other Outcomes

Description: Will be assessed by CB-839 HCl drug levels following both single agent therapy as well as combination therapy with CB-839 HCl and osimertinib (AZD9291). Will explore PK endpoints such as concentration steady state (Css), area under the curve (AUC), clearance (CL), volume of distribution (Vd), and half-life (t1/2) computed using non-compartmental and compartmental methods. Will use graphical analyses as well as repeated measure models (linear or nonlinear mixed models, generalized estimating equations [GEE]) to assess the PK and pharmacodynamics (PD) markers described above in relation to clinical treatment outcomes, recognizing some inherent limitations due to sample size.

Measure: Post-glutaminase inhibitor CB-839 hydrochloride pharmacokinetics (PK) (CB-839 HCl) (Phase I)

Time: Day 15 of cycle 1, day 2 of cycle 2 and day 1 of each subsequent cycle

Description: Will be assessed by AZD9291 drug levels following combination therapy with CB-839 HCl and AZD9291. Will be assessed by CB-839 HCl drug levels following both single agent therapy as well as combination therapy with CB-839 HCl and AZD9291. Will explore PK endpoints such as Css, AUC, CL, Vd, and t1/2 computed using non-compartmental and compartmental methods. Will use graphical analyses as well as repeated measure models (linear or nonlinear mixed models, GEE) to assess the PK and PD markers described above in relation to clinical treatment outcomes, recognizing some inherent limitations due to sample size.

Measure: Post-AZD9291 PK (Phase I)

Time: Day 2 of cycle 2 and day 1 of each subsequent cycle

Description: Will be assessed by cell-free deoxyribonucleic acid (cfDNA). All continuous measurements will be summarized using mean +/- standard error of mean (SEM), range, and median at each time point. Changes in these measurements from baseline to after treatment, or baseline to progression will be assessed using paired Wilcoxon tests. Adjustments for multiple comparisons or multiple outcomes will be performed using Bonferroni correction.

Measure: Change in EGFR mutational status (Phase II)

Time: Baseline up to disease progression, assessed up to 30 days after completion of therapy

Description: Will be assessed by plasma concentrations of these compounds. All continuous measurements will be summarized using mean +/- SEM, range, and median at each time point. Changes in these measurements from baseline to after treatment, or baseline to progression will be assessed using paired Wilcoxon tests. Adjustments for multiple comparisons or multiple outcomes will be performed using Bonferroni correction.

Measure: Change in circulating levels of glutamine, glutamate, aspartate, and asparagine (Phase II)

Time: Baseline up to time of disease progression, assessed up to 30 days after completion of therapy

Description: Will be assessed by static (standard uptake value [SUV]max, average SUV, tumor-to-background ratio, metabolic tumor volume, total lesion glycolysis) and dynamic (net influx rate constant and glucose metabolic rate at 30 and 60 minutes) parameters. Will be summarized using mean +/- SEM, range, and median. The changes in the FDG-PET/computed tomography (CT) parameter measurements from baseline to after treatment will be compared between responders and non-responders using two sample t-test or Wilcoxon test, whichever is appropriate.

Measure: Change in 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) imaging (Phase II)

Time: Baseline up to 2 cycles of treatment

133 Phase III Randomized Trial of Atezolizumab in Elderly Patients With Advanced Non-Small-Cell Lung Cancer and Receiving Monthly Carboplatin With Weekly Paclitaxel Chemotherapy

Non Small Cell Lung Cancer (NSCLC) remains the leading cause of death by cancer in the world. Because of the increase in lung cancer incidence with age and the increase of life expectancy, about half of the patients are patients aged 70 or older. Several clinical trials have shown the interest of adding immunotherapy to standard 1st line chemotherapy in NSCLC. Although in these studies there was not necessarily a higher age limit, in fact the proportion of included patients aged 75 or older remains low (between 7 and 10%). It is therefore necessary to conduct a trial dedicated to these patients in order to determine whether immunotherapy is as effective and tolerated as in the general population.

NCT03977194 Non Small Cell Lung Cancer Metastatic Drug: Carboplatin Drug: Paclitaxel Drug: Atezolizumab
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Exclusion Criteria: 1. Small cell lung cancer or tumors with mixt histology including a SCLC component 2. Known EGFR activating tumor mutation (deletion LREA in exon 19, L858R ou L861X mutations in exon 21, G719A/S mutation in exon 18) or HER2 exon 20 insertion (either tissue or plasma cfDNA mutation). --- L858R ---

Primary Outcomes

Description: Time from randomization until death due to any cause

Measure: Overall Survival

Time: 11 months after randomization of the last subject

Secondary Outcomes

Description: Time from randomization to first observation of progression (according to RECIST v1.1) or date of death (from any cause).

Measure: Progression-free survival

Time: 11 months after randomization of the last subject

Description: Best response according to RECIST v1.1 from start to end of study treatment

Measure: Best overall response rate

Time: 11 months after randomization of the last subject

Description: Time from documentation of tumor response to disease progression

Measure: Duration of response

Time: 11 months after randomization of the last subject

134 A Phase Ib Clinical Study With Extension Phase to Evaluate Safety and Efficacy of Genolimzumab (GB226) in Combination With Fruquintinib in the Treatment of Relapsed or Metastatic NSCLC Patients With EGFR-sensitive Mutation Who Have Failed Respond to Treatment With EGFR-TKI.

This study is a multi-center, open-label, dose-finding phase Ib clinical study with extension phase, which is aimed at evaluating the efficacy and safety of GB226 combined with fruquintinib in treatment of relapsed or metastatic NSCLC patients with EGFR-sensitive mutations who have failed to respond to EGFR-TKI treatment,evaluating the pharmacokinetic characteristics of GB226 and fruquintinib, and the immunogenicity of GB226, and preliminarily evaluating the antitumor activity of GB226 and fruquintinib.

NCT03976856 Metastatic Non-small Cell Lung Cancer Drug: GB226 Drug: Fruquintinib
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

Inclusion Criteria: 1. Aged 18-75 years, male or female; 2. Understanding the procedures and contents of the study, and voluntarily signing the written informed consent form; 3. Histologically or cytology confirmed relapsed or metastatic NSCLC; 4. EGFR gene sensitive mutation is confirmed positive, any of following is met: exon 19 deletion (19DEL), exon 21 point mutation (L858R / L861Q), 18 exon point mutation (G719X), 20 exon point mutation (S768I). --- L858R ---

Primary Outcomes

Description: Assessment of adverse events (AEs) graded by Common Terminology Criteria for Adverse Events (CTCAE) v4.03

Measure: Incidence of Adverse Event

Time: all adverse events will be recorded from the time the consent form is signed through 90 days following cessation of treatment.

Description: Assessment of serious adverse events (SAEs) graded by Common Terminology Criteria for Adverse Events (CTCAE) v4.03

Measure: Incidence of Serious Adverse Event

Time: all adverse events will be recorded from the time the consent form is signed through 90 days following cessation of treatment.

Description: Incidence of Dose Limited Toxicity

Measure: Dose Limited Toxicity

Time: Day 1 to Day 28 after first dose

Description: Defined as the highest dose tested in which only 0 or 1 out of 6 evaluable patients experience a dose limiting toxicity, as graded by the National Cancer Institute (NCI) Common terminology Criteria for Adverse Events (CTCAE) version 4.03

Measure: Maximum Tolerated Dose

Time: Day 1 to Day 28 after first dose

Secondary Outcomes

Description: Objective response rate in accordance with RECIST 1.1. ORR will be calculated as the percent of patients in each of the expansion cohorts whose best confirmed response is complete response (CR) or partial response (PR).

Measure: ORR

Time: up to 52 weeks

Description: Progression-free survival. From start of treatment to time of progression or death, whichever occurs first

Measure: PFS

Time: up to 52 weeks

Description: Duration of Response. Date of CR or PR to Date of Objective Disease Progression or Death from Any Cause.

Measure: DOR

Time: up to 52 weeks

Description: Disease control rate.DCR will be the proportion of patients in each of the expansion cohorts whose best confirmed response is CR, PR, or stable disease (SD).

Measure: DCR

Time: up to 52 weeks

Description: Overall Survival. From start of treatment to time of death.

Measure: OS

Time: up to 52 weeks

Description: incidence of anti-GB226 antibody(ADA)

Measure: ADA

Time: up to 52 weeks

Description: Pharmacokinetics of GB226 and Fruquinitinib by assessment of Cmax

Measure: Cmax

Time: up to 16 weeks

Description: Pharmacokinetics of GB226 and Fruquinitinib by assessment of AUC

Measure: AUC

Time: up to 16 weeks

135 A Randomized Phase 2 Study Comparing Immunotherapy With Chemotherapy in the Treatment of Elderly Patients With Advanced NSCLC (MILES-5)

This is a randomized phase 2 trial aiming to assess the early efficacy of two experimental treatment sequences. Three arms are planned; (i) standard chemotherapy followed at progression by single agent immunotherapy with durvalumab (CT), (ii) experimental single agent immunotherapy with durvalumab followed at progression by chemotherapy, (iii) experimental combination immunotherapy with durvalumab+tremelimumab followed at progression by chemotherapy. The the two experimental strategies will be compared with the standard strategy in terms of 12-month overall survival, time considered informative for the type of treatment and disease

NCT03975114 Carcinoma, Non-Small-Cell Lung Drug: Chemotherapy Drug: Durvalumab Drug: Tremelimumab
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

Exclusion Criteria: Cancer related 1. Activating epidermal growth factor receptor mutation (exon19 deletion or exon 21 L858R mutation or other activating/sensitizing mutations). --- L858R ---

Primary Outcomes

Description: 12-month overall survival is defined as the Kaplan-Meier (K-M) survival probability at 12 months after randomization (Chen 2015).

Measure: 12-month overall survival

Time: 12 months

136 A Prospective, Open-label, Single Arm, Multi-center, Phase II Exploratory Trial to Evaluate the Efficacy and Safety of NOV120101 (Poziotinib) as the First-line Treatment Medication in Patients With Harboring EGFR Mutations

The purpose of this open-label, single-arm, multi-center phase II trial is to evaluate the efficacy and safety of novel pan-HER inhibitor, NOV120101 (Poziotinib), as a first-line monotherapeutic agent in patients with lung adenocarcinoma harboring EGFR mutation.

NCT01819428 Adenocarcinoma of Lung Stage IIIB Adenocarcinoma of Lung Stage IV Drug: NOV120101 (Poziotinib)
MeSH: Adenocarcinoma Adenocarcinoma of Lung

Inclusion Criteria: 1. Male or female patients aged 20 years or older 2. Pathologically confirmed stage IIIB (unresectable) or IV lung adenocarcinoma 3. Documented EGFR mutation (e.g., exon 19 deletion, exon 21 L858R, etc.) with tumor tissue 4. Patients who have 1 or more measurable lesions according to RECIST version 1.1 5. ECOG performance status 2 or less 6. --- L858R ---

Patients who cannot participate in this trial by investigator's judgment Inclusion Criteria: 1. Male or female patients aged 20 years or older 2. Pathologically confirmed stage IIIB (unresectable) or IV lung adenocarcinoma 3. Documented EGFR mutation (e.g., exon 19 deletion, exon 21 L858R, etc.) with tumor tissue 4. Patients who have 1 or more measurable lesions according to RECIST version 1.1 5. ECOG performance status 2 or less 6. --- L858R ---

Primary Outcomes

Description: the proportion of patients with complete response (CR) and/or partial response (PR)

Measure: Objective response rate (ORR)

Time: about 3 years

Secondary Outcomes

Description: the proportion of patients with complete response (CR) and/or partial response (PR) at 12 months following start of study drug administration.

Measure: Progression free survival (PFS) rate at 12 months

Time: 12 months after enrollment of the last subject

Description: the proportion of patients with CR, PR and/or stable disease (SD)

Measure: Disease control rate (DCR)

Time: 3 years

Description: The length of time during and after medication or treatment during which the disease being treated (usually cnacer) does not get worse.

Measure: Progression free survival (PFS)

Time: 3 years

Description: the time from study drug administration until death from any cause

Measure: Overall survival (OS)

Time: 3 years

Description: Change means the end of treatment minus baseline in each patient

Measure: Change of quality of life (QoL) measured by EQ-5D questionnaire

Time: 3 years

Other Outcomes

Description: to observe pharmacokinetic parameter, inter-individual variability and intra-individual variability considering covariates, demographic factors, influencing PK profile.

Measure: Population pharmacokinetics (PK) of NOV120101 (Poziotinib)

Time: 3 months after enrollment of the last subject

Description: to observe HGF expression status in plasma and T790M mutation induction status from plasma DNA

Measure: Subgroup analyses according to the genetic information

Time: 3 years

137 A Randomized, Open-label Phase II Trial of Erlotinib 100mg Daily Versus Gefitinib 250mg Daily in Patients With Advanced Non-small Cell Lung Cancer Who Harbor EGFR Mutations.

This study is a multicenter, randomized, open-label Phase II trial that compares reduced dose erlotinib 100mg daily and standard dose gefitinib 250mg daily in patients with advanced non-small cell lung cancer who harbor EGFR mutations. The primary endpoint is disease control rate (DCR) and the key secondary endpoint is progression free survival (PFS). A total of 224 eligible patients will be randomized to receive either erlotinib 100mg daily or gefitinib 250mg daily in a 1:1 ratio until patients experience disease progression. Independent assessment of the major endpoints will be completed in a treatment-blinded manner. Randomization will be stratified based on treatment-lines (first-line vs. maintenance vs. second-line therapy). Tumor response and progression will be assessed according to RECIST 1.1.

NCT01955421 Advanced Stage Non Small Cell Lung Cancer Drug: Erlotinib 100mg qd Drug: Gefitinib 250mg qd
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

2. Harboring a PCR-confirmed activating mutation of EGFR, including an exon 19 deletion or an exon 21 L858R point mutation. --- L858R ---

Primary Outcomes

Measure: disease control rate

Time: 2 years

Secondary Outcomes

Measure: progression free survival

Time: 2 years

Description: rash, diarrhea, ILD, etc.

Measure: adverse events

Time: 2 years

138 Randomized, Double-Blind, Multicenter, Phase 2 Trial Comparing Veliparib Plus Carboplatin and Paclitaxel Versus Placebo Plus Carboplatin and Paclitaxel in Previously Untreated Metastatic or Advanced Non-Small Cell Lung Cancer (NSCLC)

A Randomized, Double-Blind, Multicenter, Phase 2 Trial Comparing Veliparib Plus Carboplatin and Paclitaxel Versus Placebo Plus Carboplatin and Paclitaxel in Previously Untreated Metastatic or Advanced Non-Small-Cell Lung Cancer (NSCLC).

NCT01560104 Non-Small -Cell Lung Cancer Drug: Veliparib Drug: Carboplatin Drug: paclitaxel Drug: placebo
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

- Subjects with peripheral neuropathy ≥ grade 2. - Subjects with a known epidermal growth factor receptor (EGFR) mutation of exon 19 deletion or L858R mutation in exon 21. (Subjects with wild type epidermal growth factor receptor (EGFR), unknown status or other type of epidermal growth factor receptor (EGFR) mutation will be considered eligible). --- L858R ---

Primary Outcomes

Measure: Progression Free Survival (PFS)

Time: Radiographic evaluation starting from the third day of study treatment and on average every 6 weeks until documented progression or date of death from any cause, whichever came first, until patient is registered as off study.

Secondary Outcomes

Description: Continuously from date of randomization until date of death from any cause or until patient is registered as off study, whichever came first.

Measure: Overall Survival (OS)

Time: Monthly after patient is registered off study up to 36 months or until date of death from any cause, whichever came first.

Measure: Objective Response Rate (ORR)

Time: Radiographic evaluation starting from the third day of study treatment and on average every 6 weeks until documented progression or date of death from any cause, whichever came first, until patient is registered as off study.

Measure: Chemotherapy Induced Peripheral Neuropathy (CIPN)

Time: From date of screening, first day of study treatment and then every cycle (about every 3 weeks) until date of death from any cause or patient is registered as off study, whichever came first.

139 An Open-label Phase II Trial of Erlotinib and Bevacizumab in Patients With Advanced Non-small Cell Lung Cancer and Activating EGFR Mutations

Rationale: Advanced non-small-cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations (del19 or L858R) show an impressive progression-free survival between 9 and 14 months when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. The investigators hypothesize that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways. The investigators propose a model of treatment whereby patients with EGFR mutations (single or with T790M) can attain a benefit with longer overall PFS when treated with erlotinib plus bevacizumab. When the patients are grouped by BRCA1 mRNA levels and T790M the hypothesis is that the combination of erlotinib plus bevacizumab can improve the PFS in all subgroups.

NCT01562028 Lung Cancer Drug: Erlotinib Drug: Bevacizumab
MeSH: Lung Neoplasms
HPO: Neoplasm of the lung

BELIEF (Bevacizumab and ErLotinib In EGFR Mut+ NSCLC) Rationale: Advanced non-small-cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations (del19 or L858R) show an impressive progression-free survival between 9 and 14 months when treated with erlotinib. --- L858R ---

- Centrally confirmed EGFR exon 19 deletion (del19) or exon 21 mutation (L858R) Exclusion Criteria: - Patients with increased risk of bleeding - Patients with clinically significant cardiovascular diseases - Patients with a history of thrombosis or thromboembolism in the 6 months prior to treatment - Patients with gastrointestinal problems - Patients with neurologic problems - Patients who have had in the past 5 years any previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ breast carcinoma. --- L858R ---

Primary Outcomes

Description: Time from the date of enrolment until documented progression or death, whichever occurs first.

Measure: Progression free survival

Time: Within 6 months of the last visit of last patient, approximately 54 months after inclusion of first patient

Secondary Outcomes

Description: Time from the date of enrolment to discontinuation of treatment for any reason (including progression of disease, treatment toxicity, refusal and death).

Measure: Time to treatment failure

Time: Within 6 months of the last visit of last patient, approximately 54 months after inclusion of first patient

Description: Best overall response (complete remission or partial remission) across all assessment time-points according to RECIST Criteria 1.1, during the period from enrolment to termination of trial treatment.

Measure: Objective response

Time: termination of trial treatment

Description: Adverse events graded according to NCI CTCAE V4.

Measure: Adverse events

Time: Within 6 months of the last visit of last patient, approximately 54 months after inclusion of first patient

Description: Achievement of objective response or stable disease for at least 6 weeks.

Measure: Disease control

Time: Within 6 months of the last visit of last patient, approximately 54 months after inclusion of first patient

Description: Interval from the date of first documentation of objective response by RECIST to the date of first documented progression or relapse.

Measure: Duration of response

Time: Within 6 months of the last visit of last patient, approximately 54 months after inclusion of first patient

Description: Time from the date of enrolment until death from any cause.

Measure: Overall survival (OS)

Time: Within 6 months of the last visit of last patient, approximately 54 months after inclusion of first patient

140 PHASE 1/2 OPEN-LABEL STUDY OF PF-06747775 (EPIDERMAL GROWTH FACTOR RECEPTOR T790M INHIBITOR) IN PATIENTS WITH ADVANCED EPIDERMAL GROWTH FACTOR RECEPTOR MUTANT (DEL 19 OR L858R ± T790M) NON-SMALL CELL LUNG CANCER

This is a Phase 1/2 study of PF-06747775 as a single agent and in combination with other cancer treatments in patients with advanced EGFRm NSCLC. The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M).

NCT02349633 Non-Small Cell Lung Cancer Drug: PF-06747775 Drug: Palbociclib Drug: Avelumab
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

PHASE 1/2 OPEN-LABEL STUDY OF PF-06747775 (EPIDERMAL GROWTH FACTOR RECEPTOR T790M INHIBITOR) IN PATIENTS WITH ADVANCED EPIDERMAL GROWTH FACTOR RECEPTOR MUTANT (DEL 19 OR L858R ± T790M) NON-SMALL CELL LUNG CANCER. --- T790M --- --- L858R ---

Study For Patients With NSCLC EGFR Mutations (Del 19 or L858R +/- T790M) This is a Phase 1/2 study of PF-06747775 as a single agent and in combination with other cancer treatments in patients with advanced EGFRm NSCLC. --- L858R ---

The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M). --- T790M --- --- T790M --- --- L858R ---

The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M). --- T790M --- --- T790M --- --- L858R --- --- T790M --- --- T790M --- --- T790M --- --- L858R ---

Partial Inclusion criteria: Evidence of histologically or cytologically confirmed diagnosis of locally advanced or metastatic EGFRm (del 19 or L858R) NSCLC: 1. --- L858R ---

In the PK sub-studies involving food/antacid and CYP3A4 effects, patients with EGFRm (del 19 or L858R) with any T790M status are eligible to enroll. --- L858R ---

Cohort 2 and Cohort 3: Patients must have EGRFm (del 19 AND T790M or L858R AND T790M) NSCLC tumors as detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR RGQ PCR kit, Roche cobas® EGFR Mutation Test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which will then be retrospectively confirmed by the central validated Thermo Fisher Scientific Oncomine Next Generation Sequencing (NGS) cancer panel test. --- T790M --- --- L858R ---

Patients will also be enrolled if they solely test positive for EGFR (del 19 AND T790M or L858R AND T790M) NSCLC in plasma detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR Plasma RGQ kit, Roche cobas® EGFR mutation test v2 (US-IVD) or Sysmex Inostic's OncoBEAMTM EGFR test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which will then be retrospectively confirmed by a validated cfDNA test as determined by the Sponsor. --- T790M --- --- L858R ---

Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible Use of immunosuppressive medication at time of randomization Partial Inclusion criteria: Evidence of histologically or cytologically confirmed diagnosis of locally advanced or metastatic EGFRm (del 19 or L858R) NSCLC: 1. --- L858R ---

Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible Use of immunosuppressive medication at time of randomization Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung There remains an unmet medical need to develop EGFR TKI agents that effectively target both the single activating mutations of del 19 and L858R, and the secondary resistance mutation T790M, while sparing WT EGFR. --- L858R ---

Primary Outcomes

Description: The target probability of DLT at MTD will be 30%

Measure: Phase 1 Primary Endpoint - Number of patients with dose limiting toxicities during Phase 1

Time: 21 days

Description: Cohort 1 is an evaluation of PF 06747775 single agent at RP2D Cohorts 2A and 3 will determine the RP2D of PF-06747775 in combination with either palbociclib or avelumab, respectively, based on safety and tolerability. Determination of the RP2D will be performed using the mTPI design. For Cohort 2A, after determination of the RP2D for the PF-06747775 and palbociclib combination, a randomized evaluation of the combination vs PF-06747775 single agent (2:1 ratio) will be initiated (Cohort 2B). For Cohort 3, after determination of the RP2D for the PF-06747775 and avelumab combination, the dose level will be expanded to enroll an overall total of approximately 20 patients to further explore the safety, PK, and antitumor activity of the combination.

Measure: Phase 1b/2 - Cohort 1 = confirmed OR per RECIST; Cohort 2A = Cycle 2 DLT; Cohort 2B = PFS and Cohort 3 = Cycle 1 DLT

Time: Cohorts 1, 2A and 2B = 21 day cycles and Cohort 3 = 28 day cycles

Secondary Outcomes

Description: Number of patients with OR based assessment of confirmed CR or PR according to RECIST. CR are those that persist on repeat imaging at least 4 weeks after the initial documentation of response. PR are those that are greater or equal to a 30% decrease ( per RECIST) under the baseline of the sum of diameters of all target measurable disease

Measure: Phase 1: Secondary Endpoint - Number of patients with Objective Response (OR)

Time: Time from first dose of study drug until OR of CR or PR up to 24 months

Description: PFS (cohort 1, 2A and 3) ORR (cohort 2A, 2B and 3) DOR (All cohorts)

Measure: Phase 1b/2

Time: Time from first dose of study drug until Disease Progression or death (whichever first) up to 24 months

141 A Phase 1b Study of Erlotinib and Momelotinib for the Treatment of Epidermal Growth Factor Receptor (EGFR) Mutated EGFR Tyrosine Kinase Inhibitor (TKI) Naïve Metastatic Non-Small Cell Lung Cancer (NSCLC)

This study will evaluate the safety, preliminary efficacy, and pharmacokinetics (PK) of momelotinib (MMB) and erlotinib, as well as define the maximum tolerated dose (MTD) of momelotinib (MMB) combined with erlotinib in adults with epidermal growth factor receptor (EGFR)-mutated, EGFR tyrosine kinase inhibitor (TKI) naive metastatic non-small cell lung cancer (NSCLC). Participants will be sequentially enrolled to receive progressively increasing doses of momelotinib (MMB) in combination with erlotinib. Escalation of momelotinib (MMB) doses will proceed to the MTD, defined as the highest tested dose associated with dose-limiting toxicities (DLT) during the first 28 days of combined erlotinib and momelotinib (MMB) treatment. There will be four dose levels and each treatment cycle will consist of 28 days.

NCT02206763 EGFR Mutated EGFR TKI Naive Metastatic NSCLC Drug: Momelotinib (MMB) Drug: Erlotinib
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).. Key Inclusion Criteria: - Metastatic NSCLC with documented EGFR exon 19 deletion or exon 21 (L858R) substitution mutation - Treatment naive OR one prior standard chemotherapy that is platinum-based - Adequate organ function defined as follows: - Hepatic: Total bilirubin < upper limit of the normal range (ULN); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN - Hematological: absolute neutrophil count (ANC) ≥1500 cells/mm^3, platelet ≥ 100,000 cells/mm^3, hemoglobin ≥ 9.0 g/dL - Renal: Serum creatinine < ULN OR calculated creatinine clearance (CLcr) of ≥ 60 ml/min - Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 Key Exclusion Criteria: - Known positive status for human immunodeficiency virus (HIV) - Chronic active or acute viral hepatitis A, B, or C infection (testing required for hepatitis B and C) - Presence of > Grade 1 peripheral neuropathy - Symptomatic leptomeningeal, brain metastases, or spinal cord compression. --- L858R ---

Key Inclusion Criteria: - Metastatic NSCLC with documented EGFR exon 19 deletion or exon 21 (L858R) substitution mutation - Treatment naive OR one prior standard chemotherapy that is platinum-based - Adequate organ function defined as follows: - Hepatic: Total bilirubin < upper limit of the normal range (ULN); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN - Hematological: absolute neutrophil count (ANC) ≥1500 cells/mm^3, platelet ≥ 100,000 cells/mm^3, hemoglobin ≥ 9.0 g/dL - Renal: Serum creatinine < ULN OR calculated creatinine clearance (CLcr) of ≥ 60 ml/min - Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 Key Exclusion Criteria: - Known positive status for human immunodeficiency virus (HIV) - Chronic active or acute viral hepatitis A, B, or C infection (testing required for hepatitis B and C) - Presence of > Grade 1 peripheral neuropathy - Symptomatic leptomeningeal, brain metastases, or spinal cord compression. --- L858R ---

Primary Outcomes

Description: Dose limiting toxicities refer to toxicities experienced during the first 28 days of combined erlotinib and momelotinib (MMB) treatment that have been judged to be clinically significant and related to study treatment.

Measure: Incidence of Dose Limiting Toxicities (DLTs)

Time: Up to 28 days

Measure: Safety as Assessed by the Incidence of Adverse Events (AEs)

Time: Up to 2 years plus 30 days

Measure: Safety as Assessed by the Percentage of Participants Experiencing Treatment-Emergent Graded Lab Abnormalities (including Chemistry, Coagulation, Hematology, and Urinalysis)

Time: Up to 2 years plus 30 days

Measure: Change from Baseline in Vital Signs

Time: Up to 2 years

Secondary Outcomes

Description: Progression-free survival is defined as the interval from first dose date of study drug (MMB/erlotinib) to the earlier of the first documentation of definitive disease progression or death from any cause; definitive disease progression is progression based on RECIST criteria v1.1.

Measure: Progression-Free Survival

Time: Until disease progression (up to 2 years)

Description: Overall survival is defined as the interval from first dose date of study drug (MMB/erlotinib) to death from any cause.

Measure: Overall Survival

Time: Until disease progression (up to 2 years)

Description: Overall response rate is defined as the proportion of participants who achieve a complete response or partial response.

Measure: Overall Response Rate

Time: Until disease progression (up to 2 years)

Description: Cmax is defined as the maximum observed concentration of drug.

Measure: Pharmacokinetic (PK) Parameter: Cmax of momelotinib (MMB)

Time: Predose and up to 24 hours postdose

Description: AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

Measure: PK Parameter: AUCtau of momelotinib (MMB)

Time: Predose and up to 24 hours postdose

Description: Cmax is defined as the maximum observed concentration of drug.

Measure: PK Parameter: Cmax of Erlotinib

Time: Predose and up to 24 hours postdose

Description: AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

Measure: PK Parameter: AUCtau of Erlotinib

Time: Predose and up to 24 hours postdose

142 An Open Label, Single-arm Phase IV Study to Assess the Efficacy and Safety of Afatinib as Second-line Therapy for Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) Harbouring an EGFR Mutation (Del19 or L858R) Who Have Failed First-line Treatment With Platinum-based Chemotherapy

The objectives of this single-arm, open-label trial are to assess the efficacy and safety of afatinib as second line treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring a common EGFR mutation who have failed first-line platinum-based chemotherapy and to demonstrate that the efficacy and safety are comparable to the results seen in previous trials.

NCT02208843 Carcinoma, Non-Small-Cell Lung Drug: Afatinib
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

An Open Label, Single-arm Phase IV Study to Assess the Efficacy and Safety of Afatinib as Second-line Therapy for Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) Harbouring an EGFR Mutation (Del19 or L858R) Who Have Failed First-line Treatment With Platinum-based Chemotherapy. --- L858R ---

2. Documented EGFR mutation (L858R and/or Deletion 19) with no other known EGFR mutation. --- L858R ---

Primary Outcomes

Description: As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by Magnetic resonance imaging (MRI): Complete Response (CR), disappearance of all target lesions; Partial Response (PR), =30% decrease in the sum of the longest diameter of target lesions

Measure: Objective Tumour Response (Complete Response [CR], Partial Response [PR]) as Assessed by the Investigator According to the RECIST Version 1.1

Time: Post baseline tumour-imaging was performed at every 8 weeks until Week 56 and then every 12 weeks; up to 802 days

Secondary Outcomes

Description: Progression-free survival (PFS) is the time from treatment start to disease progression (or death if the patient died before progression). PFS as assessed based on investigator review according to the response evaluation criteria in solid tumours (RECIST) version 1.1.

Measure: Progression-free Survival (PFS) as Assessed by the Investigator According to RECIST 1.1.

Time: Post baseline tumour-imaging was performed at every 8 weeks until Week 56 and then every 12 weeks; up to 802 days

Description: As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), =30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression.

Measure: Disease Control (CR, PR, Stable Disease [SD]) as Assessed by the Investigator According to RECIST 1.1

Time: Post baseline tumour-imaging was performed at every 8 weeks until Week 56 and then every 12 weeks; up to 802 days

143 Second Line Erlitinib Combination With Gemcitabine Cisplatinum in Non-small Cell Lung Cancer Patients Who Harbored EGFR Sensitive Mutation Developed Resistance After First Line TKI Treatment

Numerous evidences verified that erlotinib could dramatically improve the PFS and OS of non-small cell lung cancers who harbor EGFR sensitive mutations, however, primary or secondary resistance will be developed after TKI treatment, doctors do plenty of researches to overcome TKI resistance. FAST ACT-2 study present that, first line erlotinib combined with chemotherapy could improved mOS to more than 30 months in NSCLCs who harbor EGFR sensitive mutations, several study shows that sensitive mutations still exist after TKI resistance, because of the next generation TKIs(such as BIBW2992) are not avaliable at present, agents for met amplification(such as Crizotinib) are so expensive that many Chinese patients could not support. Thus, the investigators hypothesis that, after first line TKI treatment, the patients who developed TKI resistance could still benefit from second line TKI combined with chemotherapy.

NCT02098954 Carcinoma, Non-Small Cell Lung EGFR Gene Mutation Drug: Gemcitabine platinum combined with erlotinib
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

Inclusion Criteria: - advanced non-small cell lung cancer, stage IIIB/IV - non-squamous - EGFR sensitive mutations, such as exon 19 del, or exon 21 L858R - received first line TKIs treatment and developed TKI resistance - ECOG 0-2 Exclusion Criteria: - squamous non-small cell lung cancer - patients have unstable brain metastasis, predict survival less than 8 weeks - spinal-cord compression without evidence of stabilisation or treatment - women who were pregnant or lactating; women with a positive or no available pregnancy test result at baseline - patients have any unstable illness that could not receive further treatment Inclusion Criteria: - advanced non-small cell lung cancer, stage IIIB/IV - non-squamous - EGFR sensitive mutations, such as exon 19 del, or exon 21 L858R - received first line TKIs treatment and developed TKI resistance - ECOG 0-2 Exclusion Criteria: - squamous non-small cell lung cancer - patients have unstable brain metastasis, predict survival less than 8 weeks - spinal-cord compression without evidence of stabilisation or treatment - women who were pregnant or lactating; women with a positive or no available pregnancy test result at baseline - patients have any unstable illness that could not receive further treatment Carcinoma, Non-Small Cell Lung EGFR Gene Mutation Carcinoma, Non-Small-Cell Lung The investigators will enroll patients diagnosed with advanced non-squamous,non-small cell lung cancer, patients with EGFR TKI sensitive mutations and developed TKI resistance in first line treatment. --- L858R ---

Inclusion Criteria: - advanced non-small cell lung cancer, stage IIIB/IV - non-squamous - EGFR sensitive mutations, such as exon 19 del, or exon 21 L858R - received first line TKIs treatment and developed TKI resistance - ECOG 0-2 Exclusion Criteria: - squamous non-small cell lung cancer - patients have unstable brain metastasis, predict survival less than 8 weeks - spinal-cord compression without evidence of stabilisation or treatment - women who were pregnant or lactating; women with a positive or no available pregnancy test result at baseline - patients have any unstable illness that could not receive further treatment Inclusion Criteria: - advanced non-small cell lung cancer, stage IIIB/IV - non-squamous - EGFR sensitive mutations, such as exon 19 del, or exon 21 L858R - received first line TKIs treatment and developed TKI resistance - ECOG 0-2 Exclusion Criteria: - squamous non-small cell lung cancer - patients have unstable brain metastasis, predict survival less than 8 weeks - spinal-cord compression without evidence of stabilisation or treatment - women who were pregnant or lactating; women with a positive or no available pregnancy test result at baseline - patients have any unstable illness that could not receive further treatment Carcinoma, Non-Small Cell Lung EGFR Gene Mutation Carcinoma, Non-Small-Cell Lung The investigators will enroll patients diagnosed with advanced non-squamous,non-small cell lung cancer, patients with EGFR TKI sensitive mutations and developed TKI resistance in first line treatment. --- L858R --- --- L858R ---

Primary Outcomes

Description: mean progression free survival(mPFS) will be recorded in enroll patients who received second line gemcitabine platinum combined with erlotinib. mPFS should be measured before second line treatment, before the third combined chemotherapy, after the fourth combined chemotherapy, every 3 months during erlotinib treatment, mPFS should be measured up to two years or every time progression disease occurs within two years.

Measure: mean progression free survival(mPFS)

Time: after patients receive treatment, mPFS should be measured before the third cycle of chemotherapy, after the fourth cycle, mPFS should be measured every 3 months up to two years

Secondary Outcomes

Description: mOS should be measured since enrollment, every 3 months we will contact patients to find out detail survival data of each patient until 3 years, or within 3 years if all survival data is obtained.

Measure: mean overall survival(mOS)

Time: every 3 months up to 3 years, or until all the survival data is obtained

Description: 8 week ORR should be measured after enrollment, after combined chemotherapy for 8 weeks, the exact time point should be the ninth week during combined chemotherapy. CR, PR, SD shoud be measured according to RESICT 1.1

Measure: 8 week overall response rate(8 week ORR)

Time: 8 week ORR should be measured after enrollment, the exact time point should be the ninth week after combined chemotherapy

144 My Pathway: An Open-Label Phase IIa Study Evaluating Trastuzumab/Pertuzumab, Erlotinib, Vemurafenib/Cobimetinib, Vismodegib, Alectinib, and Atezolizumab in Patients Who Have Advanced Solid Tumors With Mutations or Gene Expression Abnormalities Predictive of Response to One of These Agents

This multicenter, non-randomized, open-label study will evaluate the efficacy and safety of six treatment regimens in participants with advanced solid tumors for whom therapies that will convey clinical benefit are not available and/or are not suitable options per the treating physician's judgment.

NCT02091141 Neoplasms Solid Tumors Biliary Cancer Salivary Cancer Bladder Cancer Drug: Trastuzumab Drug: Pertuzumab Drug: Erlotinib Drug: Vemurafenib Drug: Cobimetinib Drug: Vismodegib Drug: Alectinib Drug: Atezolizumab
MeSH: Urinary Bladder Neoplasms
HPO: Bladder neoplasm

The tissue sample must be submitted within 4 weeks after enrollment General Exclusion Criteria: - Participants with hematologic malignancies - Concurrent administration of any other anti-cancer therapy (except male participants with prostate cancer receiving androgen blockade): Bisphosphonates and denosumab are allowed; Most recent anti-cancer therapy ≤28 days and have not recovered from the side effects, excluding alopecia; Radiation therapy within ≤14 days - Active or untreated brain metastases - History of carcinomatous meningitis - Uncontrolled concurrent malignancy (early stage is allowed if not requiring active therapy or intervention) - Pregnant or breastfeeding women, or intending to become pregnant during the study - Any significant cardiovascular events within 6 months prior to study entry - Pulmonary embolism within 30 days prior to study entry - History or presence of clinically significant ventricular or atrial dysrhythmia >Grade 2 per NCI CTCAE v4.0 - Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results - Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol Study-Drug Specific Exclusion Criteria: Trastuzumab plus Pertuzumab - Previous treatment with any HER2-targeted therapy Erlotinib - Non-small cell lung cancer (NSCLC) or pancreatic cancer identified by exon 19 deletions or exon 21 L858R substitution mutations - EGFR amplifications in the absence of EGFR-activating mutations - Cancers with exon 20 mutations - Previous treatment with erlotinib or any other EGFR inhibitor - Inability to swallow pills - Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude absorption of erlotinib Vemurafenib plus Cobimetinib - Malignant melanoma, papillary thyroid cancer, colorectal cancer, or hematologic malignancy including multiple myeloma - LVEF below institutional lower level of normal (LLN) or below 50%, whichever is lower - History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration - Presence of any of the following conditions, which are risk factors for RVO: Uncontrolled glaucoma with intraocular pressure >21 millimetres of mercury (mm Hg); Serum cholesterol ≥Grade 2; Hypertriglyceridemia ≥Grade 2; Hyperglycemia (fasting) ≥Grade 2; Grade ≥2 uncontrolled hypertension (participants with a history of hypertension controlled with anti-hypertensive medication to Grade L858R ---

Primary Outcomes

Description: Tumor response will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for all arms.

Measure: Percentage of Participants in All Tumor-Pathway Cohorts With Overall Response, as Assessed by the Investigator

Time: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Description: Tumor response will be assessed using RECIST version 1.1.

Measure: Percentage of Atezolizumab-Treated Participants With Tissue Tumor Mutational Burden (tTMB) ≥16 Mutations/Mb With Overall Response, as Assessed by the Independent Review Committee (IRC)

Time: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Secondary Outcomes

Description: Tumor response will be assessed using RECIST version 1.1 for all arms.

Measure: Percentage of Participants With Disease Control

Time: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Description: Tumor response will be assessed using RECIST version 1.1 for all arms.

Measure: Progression-Free Survival (PFS)

Time: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Measure: Percentage of Participants who are Alive at Year 1

Time: 1 year

Description: Tumor response will be assessed using RECIST version 1.1 for all arms.

Measure: Duration of Response

Time: From the date of first documented response (complete response [CR] or partial response [PR]) to the time of disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Description: Tumor response will be assessed using RECIST version 1.1.

Measure: Percentage of Atezolizumab-Treated Participants with tTMB ≥10 Mutations/Mb and <16 Mutations/Mb With Overall Response, as Assessed by the Investigator

Time: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Description: Tumor response will be assessed using RECIST version 1.1.

Measure: Percentage of Atezolizumab-Treated Participants with Blood Tumor Mutational Burden (bTMB) ≥16 Mutations With Overall Response, as Assessed by the IRC

Time: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Measure: Percentage of Participants With Adverse Events

Time: From first study treatment administration to 30 days (45 days for vismodegib, 90 days for atezolizumab) after the last dose (up to approximately 5 years)

145 Phase II, Open Label, Single-arm Study to Assess Safety and Efficacy of AZD9291 in Patients With Locally Advanced/Metastatic NSCLC Whose Disease Has Progressed With Previous EGFR TKI and Whose Tumours Are EGFR and T790M Mutation Positive

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Patients with Locally Advanced/Metastatic Non Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours are Epidermal Growth Factor Receptor Mutation and T790M Mutation Positive

NCT02094261 Non Small Cell Lung Cancer Drug: AZD9291
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

- Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). --- L858R ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR was defined as the time from the date of first documented response (CR or PR that was subsequently confirmed) until the date of documented progression (PD) or death in the absence of disease progression (by investigator assessment).

Measure: Duration of Response (DoR)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.

Measure: Disease Control Rate (DCR)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of first dose until the date of PD (by independent review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from AZD9291 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Measure: Progression-Free Survival (PFS)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

146 Intercalated Combination of Chemotherapy and Erlotinib in 1st Line Setting for Patients Advanced Stage Non-small-cell Lung Cancer With Low Abundant Activating EGFR Mutation(INNOVATE)

This is a single arm phase II clinical trial, which aims to evaluate the effectiveness of intercalated combination of doublet chemotherapy of paclitaxel plus carboplatin and erlotinib on patients with advanced stage non-small-cell lung cancer with low abundant activating EGFR mutation.

NCT02095782 Non-small-cell Lung Cancer Drug: Intercalated combination of chemotherapy and erlotinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Low abundant activating EGFR mutation: EGFR exon 19 deletion or exon 21 L858R, which are positive by real-time PCR methods and negative by standard sequencing methods. --- L858R ---

Primary Outcomes

Description: From start of anti-cancer therapy untill progression or death

Measure: Progression free survival defined by imagery methods

Time: 8 weeks

Secondary Outcomes

Description: From start of anti-cancer therapy till progression of death

Measure: Toxicities related to anti-cancer therapy

Time: 8 weeks

147 A Multicenter, Phase 1/1b, Open-Label, Dose-Escalation Study of ABBV-399, an Antibody Drug Conjugate, in Subjects With Advanced Solid Tumors

This is a Phase 1/1b open-label study evaluating the safety, pharmacokinetics (PK), and preliminary efficacy of ABBV-399 in subjects with advanced solid tumors. Enrollment is closed for Arms A and D.

NCT02099058 Advanced Solid Tumors Cancer Drug: Osimertinib Drug: Nivolumab Drug: ABBV-399 Drug: ABBV-399 Drug: Erlotinib

- Subject must have metastatic NSCLC with documented Epidermal Growth Factor Receptor (EGFR) mutation(s) known to be sensitive to osimertinib, including del19, L858R, G719X or L861Q. --- L858R ---

Primary Outcomes

Description: AUC (0-t) = Area under the serum concentration versus time curve from time zero (pre-dose) to the time of the last measurable concentration.

Measure: Area under the curve (AUC) from time zero to the last measurable concentration AUC (0-t)

Time: Up to 24 months

Description: Maximum observed plasma concentration (Cmax)

Measure: Maximum observed plasma concentration (Cmax)

Time: Up to 24 months

Description: Time to Cmax (Tmax)

Measure: Time to Cmax (Tmax)

Time: Up to 24 months

Measure: Terminal elimination half life

Time: Up to 24 months

Secondary Outcomes

Description: ORR is defined as the proportion of the subjects who have a complete response (CR) or partial response (PR).

Measure: Objective response rate (ORR)

Time: Up to 24 months

Description: PFS is defined as the time from the first dose date of ABBV-399 to either disease progression or death, whichever occurs first.

Measure: Progression free survival (PFS)

Time: Up to 24 months

Description: DOR is defined as the time from the subject's initial CR or PR to the time of disease progression.

Measure: Duration of overall response (DOR)

Time: Up to 24 months

148 A Randomized, Double-blind Phase 2 Study of Itacitinib in Combination With Erlotinib Versus Erlotinib Alone in Subjects With Stage IIIB/ IV or Recurrent Non-Small Cell Lung Cancer (NSCLC) Whose Tumors Have Epidermal Growth Factor Receptor (EGFR) Activating Mutations

The purpose of this study is to determine if Itacitinib in combination with erlotinib is safe and effective in the treatment of nonsquamous non-small cell lung cancer (NSCLC) that is Stage IIIB/Stage IV or recurrent whose tumors have EGFR activating mutations.

NCT02355431 Solid Tumors and Hematologic Malignancy NSCLC (Non-small Cell Lung Carcinoma) Drug: Itacitinib Drug: erlotinib Drug: placebo
MeSH: Carcinoma, Non-Small-Cell Lung Lung Neoplasms
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of nonsquamous NSCLC that is Stage IIIB, Stage IV, or recurrent (including Stage II). - Documented evidence of an activating mutation in EGFR in tumor samples (exon 19 deletions or point mutation L858R in exon 21 or point mutations at codon 719). --- L858R ---

Primary Outcomes

Description: Subjects will take erlotinib daily and begin dosing with itacitinib once daily (QD) on Cycle 1, Day 1. The safety and tolerability of the regimen will be assessed during the first 21 days of therapy

Measure: Part 1: Determination of the dose of itacitinib that is safe and tolerable in combination with erlotinib as measured by the number of dose-limiting toxicities (DLTs) observed in the evaluation cohort.

Time: Baseline through Day 21

Measure: Part 2: Overall Survival (OS)

Time: Randomization until death. Approximately 31 months.

Description: PFS is defined as the time from randomization until the earliest date of disease progression determined by investigator assessment of objective radiographic disease assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause if sooner.

Measure: Part 2: Progression-free survival (PFS)

Time: Randomization to disease progression, or death due to any cause if sooner. Approximately 23 months.

Secondary Outcomes

Description: Objective response determined by radiographic disease assessments per RECIST (v1.1), by investigator assessment

Measure: Part 2: Objective Response

Time: Baseline through end of study. Approximately 31 months.

Description: Duration of response determined by radiographic disease assessments per RECIST (v1.1), by investigator assessment Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Measure: Part 2: Duration of Response

Time: Baseline through end of study. Approximately 31 months.

Measure: Part 2: Safety and tolerability of the treatment regimens assessed by a summary of adverse events and clinical laboratory assessments.

Time: Baseline through approximately 30 days post treatment discontinuation. Assessed after approximately 31 months.

149 A Multi-center, Randomized, Double-blind, Placebo-controlled, Phase 3 Study of Single-agent Tarceva® (Erlotinib) Following Complete Tumor Resection With or Without Adjuvant Chemotherapy in Patients With Stage IB-IIIA Non-small Cell Lung Carcinoma Who Have EGFR-positive Tumors

This is a study to evaluate the effectiveness of erlotinib compared with a placebo sugar pill following complete surgical removal of the tumor with or without chemotherapy after surgery in Stage IB-IIIA NSCLC patients.

NCT00373425 Non-small Cell Lung Cancer Drug: Erlotinib Drug: Placebo
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.. Disease-free Survival in Participants With EGFR Mutation - Positive Tumors. --- L858R ---

Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.. Overall Survival in Participants With EGFR Mutation - Positive Tumors. --- L858R ---

Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.. Number of Participants With Adverse Events (AEs). --- L858R ---

Primary Outcomes

Description: DFS is the time from the date of randomization until the first day non-small cell lung cancer (NSCLC) relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date.

Measure: Disease Free Survival (DFS)

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months).

Description: DFS is the time from the date of randomization until the first day that non-small cell lung cancer (NSCLC) relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date.

Measure: Disease Free Survival (DFS)

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cutoff date of 11 June 2014 (maximum time on follow-up was 78 months).

Secondary Outcomes

Description: Overall survival was defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive.

Measure: Overall Survival (OS)

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months).

Description: Overall survival was defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive.

Measure: Overall Survival (OS)

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 11 June 2014 (maximum time on follow-up was 78 months).

Description: Disease-free survival (DFS) is the time from the date of randomization until the first day NSCLC relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.

Measure: Disease-free Survival in Participants With EGFR Mutation - Positive Tumors

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months).

Description: Disease-free survival (DFS) is the time from the date of randomization until the first day NSCLC relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.

Measure: Disease-free Survival in Participants With EGFR Mutation - Positive Tumors

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 11 June 2014 (maximum time on follow-up was 78 months).

Description: Overall survival is defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.

Measure: Overall Survival in Participants With EGFR Mutation - Positive Tumors

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months)

Description: Overall survival is defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.

Measure: Overall Survival in Participants With EGFR Mutation - Positive Tumors

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 11 June 2014 (maximum time on follow-up was 78 months)

Description: An AE was defined as any untoward medical occurrence in a study participant and did not necessarily have a causal relationship with study treatment. An AE was considered serious if it resulted in death, a life-threatening situation, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect in the offspring of a participant, other important medical events, or is on the Astellas Always Serious List. A drug-related AE was any AE with at least a possible relationship to study treatment as assessed by the investigator. Severity was graded by the investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v3.0, where Grade 1=Mild AE; Grade=2 Moderate AE; Grade 3=Severe AE; Grade 4=Life-threatening or disabling; Grade 5=Death related to AE. AEs leading to death include deaths that occurred more than 30 days after the last dose of study drug.

Measure: Number of Participants With Adverse Events (AEs)

Time: From the date of first dose of study drug until 30 days after the last dose. The median time on treatment was 11.9 months for erlotinib and 21.9 months for placebo. Data are based off the 11 June 2014 data cut-off date.

150 A Single-arm Phase II Study to Determine the Efficacy of Preemptive Local Ablative Therapy to Residual Metabolic Active Oligo-metastases in Those EGFR Mutation Positive Non-small Cell Lung Cancer Patients Who Have Achieved a Good Partial Response With First-line EGFR TKI (ATOM)

To determine the efficacy of preemptive local ablative therapy in NSCLC patients with activating EGFR mutation who have oligometastatic residual metabolic-active disease after first-line EGFR TKI, as measured by PFS rate at 1 year from the trial enrollment.

NCT01941654 NSCLC Activating EGFR Mutation Radiation: preemptive local ablative therapy Drug: Oral TKI

Inclusion Criteria: 1. Pathologically confirmed UICC 7th edition Stage IIIB (not amenable for curative intent local radiotherapy)/IV (metastatic or recurrent) non-small cell carcinoma of lung 2. Documented activating EGFR mutation (exon 19 deletion or exon 21 L858R only) in tumor tissues 3. Treated with first-line EGFR TKI for 3 months and achieved good radiological partial response that was documented with a CT scan 4. --- L858R ---

Non-compliance to the study procedure Inclusion Criteria: 1. Pathologically confirmed UICC 7th edition Stage IIIB (not amenable for curative intent local radiotherapy)/IV (metastatic or recurrent) non-small cell carcinoma of lung 2. Documented activating EGFR mutation (exon 19 deletion or exon 21 L858R only) in tumor tissues 3. Treated with first-line EGFR TKI for 3 months and achieved good radiological partial response that was documented with a CT scan 4. --- L858R ---

Primary Outcomes

Measure: PFS rate at 1 year

Time: 2 years

Secondary Outcomes

Measure: Overall survival

Time: 2 years

Measure: Progression-free survival

Time: 2 years

Measure: radiologic change on PET-CT scan 3 months after SABR

Time: 3 months

Measure: Number of Participants with Adverse Events as a Measure of safety

Time: 2 years

151 Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AZD9291 in Patients With Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent

This study will treat patients with advanced NSCLC who have already received at least one course of specific anti-cancer treatment but the tumour has started to re-grow following that treatment. This is the first time this drug has ever been tested in patients, and so it will help to understand what type of side effects may occur with the drug treatment, it will measure the levels of drug in the body, it will also measure the anti-cancer activity. By using these pieces of information together the best dose of this drug to use in further clinical trials will be selected.

NCT01802632 Advanced Non Small Cell Lung Cancer Advanced (Inoperable) Non Small Cell Lung Cancer Drug: AZD9291
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

- Patients (with the exception of 1st line expansion cohort) must fulfil one of the following: - Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR - Must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria (Jackman et al 2010) followed by systemic objective progression (RECIST or WHO) while on continuous treatment with EGFR TKI. - Previous treatment with a single-agent EGFR TKI (e.g. --- L858R ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (by investigator assessment) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR) for Dose Expansion Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.

Measure: Best Objective Response (BOR) for Dose Escalation Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 25 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (by independent central review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR) for Extension Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 months (at the time of analysis)

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR was defined as the time from the date of first documented response (CR or PR that was subsequently confirmed) until the date of documented progression (PD) or death in the absence of disease progression (by investigator assessment).

Measure: Duration of Response (DoR) for Dose Expansion Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of first dose until the date of PD (by independent central review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from AZD9291 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Measure: Progression-Free Survival (PFS) for Dose Expansion Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.

Measure: Best Objective Response (BOR) for 80mg AZD9291 Extension Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 months (at the time of analysis)

152 Randomized Phase II Trial of Local Consolidation Therapy (LCT) After Osimertinib for Patients With EGFR Mutant Metastatic Non-Small Cell Lung Cancer (NSCLC)

This phase II trial studies how well osimertinib, surgery, and radiation therapy work in treating patients with stage IIIB or IV non-small cell lung cancer with EGFR mutations. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving osimertinib, surgery, and radiation therapy may work better at treating non-small cell lung cancer with EGFR mutations.

NCT03410043 EGFR Exon 19 Deletion Mutation EGFR NP_005219.2:p.L858R EGFR NP_005219.2:p.T790M Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IIIB Lung Cancer AJCC v8 Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8 Drug: Osimertinib Radiation: Radiation Therapy Procedure: Therapeutic Conventional Surgery
MeSH: Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

The association between the types and severity of toxicity and the treatment groups will be evaluated.. Inclusion Criteria: - Histologically or cytologically confirmed non-small cell lung cancer - Stage IIIB/IV or recurrent non-small cell lung cancer which is not amenable to curative intent therapy - Patients must have one of the following: - NSCLC which harbors EGFR exon 19 deletion or L858R mutation. --- L858R ---

In addition, these lesions will be counted towards the total number of metastases, and will also be counted as target lesions Inclusion Criteria: - Histologically or cytologically confirmed non-small cell lung cancer - Stage IIIB/IV or recurrent non-small cell lung cancer which is not amenable to curative intent therapy - Patients must have one of the following: - NSCLC which harbors EGFR exon 19 deletion or L858R mutation. --- L858R ---

Primary Outcomes

Description: Will be estimated using Kaplan-Meier method. The stratified log-rank test will be performed to test the difference in time-to-event distributions between treatment groups. Stratified Cox proportional hazards model will be utilized to include multiple covariates in the time-to-event analysis and to estimate hazard ratios.