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.
Name: Bevacizumab
Description: Given IVType: BiologicalArm B (erlotinib hydrochloride, bevacizumab)
Name: Erlotinib Hydrochloride
Description: Given POType: DrugArm A (erlotinib hydrochloride) Arm B (erlotinib hydrochloride, bevacizumab)
Name: Laboratory Biomarker Analysis
Description: Correlative studiesType: OtherArm A (erlotinib hydrochloride) Arm B (erlotinib hydrochloride, bevacizumab)
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 yearsDescription: 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 yearsDescription: 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 yearsDescription: 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 yearsDescription: 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 discontinuationDescription: 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 discontinuationDescription: 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 yearsDescription: 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 yearsDescription: 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: BaselineDescription: 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 yearsDescription: 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: BaselineAllocation: Randomized
Parallel Assignment
There are 2 SNPs
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 ---
Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.. Prevalence of EGFR T790M resistance mutations from pretreatment tumor biopsies using more sensitive mutation detection methods. --- T790M ---
The robustness of treatment effect in different subgroups will be examined in a Forest plot.. EGFR T790M mutations. --- T790M ---
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. --- T790M ---
To estimate the prevalence of EGFR T790M resistance mutations from pretreatment tumor biopsies using more sensitive mutation detection methods. --- T790M ---
To investigate progression free survival of EGFR mutant NSCLC patients with and without concurrent EGFR T790M detected from pre-treatment tumor specimen using allele specific quantitative polymerase chain reaction (PCR). --- T790M ---