RATIONALE: Drugs used in chemotherapy, such as paclitaxel and carboplatin, 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 bevacizumab, 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. Bevacizumab may also stop the growth of non-small cell lung cancer by blocking blood flow to the tumor. Pemetrexed disodium may stop the growth of tumor cells by blocking some enzymes needed for cell growth. It is not yet known whether giving bevacizumab or pemetrexed disodium alone or in combination is more effective in treating non-squamous non-small cell lung cancer.

PURPOSE: This randomized phase III trial is studying bevacizumab and pemetrexed disodium alone or in combination after induction therapy to see how well they work in treating patients with advanced non-squamous non-small cell lung cancer.

OBJECTIVES:

Primary

• To compare the overall survival (OS) of patients with advanced non-squamous non-small cell lung cancer (NSCLC) treated with maintenance therapy with bevacizumab vs pemetrexed disodium vs bevacizumab and pemetrexed disodium following induction therapy.

Secondary

• To determine the response rate in patients treated with these regimens.
• To evaluate the progression-free survival (PFS) of patients treated with these regimens.
• To define the toxicity of these regimens in these patients.
• To determine the frequency of polymorphisms in VEGF 3578 AA, 1154 AA, ABCB1 G2677TT/AA, and ERCC-118 TT in patients treated with induction therapy comprising paclitaxel, carboplatin and bevacizumab and determine the association between genotypes and response rate.
• To determine the association between bevacizumab and pemetrexed disodium population pharmacokinetics and patient-specific covariate with bevacizumab or pemetrexed disodium toxicity.
• To determine the frequency of TSER*3 polymorphisms in NSCLC and the association between TSER polymorphisms and benefit from pemetrexed disodium.
• To evaluate TS and ERCC1 expression by RT-PCR and MTAP mutations in existing tumor specimens as a predictor of pemetrexed disodium response.
• To evaluate polymorphisms within CYPs 2C8, 3A4, 3A5 and/or the UGT1A1 collectively or monogenically as markers for variation in efficacious and/or toxic response of individuals to treatment with taxanes.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to gender (male vs female), stage of disease (IIIB-T4Nx [with nodule in ipsilateral lung lobe and not candidate for combined chemotherapy and radiation] and IV M1a vs IV M1b vs recurrent), best response to first-time therapy (complete response/partial response vs stable disease), and smoking status (never vs smoker).

• Induction therapy (Arm I): Patients receive paclitaxel IV over 3 hours, carboplatin IV over 15-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

• Maintenance Therapy: Patients achieving complete response, partial response or stable disease following induction therapy are randomized to 1 of 3 treatment arms. Treatment begins within 6 weeks of the last day of induction chemotherapy administration.

  • Arm A: Patients receive bevacizumab IV over 30-90 minutes on day 1.
  • Arm B: Patients receive pemetrexed disodium IV over 10 minutes on day 1.
  • Arm C: Patients receive bevacizumab as in arm A and pemetrexed as in arm B. In all arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Some patients undergo blood sample collection at baseline and periodically during study for correlative studies.

After completion of study therapy, patients are followed up every 3 months for 2 years and then every 6 months for 2-5 years.

Inclusion Criteria (Step 1 Induction Therapy):

• Cytologically or histologically confirmed non-small cell lung cancer (NSCLC)
• Predominant non-squamous histology (NSCLC not otherwise specified allowed). Mixed tumors are categorized by the predominant cell type.
• Stage IV disease including M1a or M1b stages or recurrent disease
• Stage IIIB (T4NX) disease with ipsilateral lung lobe allowed provided patients are not candidates for combined chemotherapy or radiotherapy
• At least 12 months since prior adjuvant chemotherapy
• At least 2 weeks since prior radiotherapy
• Prior carboplatin allowed provided it was given as part of adjuvant chemotherapy
• Patients with brain metastasis must have received local therapy to the brain and have no evidence of progression in the brain for at least 2 weeks from the time of completion of local therapy, prior to registration
• ECOG (Eastern Cooperative Oncology Group) performance status 0-1
• Leukocytes ≥ 3,000/mm^3
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Total bilirubin ≤ institutional upper limit of normal (ULN)
• AST and ALT ≤ 3 times ULN
• Creatinine ≤ institutional ULN OR creatinine clearance ≥ 60 mL/min
• Urine protein:urine dipstick ≤ 0-1+ (if > 1+, urine protein creatinine ratio must be < 1)
• Measurable or non-measurable disease as defined by RECIST (Response Evaluation Criteria in Solid Tumours) criteria
• Patients with hypertension must be adequately controlled (BP < 150/100 mm Hg) with appropriate anti-hypertensive therapy or diet
• Concurrent therapeutic anti-coagulation allowed
• Fertile patients must agree to abstain from sexual intercourse or to use adequate contraceptive methods during and for at least 6 months after completion of study therapy

Exclusion Criteria (Step 1 Induction Therapy):

• Prior malignancy within the past 3 years except superficial melanoma, basal cell carcinoma, or carcinoma in situ
• Prior systemic chemotherapy for advanced stage lung cancer
• Prior use of paclitaxel, pemetrexed disodium, or bevacizumab
• Major hemoptysis within the past 4 weeks
• Uncontrolled intercurrent illness including, but not limited to, active infection, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, psychiatric illness/social situations that would limit compliance with study requirements
• History of arterial thrombotic events or major bleeding within the past 12 months
• Major surgery such as thoracotomy, laparotomy, craniotomy, or significant traumatic injury within 6 weeks prior to registration. Biopsy procedures and chest tube insertion are not considered major surgery for the purpose of this protocol.
• Core biopsy within 7 days of registration
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within the past 6 months
• Clinically significant cardiovascular disease
• Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
• History of serious non-healing wounds, ulcers, or bone fractures
• Cavitary lesions in the lungs
• Pregnant or nursing
• Concurrent anti-retroviral therapy in patients with HIV infection

Inclusion Criteria (Step 2 Maintenance Therapy):

• Patient must have an overall stable or better response after 4 courses of induction therapy
• ECOG (Eastern Cooperative Oncology Group) performance status 0-1
• Patients must be registered to Step 2 within 6 weeks of the last day of chemotherapy administration on Step 1
• Acceptable bone marrow, renal and hepatic function within 2 weeks of registration

Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.