RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or deliver cancer-killing substances to them. Combining chemotherapy with a monoclonal antibody may kill more tumor cells.

PURPOSE: This randomized phase II/III trial is to see if combination chemotherapy works better with or without bevacizumab in treating patients who have advanced, metastatic, or recurrent non-small cell lung cancer.

OBJECTIVES:

• Compare the toxicity of paclitaxel and carboplatin with or without bevacizumab in patients with advanced, metastatic, or recurrent non-squamous cell non-small cell lung cancer.
• Compare the survival of patients treated with these regimens.
• Compare the response rates and time to progression in patients treated with these regimens.

OUTLINE: This is a randomized study. Patients are stratified according to measurable disease (yes vs no), prior radiotherapy (yes vs no), weight loss (less than 5% vs 5% or more), and disease stage (IIIB vs IV vs recurrent). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive paclitaxel IV over 3 hours followed by carboplatin IV over 15-30 minutes on day 1.
• Arm II: Patients receive paclitaxel and carboplatin as in arm I followed by bevacizumab IV over 30-90 minutes on day 1.

Treatment in both arms repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of 6 courses, patients in arm II with stable or responding disease continue to receive bevacizumab only. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 2 years and then every 6 months for 3 years.

PROJECTED ACCRUAL: A total of 842 patients will be accrued for this study.

• Biological: bevacizumab
• Drug: carboplatin
• Drug: paclitaxel

• Dowlati A, Gray R, Sandler AB, Schiller JH, Johnson DH. Cell Adhesion Molecules, Vascular Endothelial Growth Factor, and Basic Fibroblast Growth Factor in Patients with Non-Small Cell Lung Cancer Treated with Chemotherapy with or without Bevacizumab--an Eastern Cooperative Oncology Group Study. Clin Cancer Res. 2008 Mar 1;14(5):1407-12.
• Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; Eastern Cooperative Oncology Group. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5.
• Somer RA, Sherman E, Langer CJ. Restrictive eligibility limits access to newer therapies in non-small-cell lung cancer: the implications of Eastern Cooperative Oncology Group 4599. Clin Lung Cancer. 2008 Mar;9(2):102-5.
• Cohen MH, Gootenberg J, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist. 2007 Jun;12(6):713-8.
• Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50.
• Tyagi P. Bevacizumab, when added to paclitaxel/carboplatin, prolongs survival in previously untreated patients with advanced non-small-cell lung cancer: preliminary results from the ECOG 4599 trial. Clin Lung Cancer. 2005 Mar;6(5):276-8. No abstract available.
• Dornbusch D, Allegra C, Willey J, Andrews M, Leff R, Epstein J, Jones J, Lokey L, Green MR. How do U.S. medical oncologists learn and apply new clinical trials information from press releases in nonmedical media? A case study based on ECOG 4599. Oncologist. 2006 Jan;11(1):31-8.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed non-small cell lung cancer (NSCLC)

  • Stage IIIB with malignant pleural effusion, stage IV, or recurrent
  • Measurable or nonmeasurable disease
• No squamous cell NSCLC
• No known CNS metastases by head CT scan or MRI within the past 4 weeks

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-1

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• No prior thrombotic or hemorrhagic disorders

Hepatic:

• Bilirubin no greater than 1.5 mg/dL
• Transaminases no greater than 5 times upper limit of normal (ULN)
• PTT normal
• INR no greater than 1.5

Renal:

• Creatinine no greater than 1.5 times ULN
• Urine protein less than 1+ (i.e., trace or 0 by dipstick or urinalysis) OR
• 24-hour urine protein less than 500 mg

Cardiovascular:

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• Concurrent hypertension allowed provided well-controlled on a stable regimen of anti-hypertensive therapy

Pulmonary:

• No history of gross hemoptysis (½ teaspoon of bright red blood or more)

Other:

• No ongoing or active infection
• No serious non-healing wound ulcer
• No bone fracture
• No psychiatric illness or social situation that would preclude study compliance
• No other concurrent comorbidities that would preclude study participation
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• At least 3 weeks since prior immunotherapy and recovered

Chemotherapy:

• No prior systemic chemotherapy

Endocrine therapy:

• At least 3 weeks since prior hormonal therapy and recovered

Radiotherapy:

• At least 3 weeks since prior radiotherapy and recovered

Surgery:

• At least 3 weeks since prior major surgery

Other:

• No concurrent therapeutic anticoagulation
• No concurrent chronic daily aspirin (greater than 325 mg/day)
• No concurrent non-steroidal anti-inflammatory agents known to inhibit platelet function (arm II only)
• No concurrent dipyridamole, ticlopidine, clopidogrel, and/or cilostazol

• National Cancer Institute (NCI)
• Cancer and Leukemia Group B