Carboplatin, Pemetrexed Disodium, and Bevacizumab for Patients With Stage III or IV Non-Small Cell Lung Cancer Who Are Light/Never Smokers

RATIONALE: Drugs used in chemotherapy, such as carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pemetrexed disodium may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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. Giving carboplatin and pemetrexed disodium together with bevacizumab may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving carboplatin and pemetrexed disodium together with bevacizumab works in treating patients with stage III or stage IV non-small cell lung cancer who are light or never smokers.

OBJECTIVES:

Primary

* To estimate the progression-free survival (PFS) of patients with advanced non-small cell lung cancer who are never or light smokers treated with carboplatin, pemetrexed disodium, and bevacizumab followed by pemetrexed disodium and bevacizumab maintenance therapy.

Secondary

* To estimate the overall survival (OS) of patients treated with this regimen.
* To estimate the toxicity of treatment using the NCI CTCAE version 3.0.
* To conduct an exploratory analysis of molecular markers, e.g., Kirsten rat sarcoma (KRAS) and epidermal growth factor receptor (EGFR) mutations, in patients with a never or light smoking history and to analyze any potential association with response, PFS, and OS.
* To assess response to second-line erlotinib hydrochloride therapy according to RECIST criteria.

OUTLINE: This is a multicenter study.

* First-line therapy: Patients receive pemetrexed disodium IV over 10 minutes, carboplatin IV over 30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve partial or complete response or have stable disease progress to maintenance therapy.
* Maintenance therapy: Patients receive pemetrexed disodium IV over 10 minutes and bevacizumab IV over 30 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Patients who experience disease progression or unacceptable toxicity may receive second-line therapy with erlotinib hydrochloride as part of standard-of-care treatment.

Tissue samples are collected at baseline for laboratory biomarker analysis.

After completion of maintenance therapy, patients are followed every 4 weeks for 2 months.

Eligibility Criteria:
DISEASE CHARACTERISTICS:

* Histologically confirmed primary lung carcinoma

  * Non-squamous histology
  * Advanced disease defined as stage IIIB disease with cytologically documented malignant pleural or pericardial effusion or stage IV disease
* Available pathology block or unstained slides from initial or subsequent diagnosis

  * Must have undergone ≥ 1 core biopsy
  * No patients whose diagnosis was made through a fine-needle aspirate
* No uncontrolled pleural effusions, ascites, or third-space fluid collections
* Meets 1 of the following criteria:

  * Non-smoker, defined as patients who smoked ≤ 100 cigarettes in their lifetime
  * Former light smoker, defined as patients who smoked between \> 100 cigarettes AND ≤ 10 pack-years AND quit ≥ 1 year ago
* No known central nervous system disease, except for treated brain metastases meeting the following criteria:

  * No evidence of progression or hemorrhage after treatment
  * No ongoing requirement for dexamethasone as ascertained by clinical examination and brain imaging (MRI or CT scan) during the screening period
  * Stable doses of anticonvulsants are allowed
  * Treatment for brain metastases may include whole-brain radiotherapy, radiosurgery (gamma knife, LINAC, or equivalent), or a combination as deemed appropriate by the treating physician
  * No patients with central nervous system (CNS) metastases treated by neurosurgical resection
  * No brain biopsy within the past 3 months

PATIENT CHARACTERISTICS:

* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Absolute neutrophil count (ANC) ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Hemoglobin ≥ 9.0 g/dL
* Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
* Aspartate aminotransferase (AST/ALT) ≤ 2.5 times ULN
* Calculated creatinine clearance \> 45 mL/min OR creatinine ≤ 1.5 times ULN
* Prothrombin time ≤ 1.5 times ULN
* Partial thromboplastin time ≤ ULN
* Urine protein:creatinine ratio ≤ 1.0
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* Patients with a history of hypertension are eligible provided it is well controlled (BP \< 150/100 mm Hg) on a stable regimen of antihypertensive therapy

  * No history of hypertensive crisis or hypertensive encephalopathy
* Able and compliant with folic acid and B12 supplementation
* Able to swallow tablets intact or dissolved in water
* No dysphagia or active gastrointestinal (GI) disease or disorder that alters GI motility or absorption
* No lack of integrity of the GI tract (e.g., a significant surgical resection of the stomach or small bowel)
* No abdominal fistula, GI perforation, or intraabdominal abscess within the past 6 months
* None of the following:

  * Ongoing or active infection
  * Symptomatic congestive heart failure (NYHA class II-IV)
  * Cardiac arrhythmia
  * Psychiatric illness, social situations, or any other medical condition that would limit compliance with study requirements
* No myocardial infarction or other evidence of arterial thrombotic disease (angina) within the past 6 months
* No history of cerebral vascular accident or transient ischemic attack within the past 6 months
* No significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within the past 6 months
* No history of bleeding diathesis or coagulopathy
* No ongoing hemoptysis, defined as ≥ ½ teaspoon of bright red blood

  * Patients with procedure-related hemoptysis that has resolved post-procedure are eligible
* No serious nonhealing wound, ulcer, bone fracture, or significant traumatic injury within the past 28 days
* No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies

PRIOR CONCURRENT THERAPY:

* No prior chemotherapy

  * Patient must be chemotherapy naive
  * Prior neoadjuvant or adjuvant chemotherapy allowed provided it was completed ≥ 6 months ago
* No prior anti-vascular endothelial growth factor therapy
* At least 3 weeks since prior major surgery
* At least 1 week since prior radiotherapy
* More than 28 days since prior and no concurrent treatment with an investigational agent
* More than 7 days since prior core biopsy
* Concurrent daily treatment with aspirin or NSAIDs are eligible provided patients are able to interrupt NSAIDs 2 days before (5 days for long-acting NSAIDs), the day of, and for 2 days following the administration of pemetrexed disodium
* No concurrent treatment with dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix), and/or cilostazol (Pletal)