BATTLE-FL: Front-Line Biomarker-Integrated Treatment Study in Non Small Cell Lung Cancer

Inclusion Criteria:

1. The patient has a diagnosis of pathologically confirmed nonsquamous (nonpredominant squamous) NSCLC by tumor biopsy and/or fine-needle aspiration. Mixed tumors will be categorized by the predominant cell type; if small cell elements are present, the patient is ineligible.
2. The patient has a diagnosis of either stage IIIB or stage IV NSCLC or has recurrent NSCLC and is not a candidate for curative treatment. Patients may not have had chemotherapy for front-line NSCLC treatment.
3. The patient has measurable NSCLC.
4. The patient's ECOG performance status is </=2 at study entry.
5. The patient has biopsy accessible tumor.
6. The patient has adequate hematologic function as defined by an absolute neutrophil count (ANC) >/= 1,500/mm^3, platelet count >/= 100,000/mm^3, WBC >/= 3,000/ mm^3, and hemoglobin >/= 9 g/dL.
7. The patient has adequate hepatic function as defined by a total bilirubin level </= 1.5 X the upper limit of normal (Serum bilirubin >/= 1.5x Upper Limit of Normal in the setting of known Gilbert's disease is allowed), and alkaline phosphatase, AST and ALT </= 2.5 X the upper limit of normal or </= 5.0 x ULN if liver metastases are present.
8. The patient has adequate renal function as defined as CrCl of at least 45ml/min.
9. If patient has brain metastasis, they must have been stable (treated and/or asymptomatic) and off steroids for at least 2 weeks.
10. The patient is >/= 18 years of age.
11. The patient has signed informed consent.
12. Women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation and for six (6) months after discontinuation of the study drugs. Childbearing potential will be defined as women who have had menses within the past 12 months, who have not had tubal ligation, hysterectomy or bilateral oophorectomy. Should a woman become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately. The patient, if a man, agrees to use effective contraception or abstinence for the duration of study participation and for six (6) months after discontinuation of the study drugs.
13. The ability to interrupt the use of NSAIDS two days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of Pemetrexed.
14. The patient has EGFR wild type.

Exclusion Criteria:

1. The patient has received prior definitive therapy (chemotherapy, surgery, or radiotherapy) within 3 months of initiating study drug or within, 2 weeks of localized palliative radiotherapy. Patients treated with initial biologic therapy that progress are eligible (no drug within 4 weeks). Patients must have recovered from the acute toxic effects prior to Day 1 of Cycle 1 to grade </= 1 or baseline.
2. Patients may not have had prior biologic therapy with antibodies targeting VEGF, EGFR or IGFR.
3. The patient has undergone prior thoracic or abdominal surgery within 30 days of study entry, excluding prior diagnostic biopsy.
4. The patient has a history of uncontrolled angina, arrhythmias, or congestive heart failure.
5. The patient has inadequately controlled hypertension (defined as systolic blood pressure > 140 and/or diastolic > 90 mm Hg on antihypertensive medications).
6. The patient has a history of stroke or transient ischemic attack within 6 months prior to Day 1 of Cycle 1.
7. The patient is unable or unwilling to take folic acid, vitamin B12 supplementation, or dexamethasone according to protocol.
8. The patient has neuropathy >/= grade 2.
9. The patient has a history of gastrointestinal fistula, perforation, or abscess, inflammatory bowel disease, or diverticulitis.
10. The patient is currently receiving ongoing treatment with full-dose warfarin or equivalent (that is, unfractionated and/or low molecular weight heparin).
11. The patient is pregnant (confirmed by serum b-HCG if applicable) or is breastfeeding.
12. Presence of significant third space fluid which cannot be controlled by drainage.
13. Patients are excluded from the Bevacizumab arm if they have a history of hemoptysis (>/= ½ teaspoon of bright red blood per episode) within 3 months prior to randomization. Patients are excluded from the IMC-A12 containing arm if they have poorly controlled diabetes: HBA1C>8% or if the patient has abnormally elevated fasting serum glucose (defined >110% ULN). Patients are excluded if they have known hypersensitivity to any of the drugs.
14. The patient's tumor harbors the EML4-ALK fusion gene.