The purpose of this trial is to evaluate three treatment regimens in patients with stage IIIB/IV Non-Small Cell Lung Cancer (NSCLC) with a performance status of 2 and who were not previously treated.

This randomized, Phase II trial will evaluate three treatment regimens in patients with previously untreated stage IIIB/IV Non-Small Cell Lung Cancer (NSCLC) and a performance status (PS) of 2. Patients will be randomized to either pemetrexed alone, pemetrexed and bevacizumab, or pemetrexed, carboplatin, and bevacizumab in a 1:1:1 fashion. All 3 regimens should be tolerable in poor performance status patients with advanced NSCLC. The 3-drug regimen (pemetrexed/carboplatin/bevacizumab) has been modified by lowering the dose of carboplatin, in order to minimize myelosuppression. This trial will be conducted at multiple study sites.

Inclusion Criteria:

1. Patients must be >=18 years of age.

2. Non-squamous NSCLC (adenocarcinoma or large cell carcinoma). Mixed tumors with small cell anaplastic elements are not eligible. Mixed tumors with squamous histology are acceptable as long as the squamous element is not the dominant histology.

3. Unresectable stage IIIB or stage IV disease. Stage IIIB disease should be ineligible for combined modality therapy (i.e., pleural effusions, pericardial effusions).

4. ECOG performance status of 2.

5. No prior systemic therapy for stage IIIB or stage IV lung cancer.

6. Life expectancy of at least 12 weeks.

7. Patients must have measurable disease per RECIST version 1.1 (see Section 8).

8. Laboratory values as follows:

   • Absolute neutrophil count (ANC) ≥1500/μL
   • Hemoglobin (Hgb) ≥10 g/dL
   • Platelets ≥100,000/μL (≤7 days prior to treatment)
   • AST or ALT and alkaline phosphatase (ALP) must be <2.5 x ULN, or <5 x ULN in patients with liver metastases.
   • Total bilirubin <1.5 x the institutional ULN
   • Calculated creatinine clearance ≥45 mL/min

9. The ability to take folic acid, Vitamin B12, and dexamethasone according to protocol.

10. Women of childbearing potential must have a negative serum or urine pregnancy test performed within 7 days prior to start of treatment. Women of childbearing potential or men with partners of childbearing potential must use effective birth control measures during treatment. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she must agree to inform her treating physician immediately.

11. Patient must be accessible for treatment and follow-up.

12. Patients must be able to understand the investigational nature of this study and give written informed consent prior to study entry.

Exclusion Criteria:

1. Squamous cell histology. Mixed tumors will be categorized by the predominant cell type unless small cell elements are present, in which case the patient will be ineligible; sputum cytology alone is unacceptable.

2. Patients with active brain metastases. Patients who have received radiation or surgery for brain metastases are eligible if there is no evidence of central nervous system (CNS) disease progression, and at least 2 weeks have elapsed since treatment. Ideally, patients should not still require use of seizure medication or steroids.

3. Patients who have had major surgical procedure (not including mediastinoscopy), open biopsy, or significant traumatic injury within 4 weeks of beginning treatment; or, the anticipation of the need for major surgical procedure during the course of the study.

4. Women who are pregnant or lactating.

5. Minor surgical procedures (with the exception of the placement of portacath or other central venous access) must be completed at least 7 days prior to beginning protocol treatment.

6. History of hypersensitivity to active or inactive excipients of any component of treatment (pemetrexed, bevacizumab, and/or carboplatin).

7. Pulmonary carcinoid tumors.

8. Patients with proteinuria at screening as demonstrated by either:

   • urine protein creatinine (UPC) ratio ≥1.0 at screening OR
   • urine dipstick for proteinuria ≥2+ (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/24 hours to be eligible) (see Appendix B)

9. Patients with a serious non healing wound, active ulcer, or untreated bone fracture.

10. Patients with evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).

11. Patients with history of hematemesis or hemoptysis (defined as having bright red blood of ½ teaspoon or more per episode) within 1 month prior to study enrollment.

12. History of myocardial infarction or unstable angina within 6 months of beginning treatment.

13. Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and /or diastolic blood pressure >100 mmHg while on antihypertensive medications).

14. New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF) (see Appendix C).

15. Serious cardiac arrhythmia requiring medication.

16. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair, or recent peripheral arterial thrombosis) within 6 months prior to Day 1 of treatment.

17. History of stroke or transient ischemic attack ≤ 6 months prior to beginning treatment.

18. Any prior history of hypertensive crisis or hypertensive encephalopathy.

19. History of abdominal fistula or gastrointestinal perforation ≤ 6 months prior to Day 1 of beginning treatment.

20. Concurrent severe, intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.

21. Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study.

22. Use of any non-approved or investigational agent ≤ 30 days of administration of the first dose of study drug. Patients may not receive any other investigational or anti-cancer treatments while participating in this study.

23. Past or current history of neoplasm other than the entry diagnosis with the exception of treated non-melanoma skin cancer or carcinoma in situ of the cervix, or other cancers cured by local therapy alone and a DFS ≥5 years.