The purpose of this study is to compare the regimens of pemetrexed, carboplatin with pemetrexed maintenance and paclitaxel, carboplatin, bevacizumab with bevacizumab maintenance in participants with Stage IV nonsquamous non-small cell lung cancer.

This is a multicenter, randomized, open-label, Phase III trial. Eligible participants will be randomized in a 1:1 ratio to receive pemetrexed and carboplatin followed by pemetrexed or paclitaxel, carboplatin, and bevacizumab followed by bevacizumab as their study treatment. Participants randomized to Pemetrexed + Carboplatin + Pemetrexed will receive folic acid, vitamin B12, and dexamethasone as stated in the pemetrexed label. Before administration of paclitaxel, participants randomized to Paclitaxel + Carboplatin + Bevacizumab will receive premedication (dexamethasone, diphenhydramine, and cimetidine or ranitidine) as recommended in the paclitaxel label.

Inclusion Criteria:

• a histologic or cytologic diagnosis of advanced non-small cell lung cancer (NSCLC) [Stage IV from the American Joint Committee on Cancer Staging Criteria (AJCC) staging system, version 7.0, including both M1a and M1b], other than predominantly squamous cell histology, that is not amenable to curative therapy. Participants may not have received any prior systemic chemotherapy, immunotherapy, targeted therapy, or biological therapy, including adjuvant therapy, for any stage of NSCLC.
• prior radiation therapy is allowed to < 25% of the bone marrow; however, prior radiation to the whole pelvis not allowed.
• good performance status.
• adequate organ function.
• estimated life expectancy of at least 12 weeks.

Exclusion Criteria:

• known central nervous system (CNS) disease, other than treated brain metastasis.
• major surgical procedure, open biopsy, open pleurodesis, or significant traumatic injury within 28 days prior to study or have an anticipated need for major surgery during the study.
• core biopsy or other minor surgical procedure, excluding placement of vascular access device, closed pleurodesis, thoracentesis, and mediastinoscopy, within 7 days prior to study.
• history of gastrointestinal fistula, perforation, or abscess, inflammatory bowel disease, or diverticulitis.
• currently receiving ongoing treatment with full-dose warfarin or equivalent
• significant vascular disease within 6 months prior to Day 1 of Cycle 1.
• evidence of bleeding diathesis or coagulopathy.
• serious concomitant systemic disorder that, in the opinion of the investigator, would compromise the participant's ability to adhere to the protocol.
• serious cardiac condition, such as myocardial infarction, angina, or heart disease.
• inadequately controlled hypertension.
• any prior history of hypertensive crisis or hypertensive encephalopathy.
• serious, nonhealing wound, active ulcer, or untreated bone fracture.
• another active malignancy, other than superficial basal cell and superficial squamous (skin) cell, or carcinoma in situ of the cervix within the last 5 years.
• previously received treatment with paclitaxel, carboplatin, pemetrexed, or bevacizumab (prior intravitreal administration of bevacizumab does not preclude study participation).
• pregnant or breast-feeding.
• history of stroke or transient ischemic attack within 6 months prior to study.
• known sensitivity to any component of paclitaxel, carboplatin, pemetrexed, or bevacizumab.
• history of hemoptysis within 3 months prior to randomization.
• unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs).
• unwilling to take folic acid or vitamin B12 supplementation.
• clinically significant third-space fluid collections, for example, ascites or pleural effusions that cannot be controlled by drainage. Participants with M1a disease with pleural effusions are eligible if the effusions can be adequately controlled.

Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.

Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.

A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.