Testing the Addition of the Pill Chemotherapy, Cabozantinib, to the Standard Immune Therapy Nivolumab Compared to Standard Chemotherapy for Non-small Cell Lung Cancer

PRIMARY OBJECTIVE: I. To determine whether cabozantinib alone, or the combination of nivolumab and cabozantinib, as compared to standard chemotherapy alone, extends progression-free survival (PFS) for this patient population with non squamous NSCLC. SECONDARY OBJECTIVES: I. To determine the overall survival for each arm of the trial. II. To evaluate the best overall radiographic response rate for each arm of the trial. III. To evaluate and describe the toxicity profile of monotherapy with cabozantinib, and the combination of nivolumab and cabozantinib in this patient population with non-squamous NSCLC. EXPLORATORY IMAGING OBJECTIVES: I. To describe time point tumor response assessment, overall best response, progression-free survival and overall survival using the conventional Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and the exploratory revised CHOI criteria with all measurements performed by the central review. II. To compare the progression-free survival using the RECIST1.1 imaging response assessment measurements by site study personnel to those performed by central review. EXPLORATORY CORRELATIVE OBJECTIVE: I. To perform correlative biomarker research on tissue and blood biospecimens collected within this trial. OUTLINE: STEP 1: Patients are randomized to 1 of 3 arms. ARM A: Patients receive cabozantinib S-malate orally (PO) once daily (QD). Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. ARM B: Patients receive cabozantinib S-malate PO QD and nivolumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. ARM C: Patients receive ramucirumab IV over 30-60 minutes and docetaxel IV over 1 hour on day 1, or docetaxel IV over 1 hour on days 1 and 8, or gemcitabine hydrochloride IV on days 1 and 8, or paclitaxel IV over 3 hours on day 1, or nab-paclitaxel IV over 30 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity and at the discretion of the treating physician. STEP 2: Patients in Arm C experiencing disease progression are assigned to Arm Z. ARM Z: Patients receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients in all arms undergo echocardiogram (ECHO) as clinically indicated, computed tomography (CT) throughout the trial, and collection of blood on study. After the completion of study treatment, patients are followed up every 3 months for up to 3 years.