PRIMARY OBJECTIVES:~I. To demonstrate whether combination therapy of nivolumab and cabozantinib s-malate (cabozantinib), or of nivolumab and cabozantinib, and ipilimumab as compared to nivolumab alone, extends progression-free survival (PFS) for this patient population with non-squamous non-small cell lung cancer (NSCLC).~SECONDARY OBJECTIVES:~I. To estimate the overall survival for each arm of the trial. II. To estimate the best overall response rate for each arm of the trial. III. To estimate the progression free survival of the targeted therapy arm of the trial.~IV. To describe the toxicity profile of monotherapy with nivolumab, and the combination of nivolumab and cabozantinib, and the combination of nivolumab and cabozantinib and ipilimumab, in this patient population with non-squamous NSCLC.~CORRELATIVE OBJECTIVES:~I. To adjust progression free survival for each arm based on PD-L1 tumor status.~IMAGING OBJECTIVES:~I. To describe time point tumor response assessment, overall best response and progression-free survival using the conventional Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and the exploratory uni-dimensional immune response criteria (iRRC) and the imaging (i)RECIST criteria with all measurements performed by the central review.~II. To compare RECIST 1.1 imaging response assessment measurements (time point response assessment and overall best response) assess by site study personnel to those performed by central review.~EXPLORATORY TOBACCO USE OBJECTIVES:~I. To determine the effects of tobacco, operationalized as combustible tobacco (1a), other forms of tobacco (1b), and environmental tobacco exposure (ETS) (1c) on provider-reported cancer-treatment toxicity (adverse events (both clinical and hematologic) and dose modifications).~II. To determine the effects of tobacco on patient-reported physical symptoms and psychological symptoms.~III. To examine quitting behaviors and behavioral counseling/support and cessation medication utilization.~IV. To explore the effect of tobacco use and exposure on treatment duration, relative dose intensity, and therapeutic benefit.~OUTLINE: Patients are randomized to 1 of 3 arms. Patients with ROS1 gene rearrangement, MET exon 14 splice mutations, MET high amplification, or RET gene rearrangement are assigned to Arm T.~ARM A: Patients receive nivolumab at 480 mg intravenously (IV) over 60 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.~ARM B: Patients receive nivolumab at 480 mg IV over 60 minutes on day 1 and cabozantinib s-malate at 40 mg orally (PO) daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.~ARM C: Patients receive nivolumab at 480 mg IV over 60 minutes on day 1, cabozantinib s-malate at 40 mg PO daily on days 1-28, and ipilimumab at 1 mg/kg IV over 90 minutes every 8 weeks. Cycles for nivolumab and cabozantinib s-malate repeat every 28 days in the absence of disease progression or unacceptable toxicity.~ARM T: Patients with ROS1 gene rearrangement, MET exon 14 splice mutations, MET high amplification, or RET gene rearrangement receive nivolumab at 480 mg IV over 60 minutes on day 1 and cabozantinib s-malate at 40 mg PO daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.~After completion of study treatment, patients are followed up every 3 months for up to 5 years.
This partially randomized phase II trial studies how well nivolumab, cabozantinib s-malate, and ipilimumab work in treating patients with stage IV non-small cell lung cancer that has come back. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving nivolumab, cabozantinib s-malate, and ipilimumab may work better than cabozantinib s-malate alone in treating patients with stage IV non-small cell lung cancer.