Nivolumab, Cabozantinib S-Malate, and Ipilimumab in Treating Patients With Recurrent Stage IV Non-small Cell Lung Cancer

Inclusion Criteria (Step 0):

• Patients with tumors with the following molecular alterations must submit testing results via Medidata Rave to determine eligibility to Arm T; the study chair, co-chair, biology co-chair, or a delegate must review the molecular testing and agree that the testing meets one of the molecular eligibility criteria below:
• ROS1 gene rearrangement by fluorescence in situ hybridization (FISH) or deoxyribonucleic acid (DNA) analysis (may have progressed on prior crizotinib therapy)
• MET exon 14 splice mutations on DNA analysis (may have progressed on prior crizotinib therapy)
• MET high amplification by FISH or DNA analysis or other MET mutations predicted to be sensitive to MET inhibitor (no prior targeted therapy allowed)
• RET gene rearrangement by FISH or DNA analysis (no prior targeted therapy allowed)
• Institutions will be notified of the patient's eligibility status for Arm T within two (2) business days of submission of the molecular testing reports
• If patients do not have tumors with the above molecular alterations noted proceed directly to step 1

Inclusion Criteria (Step 1):

• For patients with known molecular alterations, institution has been notified that patient is deemed eligible for Arm T per review of molecular testing reports
• Pathologically confirmed non-squamous non-small cell lung carcinoma (NSCLC)
• Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th edition of the lung cancer tumor, node, and metastasis (TNM) classification system
• Predominant non-squamous histology (patients with NSCLC not otherwise specified [NOS] are eligible); mixed tumors will be categorized by the predominant cell type; if small cell elements are present the patient is ineligible
• Tumors must be tested and known negative for EGFR tyrosine kinase inhibitor (TKI) sensitizing mutations (EGFR exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements by routine Clinical Laboratory Improvement Act (CLIA)-certified clinical testing methods; negative circulating tumor DNA results alone are not acceptable; prior testing for tumor PD-L1 status is not required
• Patients must have progressed radiographically following first line platinum-based chemotherapy, no additional lines of therapy are permitted
• NOTE: Prior adjuvant chemotherapy for early stage disease does not count as one line of therapy if 12 months or greater elapsed between completion of adjuvant therapy and initiation of first-line systemic therapy; if less than 12 months elapsed, adjuvant chemotherapy counts as one line of therapy
• Exception for targeted therapy sub-study (Arm T): At least one line of prior chemotherapy or targeted therapy is required, but there is no limit on number of prior treatments
• Patients must have measurable disease as defined by RECIST v. 1.1 criteria; baseline measurements and evaluation of all sites of disease must be obtained within 4 weeks prior to registration
• Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the following times prior to registration:
• Chemotherapy/ targeted oral therapy administered in a daily or weekly schedule must be completed >= 1 week prior to registration;
• Any chemotherapy administered in an every 2 week or greater schedule must be completed >= 2 weeks prior to registration
• Additionally, patients should be recovered to equal to or less than grade 1 toxicities related to any prior treatment, unless adverse event (AE)(s) are clinically nonsignificant and/or stable on supportive therapy
• Patients with no known brain metastasis must have baseline brain imaging within 12 weeks prior to study registration not demonstrating brain metastases OR patients with known brain metastases must have baseline brain imaging within 4 weeks prior to study registration and meet all of the following criteria:
• Have completed treatment to all symptomatic brain metastases (with whole brain radiation or