Genetic Testing to Select Therapy for the Treatment of Advanced or Metastatic Kidney Cancer, OPTIC RCC Study

Eligibility Criteria

• * Histological confirmation of RCC with a clear cell component
• * Advanced (not amenable to curative surgery or radiation therapy) or metastatic (American Joint Committee on Cancer \[AJCC\] stage IV) RCC
• * Patient can comprehend and sign the study informed consent form
• * Male or female \>= 18 years of age at the time of informed consent
• * Karnofsky performance status (KPS) of \>= 70%
• * No prior systemic therapy for RCC in the neoadjuvant, adjuvant or metastatic setting
• * At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• * Tumor tissue for ribonucleic acid (RNA)-sequencing (tumor tissue from bony metastasis is not suitable but a soft tissue component around bone is acceptable)
• * Screening tissue consent- Patient must be assigned to either Cluster 1/2 or 4/5. Patients assigned to cluster 3/6/7 will not be eligible for the treatment study
• * Adequate renal function defined as calculated creatinine clearance \>= 30 mL/min per the Cockcroft and Gault formula
• * Adequate liver function defined by:
• * Total bilirubin =\< 1.5 times the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome
• * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 3 x ULN
• * Women of childbearing potential (WOCBP) must have a negative serum pregnancy test during screening and prior to receiving first dose of protocol-indicated treatment
• * Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or is not postmenopausal
• * Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 years of age in the absence of other biological or physiological causes
• * =\< 14 days before first dose of protocol-indicated treatment:
• * Major surgery requiring general anesthesia
• * Inadequately controlled hypertension (systolic blood pressure \[SBP\] \> 160/90 mmHg)
• * Anti-hypertensive medications are permitted.
• * Active infection requiring infusional treatment
• * Has preexisting gastrointestinal or non-gastrointestinal fistula
• * Proteinuria \> 2 g/ 24 hours (hrs)
• * If patient has 1+ protein on urine dipstick then a 24 hr urine collection is required
• * Non-healing wounds on any part of the body (for patients assigned to Cabo/Nivo only)
• * Known clinically significant active bleeding including hemoptysis
• * Inability to swallow oral medication; or the presence of a poorly controlled gastrointestinal disorder that could significantly affect the absorption of oral study drug (for patients assigned to Cabo/Nivo only) - e.g., Crohn's disease, ulcerative colitis, chronic diarrhea (defined as \> 4 loose stools per day), malabsorption, or bowel obstruction
• * Significant cardiovascular disease or condition including:
• * Class III or IV cardiovascular disease according to the New York Heart Association (NYHA) functional criteria
• * Unstable angina pectoris (i.e., last episode =\< 3 months prior to first dose of protocol-indicated treatment)
• * Myocardial infarction within 3 months prior to starting treatment
• * Subjects with central nervous system (CNS) metastases are eligible after they have completed local therapy (e.g., whole brain radiation therapy \[WBRT\], surgery or radiosurgery)
• * Any condition requiring systemic treatment with either systemic corticosteroids (\> 10 mg/day prednisone or equivalent daily) or other immunosuppressive medications within 14 days prior to initiating protocol-indicated treatment
• * In the absence of active autoimmune disease: Subjects are permitted the use of corticosteroids with minimal systemic absorption (e.g., topical, ocular, intra-articular, intranasal, and inhalational), =\< 10 mg/day prednisone or equivalent daily; and physiologic replacement doses of systemic corticosteroids =\< 10 mg/day prednisone or equivalent daily (e.g., hormone replacement therapy needed in patients with hypophysitis)