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

Inclusion 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 SolidTumors (RECIST) 1.1

• Tumor tissue for ribonucleic acid (RNA)-sequencing (tumor tissue from bonymetastasis 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 treatmentstudy

• Adequate renal function defined as calculated creatinine clearance >= 30 mL/min perthe Cockcroft and Gault formula

• Adequate liver function defined by:

• Total bilirubin =< 1.5 times the upper limit of normal (ULN) except forunconjugated 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 testduring screening and prior to receiving first dose of protocol-indicated treatment

• Women of childbearing potential (WOCBP) is defined as any female who hasexperienced menarche who has not undergone surgical sterilization (hysterectomyor bilateral oophorectomy) or is not postmenopausal

• Menopause is defined clinically as 12 months of amenorrhea in a woman over 45years of age in the absence of other biological or physiological causes

Exclusion Criteria:

• =< 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 isrequired

• 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 controlledgastrointestinal disorder that could significantly affect the absorption of oralstudy 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 HeartAssociation (NYHA) functional criteria

• Unstable angina pectoris (i.e., last episode =< 3 months prior to first dose ofprotocol-indicated treatment)

• Myocardial infarction within 3 months prior to starting treatment

• Subjects with central nervous system (CNS) metastases are eligible after they havecompleted local therapy (e.g., whole brain radiation therapy [WBRT], surgery orradiosurgery)

• Any condition requiring systemic treatment with either systemic corticosteroids (> 10 mg/day prednisone or equivalent daily) or other immunosuppressive medicationswithin 14 days prior to initiating protocol-indicated treatment

• In the absence of active autoimmune disease: Subjects are permitted the use ofcorticosteroids with minimal systemic absorption (e.g., topical, ocular,intra-articular, intranasal, and inhalational), =< 10 mg/day prednisone orequivalent daily; and physiologic replacement doses of systemic corticosteroids =< 10 mg/day prednisone or equivalent daily (e.g., hormone replacement therapy neededin patients with hypophysitis)