Advanced Renal Cell Cancer Combination ImmunoThErapy Clinical Trial (ARCITECT)

Inclusion Criteria: Patient must have ECOG PS of ≤ 2 within 28 days of C1D1. Age ≥ 18 years old at the time of informed consent. Patient must have histological confirmation of renal carcinoma with clear cell component including advanced RCC (not amenable to curative surgery or radiation therapy) or metastatic RCC. Patient must have measurable disease by CT or MRI per RECIST 1.1 criteria. Radiated lesions cannot be used as measurable lesions unless there is clear evidence of progression. Patient must have defined IMDC risk categorization of either favorable, intermediate or poor based on clinical variables of increased risk (below). No risk factors (0) = favorable risk 1-2 risk factors = intermediate risk ≥ 3 risk factors = poor risk NOTE: Patients with all IMDC risk factors are eligible, but will be stratified according to IMDC risk, and initial analysis will be based on the IMDC intermediate and poor risk patients. IMDC Risks: KPS less than 80% Less than 1 year from diagnosis including original localized disease to randomization(if applicable) Hemoglobin less than the lower limit of normal Corrected calcium concentration greater than 10 mg/dL ANC greater than the ULN Platelet count greater than the ULN Patient must have either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue sections, obtained from a metastatic lesion, preferably within 3 months or no more than 12 months with an associated pathology report. This tissue must be identified prior to registration. Confirmation of sufficient archival tissue must be obtained after informed consent and the tissue must be shipped to the appropriate lab by end of Cycle 2. Biopsies should be excisional, incisional, or core needle. Fine needle aspiration is unacceptable for submission. Biopsies of bone lesions that do not have a soft tissue component are also unacceptable for submission. This sample is required to be eligible for the trial. If a patient is having a standard of care biopsy, part of that sample may be utilized for eligibility. Demonstrate adequate organ function as defined below; all screening labs to be obtained within 28 days prior to registration. Hematological White blood cell (WBC) ≥ 2,000/uL Absolute Neutrophil Count (ANC) ≥ 1,000/uL; without growth factor support Hemoglobin (Hgb) ≥ 8.0 g/dL; ≥ 7 days without PRBC transfusion. Platelets ≥ 75,000/uL; without platelet transfusion Renal Calculated creatinine clearance (CrCl)1 ≥ 40 mL/min Hepatic Total Bilirubin ≤ 1.5 × upper limit of normal (ULN) *EXCEPT participants with Gilbert Syndrome who must have a Total Bilirubin level of < 3.0 x ULN Aspartate aminotransferase (AST) ≤ 3.0 × ULN Alanine aminotransferase (ALT) ≤ 3.0 × ULN HIV positive patients may be eligible if either: Patients with CD4 > 200 cells/mm3 OR Patients with HIV viral load undetectable. Active HBV or active HCV patients may be eligible if: Patients with HBV infection are eligible if hepatitis B surface antigen and HBV DNA are negative. Patients with HCV infection are eligible if HCV RNA is negative. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 1 week prior to Cycle 1 Day 1. WOCBP must agree to follow instructions for method(s) of contraception. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception. Exclusion Criteria: Prior adjuvant or systemic therapy for RCC. Prior treatment with an anti-PD1 or anti-PDL1 agent, anti-CTLA4 antibody or a VEGFR TKI or anti-VEGF antibody including in the adjuvant setting. Radiotherapy within 2 weeks prior to Cycle 1 Day 1. Expected to require any other form of systemic or localized antineoplastic therapy while on trial (including maintenance therapy with another agent, radiation therapy, and/or surgical resection). Currently known active and definitive CNS metastases. Patients who have treated brain metastases (with either surgical resection or stereotactic radiosurgery (SRS)) may be eligible. Patients must not have taken any steroids ≤ 2 weeks prior to randomization for the purpose of managing their brain metastases. Repeat imaging after SRS or surgical resection is not required so long as baseline MRI is within 4 weeks of registration. Patients with multiple brain metastases treated with SRS (with or without WBRT), are not excluded. Patients with definitive CNS metastases treated with only WBRT are ineligible. Patients with potential CNS metastases that are too small for treatment with either SRS or surgery (e.g. 1-2 mm) and/or are of uncertain etiology are potentially eligible, but need to be discussed with and approved by the sponsor-investigator. Persistent toxicity of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade > 1 severity that is related to prior therapy. NOTE: Sensory neuropathy or alopecia of Grade ≤ 2 are acceptable. Known severe (Grade ≥ 3) hypersensitivity reactions to fully human monoclonal antibodies, antibody, or severe reaction to immuno-oncology agents, such as colitis or pneumonitis requiring treatment with steroids; or has a history of interstitial lung disease, any history of anaphylaxis, or uncontrolled asthma. Known condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses <10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease. NOTE: Corticosteroid use as a premedication for IV contrast allergies/reactions is allowed. Active known or suspected autoimmune disease that required systemic treatment within 2 years of the start of study drug (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (e.g., celiac disease) are permitted to enroll. Uncontrolled adrenal insufficiency based on investigator discretion. Active infection requiring systemic therapy within 14 days of Cycle 1 Day 1. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months of enrollment, unstable angina, congestive heart failure (New York Heart Association class ≥ II), or serious uncontrolled cardiac arrhythmia requiring medication. Legally incapacitated or has limited legal capacity. Pregnant or breastfeeding. Prior allogeneic tissue/solid organ transplant, except for corneal transplants. Major surgery (e.g., nephrectomy) less than 28 days prior to Cycle 1 Day 1. Prior malignancy active within the previous 2 years from screening except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast. Any condition including medical, emotional, psychiatric, or logistical that, in the opinion of the Investigator, would preclude the participant from adhering to the protocol or would increase the risk associated with study participation or study treatment administration or interfere with the interpretation of safety results. Receipt of a live/attenuated vaccine within 30 days of first study treatment. The use of inactivated seasonal influenza vaccines (eg, Fluzone®) will be permitted on study without restriction.