Trial of Zanzalintinib (XL092) in Combination With Immunotherapy in Patients Who Progress on Adjuvant Therapy in Clear Cell RCC

Inclusion Criteria: 1. Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. 2. Age ≥ 18 years at the time of consent. 3. ECOG Performance Status of 0-1 within 28 days prior to registration. 4. Advanced or metastatic RCC with a clear cell component. 5. Prior treatment must have included an anti-PD-1. Subjects must have progressed on or after adjuvant anti-PD-1 therapy. A washout period of 14 days prior to study treatment initiation is required. Subjects must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to Grade ≤ 1 or baseline. Unresolved grade 2 or greater toxicity from prior checkpoint inhibitor therapy will exclude a subject from enrolling. Subjects that received other systemic therapy after anti-PD1 are not eligible. 6. Measurable disease per RECIST 1.1. 7. Demonstrate adequate organ function as defined below. All screening labs are to be obtained within 2 weeks prior to registration. * Absolute Neutrophil Count (ANC): ≥ 1500/mm3 without granulocytes colony-stimulating factor support within 2 weeks of screening laboratory collection * Platelet Count (PLT): ≥ 100,000/mm3; without transfusion within 2 weeks of screening laboratory sample collection. * Hemoglobin (Hgb): ≥ 9 g/dL * Serum Creatinine OR Calculated CrCl using Cockgroft Gault equation: Serum creatinine \< 1.5 upper limit of normal (ULN) OR calculated Cr Clearance \>40mL/min * Urine protein-to-creatinine ratio (UPCR): ≤1mg/mg (≤ 113.2mg/mmol) creatinine * Bilirubin: ≤ 1.5 × ULN (for subjects with Gilbert's disease \< 3 x ULN) * Aspartate aminotransferase (AST): ≤ 3 × ULN * Alanine aminotransferase (ALT): ≤ 3 × ULN * Alkaline phosphatase (ALP): ≤ 3 × ULN. For subjects with documented bone metastasis ALP ≤ 5x ULN * International Normalized Ratio (INR): ≤ 1.5 x ULN * Activated Partial Thromboplastin Time (aPTT): ≤ 1.2 × ULN 8. Females of childbearing potential must have a negative urine or serum pregnancy test within 2 weeks prior to registration. If a urine test is done and it is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 9. Females of childbearing potential who are sexually active with a male able to father a child must be willing to abstain from penile-vaginal intercourse or to use an effective method(s) of contraception. Males able to father a child who are sexually active with female of childbearing potential must be willing to abstain from penile-vaginal intercourse or to use an effective method(s) of contraception. 10. Known HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial. Testing is not required at screening unless mandated by local policy. 11. Patients with known chronic hepatitis B virus (HBV) infection, must have an undetectable HBV viral load on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, the HCV viral load must be undetectable to be eligible for this trial. Testing is not required at screening unless mandated by local policy. 12. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study. Exclusion Criteria: 1. Prior treatment with Zanzalintinib. 2. Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 14 days prior to study treatment initiation. 3. Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 28 days prior to study treatment initiation unless otherwise specified. 4. Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible. 4\. Radiation therapy for bone metastasis within 14 days, any other radiation therapy within 28 days prior to study treatment initiation. Systemic treatment with radionuclides within 6 weeks prior to study treatment initiation. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible. 5\. Known brain metastases or cranial epidural disease. Subjects adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 28 days prior to study treatment initiation may be eligible. NOTE: Subjects with an incidental finding of an isolated brain lesion \< 1 cm in diameter may be eligible after sponsor-investigator approval if the lesion is radiographically stable for 28 days prior to study treatment initiation and does not require treatment per Investigator judgement. NOTE: Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of study treatment initiation. 6\. Any complementary medications (eg, herbal supplements or traditional Chinese medicines) to treat the disease under study within 14 days prior to study treatment initiation. 7\. Active infection requiring systemic therapy. NOTE: Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study. 8\. Positive TB test with active mycobacterial infection requiring systemic treatment. 9\. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study). 10\. History of severe allergic anaphylactic reactions to study drug(s) or any of their excipients. 11