Substudy 03C: A Study of Combination Therapies in Participants With Renal Cell Carcinoma With Recurrent Disease During or After Anti-PD-(L)1 Therapy (MK-3475-03C/KEYMAKER-U03)

For people ages 18-120

The main inclusion criteria include but are not limited to the following:

• Has a histologically confirmed diagnosis of unresectable locally advanced/metastatic RCC with clear cell component (with or without sarcomatoid features).
• Has received no other prior systemic therapy for treatment of advanced/metastatic ccRCC except for adjuvant (PD-(L)1) therapy.
• Has disease recurrence during adjuvant anti- PD-(L)1 therapy or ≤24 months following the last dose of adjuvant anti-PD-(L)1 therapy.
• Has measurable disease per RECIST 1.1 as assessed by investigator and verified by BICR.
• Is able to swallow oral medication.
• Submits an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated.
• Participants receiving bone resorptive therapy (must have therapy initiated at least 2 weeks before allocation/randomization).
• Has adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤140/90 mm Hg with no change in antihypertensive medications within 1 week before allocation/randomization.
• Has adequate organ function.
• A participant assigned male sex at birth, capable of producing sperm, continues contraception at least 7 days after the last dose of Belzutifan, and at least 96 days after the last dose of Zanzalintinib. Refrains from donating sperm and abstains from penile-vaginal intercourse and remains abstinent, or uses external condom or contraceptives consistent with local regulations.
• A participant assigned female sex at birth is not breast feeding at least 96 days after the last dose of study intervention. A participant of childbearing potential (POCBP) is not pregnant and has a negative highly sensitive pregnancy test before the first dose of study intervention. A POCBP uses a highly effective contraceptive method, and continues using contraception at least 30 days after the last dose of Belzutifan, and at least 186 days after the last dose of Zanzalintinib.

The main exclusion criteria include but are not limited to the following:

• Has clinically significant hematuria, hematemesis, or hemoptysis of (>2.5 mL) of red blood, or other history of significant bleeding.
• Has clinically significant cardiovascular disease within 12 months from first dose of study intervention.
• Has deep vein thrombosis within 3 months before allocation/randomization unless stable, asymptomatic, and treated with therapeutic anticoagulation for at least 4 weeks before allocation/randomization.
• Has history of idiopathic pulmonary fibrosis, organizing pneumonia, or evidence of active pneumonitis.
• Has a left ventricular ejection fraction (LVEF) ≤50% or below the institutional (or local laboratory) normal range.
• Has serious wound, ulcer or bone fracture or has had major surgery within 8 weeks before first dose of study intervention.
• Has symptomatic pleural effusion (for example cough, dyspnea, pleuritic chest pain), ascites, or pericardial fluid requiring drainage in the last 4 weeks before allocation/randomization.
• Has gastrointestinal (GI) disorders, including those associated with a high risk of perforation or fistula formation.
• Has malabsorption due to prior GI surgery or GI disease.
• Has moderate to severe hepatic impairment (Child-Pugh B or C).
• Has received colony-stimulating factors within 28 days prior to intervention allocation/randomization.
• Has received prior treatment with HIF-2α and/or Vascular Endothelial Growth Factor-Tyrosine Kinase Inhibitor (VEGF/TKI) inhibitors.
• Has received prior radiotherapy within 2 weeks of start of study intervention, or has radiation-related toxicities, requiring corticosteroids.
• Is currently receiving strong inhibitors of cytochrome P450 3A4 (CYP3A4) that cannot be discontinued for the duration of the study.
• Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention.
• Is currently receiving anticoagulants or platelet inhibitors that cannot be discontinued for the duration of the study.
• Have been previously allocated/randomized to study intervention in any substudy of protocol MK-3475-U03.
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation.
• Has active autoimmune disease that has required systemic treatment in the past 2 years.
• Has an active infection requiring systemic therapy.
• Has history of human immunodeficiency virus (HIV) infection.
• Has hepatitis B or hepatitis C virus infection.