A Study of Belzutifan (MK-6482) in Combination With Lenvatinib Versus Cabozantinib for Treatment of Renal Cell Carcinoma (MK-6482-011)

This study will compare the efficacy and safety of belzutifan + lenvatinib versus cabozantinib in participants with advanced renal cell carcinoma (RCC) with clear cell component after prior therapy. The primary hypothesis is that belzutifan + lenvatinib is superior to cabozantinib in terms of progression-free survival or overall survival.

Inclusion Criteria: * Unresectable, locally advanced or metastatic clear cell renal cell carcinoma (RCC). * Disease progression on or after an anti-programmed cell death-1/ligand 1 (PD-1/L1) therapy as either first or second-line treatment for locally advanced/metastatic RCC or as adjuvant treatment or neoadjuvant/adjuvant with progression on or within 6 months of last dose. * Measurable disease per RECIST 1.1 criteria as assessed by local study investigator. * Karnofsky performance status (KPS) score of at least 70% assessed within 10 days before randomization. * Received no more than 2 prior systemic regimens including: one anti-PD-1/L1 containing adjuvant or neoadjuvant/adjuvant regimens with progression on or within 6 months from the last dose of that regimen OR one or 2 regimens for locoregional/advanced disease * Received only 1 prior antiPD-1/L1 therapy for adjuvant, neoadjuvant/adjuvant or locally advanced/metastatic RCC. * A male participant is eligible to participate if he is abstinent from heterosexual intercourse or agrees to use contraception during the intervention period and for at least 7 days after the last dose of belzutifan or lenvatinib in the belzutifan+lenvatinib arm, whichever occurs last, and 23 days after the last dose of cabozantinib. * A female participant is eligible to participate if they are not pregnant, not breastfeeding, and at least 1 of the following conditions applies: Not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive guidance during the intervention period and for at least 30 days after the last dose of study intervention in the belzutifan+ lenvatinib arm, or 120 days after the last dose of study intervention in the cabozantinib arm. * Adequately controlled blood pressure. * Adequate organ function. Exclusion Criteria: * A pulse oximeter reading \<92% at rest, requires intermittent supplemental oxygen, or requires chronic supplemental oxygen. * Known additional malignancy that is progressing or has required active treatment within the past 3 years except for basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy. * Known central nervous system (CNS) metastases and/or carcinomatous meningitis. * Clinically significant cardiac disease within 6 months of first dose of study intervention. * Prolongation of QTc interval to \>480 ms. * Symptomatic pleural effusion (e.g.,cough, dyspnea, pleuritic chest pain) that is not clinically stable. * Pre-existing ≥Grade 3 gastrointestinal or nongastrointestinal fistula. * Moderate to severe hepatic impairment. * History of significant bleeding within 3 months before randomization. * History of solid organ transplantation. * Known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study. * Unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (e.g., gastrectomy, partial bowel obstruction, malabsorption). * Known hypersensitivity or allergy to the active pharmaceutical ingredients or any component of the study intervention formulations. * Received colony-stimulating factors \[eg, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GMCSF) or recombinant erythropoietin (EPO)\] within 28 days before randomization. * Prior treatment with belzutifan or another hypoxia-inducible factor (HIF)-2α inhibitor. * Prior treatment with lenvatinib. * Prior treatment with cabozantinib. * Currently participating in a study of an investigational agent or using an investigational device. * Active infection requiring systemic therapy. * History of human immunodeficiency virus (HIV) infection. * History of hepatitis B or known active hepatitis C infection.