A Study of Belzutifan (MK-6482) in Participants With Advanced Renal Cell Carcinoma (MK-6482-013)

This study will compare the efficacy and safety of two doses of belzutifan in participants with advanced renal cell carcinoma (RCC) with clear cell component after prior therapy. The primary hypothesis is that the higher dose of belzutifan is superior to the standard dose in terms of objective response rate (ORR).

Inclusion Criteria: * Has a histologically confirmed diagnosis of locally advanced/metastatic RCC with clear cell component * Has measurable disease per RECIST 1.1 as assessed by BICR * Can submit an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated * Has experienced disease progression on or after systemic treatment with an anti-programmed cell death 1 (PD-1)/Ligand 1 (L1) therapy for locally advanced or metastatic RCC. The anti-PD-1/L1 therapy may be monotherapy or in combination with other agent(s) such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or vascular endothelial growth factor (VEGF) targeted- tyrosine kinase inhibitor (TKI). The immediately preceding line of treatment has to have been an anti-PD-1/L1 therapy * Has received no more than 3 prior systemic regimens for locally advanced or metastatic RCC * Has received only 1 prior anti-PD-1/L1 therapy for locally advanced or metastatic RCC * Has recovered from all AEs due to previous therapies to ≤Grade 1 or baseline, with the exception of ≤Grade 2 neuropathy or endocrine-related AEs ≤Grade 2 requiring treatment or hormone replacement * Has a Karnofsky performance status (KPS) score of at least 70% assessed within 10 days prior to the first dose of study intervention * 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 study intervention * A female participant is eligible to participate if she is 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 * A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) within 24 hours before the first dose of study intervention Exclusion Criteria: * Has hypoxia (a pulse oximeter reading \<92% at rest), requires intermittent supplemental oxygen, or requires chronic supplemental oxygen * Has a 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 \[e.g., breast carcinoma, cervical cancer in situ\] that have undergone potentially curative therapy * Has known central nervous system (CNS) metastases and/or carcinomatous meningitis * Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction ≤6 months from Day 1 of study drug administration or New York Heart Association Class III or IV congestive heart failure * Has moderate to severe hepatic impairment (Child-Pugh B or C) * Has received colony-stimulating factors (eg, granulocyte colony-stimulating factor \[G-CSF\], granulocyte-macrophage colony-stimulating factor \[GM-CSF\], or recombinant erythropoietin \[EPO\]) ≤28 days prior to the first dose of study intervention * Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study * Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, malabsorption) * Has known hypersensitivity or allergy to the active pharmaceutical ingredient or any component of the study intervention (belzutifan) formulations * Has received prior treatment with belzutifan or another hypoxia-inducible factor (HIF)-2α inhibitor * Has received any type of small molecule kinase inhibitor (including investigational kinase inhibitor) ≤2 weeks before randomization * Has received any type of systemic anticancer antibody (including investigational antibody) ≤4 weeks before randomization * Has received prior radiotherapy ≤2 weeks prior to first dose of study intervention. Participants must have recovered from all radiation-related toxicities and not require corticosteroids * Has had major surgery ≤3 weeks prior to first dose of study intervention * Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate (eg, bosentan, efavirenz, modafinil) inducers of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study * Is currently participating in a study of an investigational agent or is currently using an investigational device * Has an active infection requiring systemic therapy * Has active tuberculosis (TB) * Has a diagnosis of immunodeficiency * Has a known history of human immunodeficiency virus (HIV) infection * Has a known history of hepatitis B (HBV) or known active hepatitis C (HCV) infection * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not the best interest of the participant to participate, in the opinion of the treating investigator