A Study of Pembrolizumab (MK-3475) in Combination With Belzutifan (MK-6482) and Lenvatinib (MK-7902), or Pembrolizumab/Quavonlimab (MK-1308A) in Combination With Lenvatinib, Versus Pembrolizumab and Lenvatinib, for Treatment of Advanced Clear Cell Renal Cell Carcinoma (MK-6482-012)

Prior treatment

• Has had major surgery, other than nephrectomy within 4 weeks prior to randomization
• Has received prior radiotherapy within 2 weeks prior to first dose of study intervention
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
• Has received a live or live-attenuated vaccine within 30 days before the first dose of study drug; killed vaccines are allowed
• Has clinically significant history of bleeding within 3 months prior to randomization
• Has had an allogenic tissue/solid organ transplant

Other illness

• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
• Has clinically significant cardiac disease within 12 months from first dose of study intervention
• Has a history of interstitial lung disease
• Has symptomatic pleural effusion; a participant who is clinically stable following treatment of this condition is eligible
• Has preexisting gastrointestinal or non-gastrointestinal fistula
• Has a known psychiatric or substance abuse disorder that would interfere with requirements of the study
• Has an active autoimmune disease that has required systemic treatment in the past 2 years
• Has a history of noninfectious pneumonitis that required steroids or has current pneumonitis
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has a known history of Hepatitis B

Other

• Has known central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has hypoxia or requires intermittent supplemental oxygen or requires chronic supplemental oxygen
• Has radiographic evidence of intratumoral cavitation, encasement or invasion of a major blood vessel

• Has histologically confirmed diagnosis of RCC with clear cell component.
• Has received no prior systemic therapy for advanced ccRCC
• Male participants are abstinent from heterosexual intercourse or agree to use contraception during and for at least 7 days after last dose of study intervention with belzutifan and lenvatinib.
• Female participants are not pregnant or breastfeeding and are either not a woman of child-bearing potential (WOCBP) or use a contraceptive method that is highly effective or are abstinent from heterosexual intercourse during the intervention period and for at least 120 days after pembrolizumab or pembrolizumab/quavonlimab or for at least 30 days after last dose of lenvatinib or belzutifan, whichever occurs last
• Has adequately controlled blood pressure with or without antihypertensive medications
• Has adequate organ function.
• Participants receiving bone resorptive therapy must have therapy initiated at least 2 weeks prior to randomization/allocation