Inclusion Criteria
- Has a histologically confirmed diagnosis of unresectable, locally advanced or metastatic clear cell renal cell carcinoma (RCC).
- Has measurable disease per RECIST 1.1.
- Has adequate organ function.
- Has adequately controlled blood pressure (BP).
- If participants received major surgery or radiation therapy of >30 Gy, they must have recovered from the toxicity and/or complications from the intervention.
- Has resolution of the toxic effect(s) of the most recent prior therapy.
- Participants receiving bone resorptive therapy must have therapy initiated at least 2 weeks prior to allocation.
- Is Chinese descent, defined as both biological parents and all biological grandparents are of Chinese descent.
Male Participants:
- Must be willing to use an adequate method of contraception.
Female Participants:
- Must be a woman of non-childbearing potential (WONCBP) or have a negative urine or serum pregnancy test and must be willing to use an adequate method of contraception.
For Belzutifan + Lenvatinib treatment:
- Has progressed on or after having received systemic treatment for locally advanced or metastatic RCC.
- Has no more than 3 prior systemic regimens for locally advanced or metastatic RCC.
For Belzutifan + Lenvatinib + Pembrolizumab treatment:
- Has received no prior systemic therapy for advanced RCC.
Exclusion Criteria
- Is a woman of childbearing potential (WOCBP) who has a positive urine pregnancy test within 24 hours prior to first dose of study intervention.
- Has any of the following: A pulse oximeter reading <92%, or 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.
- Has known central nervous system (CNS) metastases and/or carcinomatous meningitis.
- Has clinically significant cardiac disease.
- Has symptomatic pleural effusion.
- Has a history of inflammatory bowel disease.
- Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.
- Has clinically significant hematuria, hematemesis or hemoptysis of red blood, or other history of significant bleeding within 3 months before administration of the first dose of study intervention.
- Has other clinically significant disorders such as: A serious active non-healing wound/ulcer/bone fracture, requirement for hemodialysis or peritoneal dialysis or a history of allogenic tissue/solid organ transplantation.
- Received colony-stimulating factors, granulocyte macrophage colony-stimulating factor (GMCSF) or recombinant EPO within 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.
- Has received prior treatment with belzutifan.
- Has received prior treatment with lenvatinib.
- Has received any type of systemic anticancer antibody (including investigational antibody) ≤28 days prior to allocation.
- Has received / will be receiving any traditional Chinese medicines.
- Has received prior radiotherapy within 2 weeks prior to first dose of study intervention. Participants must have recovered from all radiation-related toxicities and not require corticosteroids.
- Is receiving concomitant treatment, in therapeutic doses, with anticoagulants.
- Is receiving chronic systemic steroids therapy (at doses >10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention.
- 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 a known history of Human Immunodeficiency Virus (HIV) infection.
- Has a known history of Hepatitis B or known active Hepatitis C virus infection.
- Has a known history of active tuberculosis.
- Has radiographic evidence of intratumoral cavitation, encasement or invasion of a major blood vessel.
- Has known hypersensitivity or allergy to the active pharmaceutical ingredient or any component of the study intervention (belzutifan or lenvatinib) formulations.
- Has had major surgery within 4 weeks prior to first dose of study intervention.
For Belzutifan + Lenvatinib + Pembrolizumab treatment:
- Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
- Has a history of hypersensitivity reaction to the active pharmaceutical ingredient or any component of pembrolizumab or monoclonal antibody (mAb).
- Has an active autoimmune disease that has required systemic treatment in the past 2 years.
- Has received a live vaccine within 30 days prior to the first dose of study intervention.