Substudy 03A: A Study of Immune and Targeted Combination Therapies in Participants With First Line (1L) Renal Cell Carcinoma (MK-3475-03A)

Inclusion Criteria:

• Has a histologically confirmed diagnosis of locally advanced/metastatic ccRCC

• Has received no prior systemic therapy for advanced RCC; prior neoadjuvant/adjuvanttherapy for RCC is acceptable if completed ≥12 months beforerandomization/allocation.

• Is able to swallow oral medication

• Has adequate organ function

• Participants receiving bone resorptive therapy must have therapy initiated at least 2 weeks before randomization/allocation

• Has resolution of toxic effects of the most recent prior therapy to ≤Grade 1

• Has adequately controlled blood pressure (BP ≤150/90 mm Hg) with no change inhypertensive medications within 1 week before randomization/allocation

• Male participants are abstinent from heterosexual intercourse or agree to usecontraception during treatment with and for at least 7 days after the last dose oflenvatinib and /or belzutifan; 7 days after lenvatinib and/or belzutifan is stopped,if the participant is only receiving pembrolizumab, pembrolizumab/quavonlimab,favezelimab/pembrolizumab or a combination of the aforementioned drugs, nocontraception is needed

• Female participants must not be pregnant and not be a woman of childbearingpotential (WOCBP) or is a WOCBP abstinent from heterosexual intercourse or usingcontraception during the intervention period and for at least 120 days after thelast dose of pembrolizumab, pembrolizumab/quavonlimab, favezelimab/pembrolizumab for 30 days after the last dose of lenvatinib or belzutifan, whichever occurs last andmust abstain from breastfeeding during the study intervention period and for atleast 120 days after study intervention

Exclusion Criteria:

• Has urine protein ≥1 g/24 hours and has any of the following: (a) a pulse oximeterreading <92% at rest, or (b) requires intermittent supplemental oxygen, or (c)requires chronic supplemental oxygen (d) active hemoptysis within 3 weeks prior tothe first dose of study intervention

• Has clinically significant cardiovascular disease within 12 months from the firstdose of study intervention administration

• Has had major surgery within 3 weeks before first dose of study interventions

• Has a history of lung disease

• Has a history of inflammatory bowel disease

• Has preexisting gastrointestinal (GI) or non-GI fistula

• Has malabsorption due to prior GI surgery or disease

• Has received prior radiotherapy within 2 weeks of start of study intervention

• Has received a live or live attenuated vaccine within 30 days before the first doseof study drug; killed vaccines are allowed

• Has received more than 4 previous systemic anticancer treatment regimens

• Has a diagnosis of immunodeficiency or is receiving any form of immunosuppressivetherapy within 7 days prior to the first dose of study intervention

• Has known additional malignancy that is progressing or has required active treatmentwithin the past 3 years

• Has known central nervous system (CNS) metastases and/or carcinomatous meningitis

• Has an active autoimmune disease that has required systemic treatment in the past 2years; replacement therapy is not considered a form of systemic treatment and isallowed

• Has an active infection requiring systemic therapy

• Has a known history of human immunodeficiency virus (HIV) infection

• Has a known history of Hepatitis B

• Has had an allogenic tissue/solid organ transplant