Pembrolizumab Plus Lenvatinib in Combination With Belzutifan in Solid Tumors (MK-6482-016)

Inclusion Criteria:

• Diagnosis of one of the following advanced (unresectable and/or metastatic) solidtumors, documented by histopathology or cytopathology:

• Hepatocellular carcinoma (HCC)

• Colorectal cancer (CRC) (non-microsatellite instability-high [non-MSI-H]/deficient mismatch repair [dMMR])

• Pancreatic ductal adenocarcinoma (PDAC).

• Biliary tract cancer (BTC) (includes intrahepatic, extrahepaticcholangiocarcinoma [CCA] and gall bladder cancer)

• Endometrial cancer (EC)

• Esophageal squamous cell carcinoma (ESCC)

• Disease progression on or since the most recent treatment (does not apply to newlydiagnosed unresectable or metastatic HCC or EC).

• Measurable disease per RECIST v1.1 as assessed locally (by investigator) andverified by BICR

• Submission of an archival tumor tissue sample or newly obtained core or excisionalbiopsy of a tumor lesion not previously irradiated

• Male participants are abstinent from heterosexual intercourse or agree to followcontraceptive guidance during and for at least 7 days after last dose of studyintervention with belzutifan and lenvatinib

• Female participants are not pregnant or breastfeeding, not a woman of child-bearingpotential (WOCBP), or is a WOCBP and agrees to follow contraceptive guidance duringthe intervention period and and for at least 120 days after the last dose ofpembrolizumab or for at least 30 days after last dose of lenvatinib or belzutifan,whichever occurs last

• Adequate organ function

• Adequately controlled blood pressure with or without antihypertensive medications

• HCC Specific Inclusion Criteria: No prior systemic chemotherapy, including anti-VEGFtherapy, anti-programmed cell-death (PD-1)/PD-L1 or any systemic investigationalanticancer agents for advanced/unresectable HCC (1L)

• CRC ([non-MSI-H/dMMR) Specific Inclusion Criteria: Received at least 2 prior linesof systemic therapy for unresectable or metastatic disease which includesfluoropyrimidine, irinotecan and oxaliplatin

• PDAC Specific Inclusion Criteria: Prior therapy with at least 1 (platinum orgemcitabine containing regimen) but no more than 2 prior systemic therapies forunresectable or metastatic pancreatic cancer

• BTC Specific Inclusion Criteria: Received at least 1 prior line of systemic therapy (containing gemcitabine or fluoropyrimidine) for unresectable or metastatic disease

• EC Specific Inclusion Criteria: Study treatment is for 1L therapy of EC andparticipants should not have received prior systemic chemotherapy. Exception: Mayhave received 1 prior line of line of systemic platinum-based adjuvant and/orneoadjuvant chemotherapy in the setting of a curative-intent resection, if therecurrence occurred ≥6 months after the last dose of chemotherapy or may havereceived prior radiation with or without chemotherapy

• ESCC Specific Inclusion Criteria: Have experienced radiographic or clinicalprogression on one prior line of standard systemic therapy (immune oncology (IO)naïve participants) or an anti-PD-1/PD-L1 (IO resistant participants)

Exclusion Criteria:

• Unable to swallow orally administered medication or presence of a gastrointestinal (GI) disorder that may affect study intervention absorption

• History of a second malignancy that is progressing or has required active treatmentwithin 3 years

• A pulse oximeter reading <92% at rest, or requirement of intermittent supplementaloxygen/ chronic supplemental oxygen

• Presence of central nervous system (CNS) metastases and/or carcinomatous meningitis

• Clinically significant cardiovascular disease within 6 months of first dose of studyintervention

• Symptomatic pleural effusion, unless clinically stable after treatment

• Preexisting ≥ Grade 3 gastrointestinal (GI) or non-GI fistula

• Moderate to severe hepatic impairment

• Clinically significant history of bleeding within 3 months before screening

• Presence of serious active nonhealing wound/ulcer/bone fracture

• Requirement for hemodialysis or peritoneal dialysis

• History of human immunodeficiency virus (HIV) infection

• History of Hepatitis B or active Hepatis C virus infections. with exceptions for HCCand BTC

• Prior therapy with a PD-1, anti-PD-L1, anti-PD-L2 agent, vascular endothelial growthfactor (VEGF) tyrosine kinase inhibitor (TKI) or hypoxia-inducible factor 2α (HIF-2α)

• Radiographic evidence of intratumoral cavitation, or invasion/infiltration of amajor blood vessel

• EC specific exclusion criteria: History of carcinosarcoma, endometrialleiomyosarcoma or other high-grade sarcomas, or endometrial stromal sarcomas

• ESCC specific exclusion criteria: Has clinically apparent ascites or pleuraleffusion or experienced weight loss >20% over approximately 3 months before firstdose of study therapy