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

A Phase 1b/2 Study of Immune and Targeted Combination Therapies in Participants With RCC (U03): Substudy 03A in First Line Metastatic Participants

Substudy 03A is part of a larger research study that is testing experimental treatments for renal cell carcinoma (RCC). The larger study is the umbrella study (U03).

The goal of substudy 03A is to evaluate the safety and efficacy of experimental combinations of investigational agents in participants with advanced first line (1L) clear cell renal cell carcinoma (ccRCC).

This substudy will have two phases: a safety lead-in phase and an efficacy phase. The safety lead-in phase will be used to demonstrate a tolerable safety profile for the combination of investigational agents. There will be no hypothesis testing in this study.

Study Overview

• Status: Active, not recruiting
• Conditions: Carcinoma, Renal Cell
• Intervention / Treatment: Drug: Lenvatinib; Biological: Pembrolizumab/Quavonlimab; Biological: Favezelimab/Pembrolizumab; Biological: Pembrolizumab; Drug: Belzutifan; Drug: Vibostolimab/Pembrolizumab

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Blacktown, New South Wales, Australia, 2148
      • Blacktown Hospital ( Site 1601)
    • Kogarah, New South Wales, Australia, 2217
      • St George Hospital ( Site 1602)
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital ( Site 1603)
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health ( Site 1600)
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1Z5
      • Princess Margaret Cancer Centre ( Site 1101)
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital ( Site 1100)
• Chile
  • Araucania
    • Temuco, Araucania, Chile, 4800827
      • James Lind Centro de Investigacion del Cancer ( Site 2108)
    • Temuco, Araucania, Chile, 4810148
      • CIDO SpA-Oncology ( Site 2106)
  • Region M. de Santiago
    • Santiago, Region M. de Santiago, Chile, 7500921
      • FALP-UIDO ( Site 2100)
    • Santiago, Region M. de Santiago, Chile, 8420383
      • Bradfordhill-Clinical Area ( Site 2101)
    • Santiago, Region M. de Santiago, Chile, 7500994
      • Oncovida ( Site 2107)
  • Valparaiso
    • Viña del Mar, Valparaiso, Chile, 2520598
      • ONCOCENTRO APYS-ACEREY ( Site 2103)
• Colombia
  • Bogota D.C.
    • Bogotá, Bogota D.C., Colombia, 111321
      • Clinica Colsanitas S.A, Sede Clínica Universitaria Colombia-Center Investigator ( Site 1900)
  • Cesar Department
    • Valledupar, Cesar Department, Colombia, 200001
      • Sociedad De Oncologia Y Hematologia Del Cesar-Oncology ( Site 1905)
  • Departamento de Córdoba
    • Montería, Departamento de Córdoba, Colombia, 230002
      • Instituto Médico de Alta Tecnologia S.A.S ( Site 1904)
  • Valle del Cauca Department
    • Cali, Valle del Cauca Department, Colombia, 760032
      • Fundación Valle del Lili ( Site 1901)
• France
  • Ain
    • Vandœuvre-lès-Nancy, Ain, France, 54519
      • Institut De Cancerologie De Lorraine ( Site 1204)
  • Bas-Rhin
    • Strasbourg, Bas-Rhin, France, 67098
      • C.H.U. de Strasbourg Hopital de Hautepierre ( Site 1203)
  • Haute-Garonne
    • Toulouse, Haute-Garonne, France, 31059
      • Institut Claudius Regaud ( Site 1200)
  • Île-de-France Region
    • Villejuif, Île-de-France Region, France, 94800
      • Gustave Roussy ( Site 1202)
• Hungary
  • Pest County
    • Budapest, Pest County, Hungary, 1122
      • Országos Onkológiai Intézet-Urogenitális Tumorok és Klinikai Farmakológiai Osztály ( Site 2301)
• Israel
  • Haifa, Israel, 3525408
    • Rambam MC ( Site 1500)
  • Jerusalem, Israel, 9112001
    • Hadassah Medical Center-Oncology ( Site 1504)
  • Petah Tikva, Israel, 4941492
    • Rabin Medical Center ( Site 1502)
  • Ramat Gan, Israel, 52621
    • Sheba Medical Center - Oncology Division ( Site 1501)
  • Tel Aviv, Israel, 6423906
    • Sourasky Medical Center ( Site 1503)
• Netherlands
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1066 CX
      • Nederlands Kanker Instituut - Antoni van Leeuwenhoek (NKI-AVL)-medical oncology ( Site 2402)
  • South Holland
    • Rotterdam, South Holland, Netherlands, 3015 GD
      • Erasmus Medisch Centrum ( Site 2401)
• New Zealand
  • Auckland, New Zealand, 1023
    • Auckland City Hospital ( Site 1700)
• Poland
  • Kuyavian-Pomeranian Voivodeship
    • Bydgoszcz, Kuyavian-Pomeranian Voivodeship, Poland, 85-796
      • Centrum Onkologii im. Prof. Franciszka Lukaszczyka-Ambulatorium Chemioterapii ( Site 2201)
  • Masovian Voivodeship
    • Warsaw, Masovian Voivodeship, Poland, 02-781
      • Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Oddzial Badan Wczesnych Faz ( Site 2200)
  • Pomeranian Voivodeship
    • Gdansk, Pomeranian Voivodeship, Poland, 80-952
      • Uniwersyteckie Centrum Kliniczne-Early Clinical Trials Unit ( Site 2202)
• South Korea
  • Seoul, South Korea, 03722
    • Severance Hospital ( Site 1802)
  • Seoul, South Korea, 06351
    • Samsung Medical Center ( Site 1801)
  • Seoul
    • Songpagu, Seoul, South Korea, 05505
      • Asan Medical Center ( Site 1800)
• Spain
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal ( Site 1301)
  • Catalonia
    • Barcelona, Catalonia, Spain, 08035
      • Hospital Universitari Vall d Hebron ( Site 1300)
• United Kingdom
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust ( Site 1400)
  • England
    • Southampton, England, United Kingdom, SO16 6YD
      • Southampton General Hospital ( Site 1403)
  • Glasgow City
    • Glasgow, Glasgow City, United Kingdom, G12 0YN
      • The Beatson West of Scotland Cancer Centre ( Site 1405)
  • Lancashire
    • Preston, Lancashire, United Kingdom, PR2 9HT
      • Royal Preston Hospital ( Site 1406)
  • Leicestershire
    • Leicester, Leicestershire, United Kingdom, LE1 5WW
      • Leicester Royal Infirmary ( Site 1408)
  • London, City of
    • London, London, City of, United Kingdom, EC1A 7BE
      • Barts Health NHS Trust ( Site 1401)
  • Midlothian
    • Edinburgh, Midlothian, United Kingdom, EH4 2XU
      • Western General Hospital ( Site 1402)
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 2TL
      • Velindre Cancer Centre Hospital ( Site 1407)
• United States
  • California
    • San Francisco, California, United States, 94158
      • University of California at San Francisco ( Site 1008)
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale-New Haven Hospital-Yale Cancer Center ( Site 1011)
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago ( Site 1013)
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa ( Site 1012)
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System ( Site 1014)
  • New York
    • New York, New York, United States, 10016
      • Laura and Isaac Perlmutter Cancer Center ( Site 1016)
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center ( Site 1002)
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Cancer Institute ( Site 1015)
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Cancer Center/Hillman Cancer Center ( Site 1017)
  • Texas
    • Dallas, Texas, United States, 75390
      • UTSW Medical Center ( Site 1003)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Has a histologically confirmed diagnosis of locally advanced/metastatic ccRCC
• Has received no prior systemic therapy for advanced RCC; prior neoadjuvant/adjuvant therapy for RCC is acceptable if completed ≥12 months before randomization/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 in hypertensive medications within 1 week before randomization/allocation
• Male participants are abstinent from heterosexual intercourse or agree to use contraception during treatment with and for at least 7 days after the last dose of lenvatinib 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, no contraception is needed
• Female participants must not be pregnant and not be a woman of childbearing potential (WOCBP) or is a WOCBP abstinent from heterosexual intercourse or using contraception during the intervention period and for at least 120 days after the last dose of pembrolizumab, pembrolizumab/quavonlimab, favezelimab/pembrolizumab for 30 days after the last dose of lenvatinib or belzutifan, whichever occurs last and must abstain from breastfeeding during the study intervention period and for at least 120 days after study intervention

Exclusion Criteria:

• Has urine protein ≥1 g/24 hours and has any of the following: (a) a pulse oximeter reading <92% at rest, or (b) requires intermittent supplemental oxygen, or (c) requires chronic supplemental oxygen (d) active hemoptysis within 3 weeks prior to the first dose of study intervention
• Has clinically significant cardiovascular disease within 12 months from the first dose 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 dose of 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 immunosuppressive therapy within 7 days prior to the first dose of study intervention
• Has 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 an active autoimmune disease that has required systemic treatment in the past 2 years; replacement therapy is not considered a form of systemic treatment and is allowed
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Coformulation Pembrolizumab/Quavonlimab + Lenvatinib; Participants will receive pembrolizumab/quavonlimab (coformulation of pembrolizumab 400 mg and quavonlimab 25 mg) PLUS lenvatinib 20 mg. Pembrolizumab/quavonlimab will be administered intravenously (IV) once every 6 weeks (Q6W) for up to 17 administrations (up to ~2 years). Lenvatinib will be administered orally once-daily (QD) until progressive disease or discontinuation.	Drug: Lenvatinib; Administered via oral capsule at a dose of 20 mg QD; Other Names: E7080; MK-7902; LENVIMA®; Biological: Pembrolizumab/Quavonlimab; Administered via IV infusion at a dose of 400 mg/25 mg Q6W; Other Names: MK-1308A
Experimental: Coformulation Favezelimab/Pembrolizumab+ Lenvatinib; Participants will receive favezelimab/pembrolizumab (coformulation of favezelimab 800 mg and pembrolizumab 200 mg) PLUS lenvatinib 20 mg. Favezelimab/Pembrolizumab will be administered IV once every 3 weeks (Q3W) for up to 35 administrations (up to ~2 years). Lenvatinib will be administered orally QD until progressive disease or discontinuation.	Drug: Lenvatinib; Administered via oral capsule at a dose of 20 mg QD; Other Names: E7080; MK-7902; LENVIMA®; Biological: Favezelimab/Pembrolizumab; Administered via IV infusion at a dose of 800 mg/200 mg Q3W; Other Names: MK-4280A
Experimental: Pembrolizumab + Belzutifan + Lenvatinib; Participants will receive pembrolizumab 400 mg PLUS belzutifan 120 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered IV Q6W for up to 17 administrations (up to ~2 years). Both belzutifan and lenvatinib will be administered orally QD until progressive disease or discontinuation.	Drug: Lenvatinib; Administered via oral capsule at a dose of 20 mg QD; Other Names: E7080; MK-7902; LENVIMA®; Biological: Pembrolizumab; Administered via IV infusion at a dose of 400 mg Q6W; Other Names: MK-3475; KEYTRUDA®; Drug: Belzutifan; Administered via oral tablet at a dose of 120 mg QD; Other Names: MK-6482; WELIREG™
Experimental: Pembrolizumab + Lenvatinib; Participants will receive pembrolizumab 400 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered IV Q6W for up to 17 administrations (up to ~ 2 years). Lenvatinib will be administered orally QD until progressive disease or discontinuation.	Drug: Lenvatinib; Administered via oral capsule at a dose of 20 mg QD; Other Names: E7080; MK-7902; LENVIMA®; Biological: Pembrolizumab; Administered via IV infusion at a dose of 400 mg Q6W; Other Names: MK-3475; KEYTRUDA®
Experimental: Coformulation Vibostolimab/Pembrolizumab+Belzutifan; Participants will receive vibostolimab/pembrolizumab (coformulation of 200 mg vibostolimab and pembrolizumab 200 mg). Vibostolimab/pembrolizumab will be administered IV once every 3 weeks (Q3W) for up to 35 administrations (up to ~2 years). Belzutifan will be administered orally QD until progressive disease or discontinuation.	Drug: Belzutifan; Administered via oral tablet at a dose of 120 mg QD; Other Names: MK-6482; WELIREG™; Drug: Vibostolimab/Pembrolizumab; Administered via IV infusion at a dose of 200 mg/200 mg Q6W; Other Names: MK-7684A

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Lead-in Phase: Number of participants who experience one or more dose-limiting toxicities (DLTs)	DLTs are defined as one or more of the following toxicities: (1) grade (gr) 4 nonhematologic toxicity (2) gr 4 hematologic toxicity lasting >7 days OR gr 4 platelet count decreased of any duration OR gr 3 platelet count decreased if associated with bleeding (3) gr 3 nonhematologic toxicity except gr 3 fatigue (lasting ≤3 days), diarrhea, nausea, vomiting or rash without standard of care (4) gr 3 or 4 nonhematologic abnormality if medical intervention is required or if it leads to hospitalization or persists for >1 week (5) gr 3 or 4 febrile neutropenia (6) gr 3 or 4 alanine aminotransferase, aspartate aminotransferase and/or bilirubin laboratory value (7) treatment related adverse event (AE) causing study intervention discontinuation during the first 21 days (8) treatment related AE causing intervention administration delay for >14 days during the first 21 days (9) gr 5 toxicity. The number of participants who experience one or more DLTs in the safety lead-in phase will be presented.	Up to ~21 days
Safety Lead-in Phase: Number of participants who experience one or more adverse events (AEs)	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experience one or more AEs in the safety lead-in phase will be presented.	Up to ~21 days
Safety Lead-in Phase: Number of participants who discontinue study treatment due to an AE	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who discontinue study treatment due to an AE in the safety lead-in phase will be presented.	Up to ~21 days
Efficacy Phase: Number of participants who experience one or more DLTs	DLTs are defined as one or more of the following toxicities: (1) grade (gr) 4 nonhematologic toxicity (2) gr 4 hematologic toxicity lasting >7 days OR gr 4 platelet count decreased of any duration OR gr 3 platelet count decreased if associated with bleeding (3) gr 3 nonhematologic toxicity except gr 3 fatigue (lasting ≤3 days), diarrhea, nausea, vomiting or rash without standard of care (4) gr 3 or 4 nonhematologic abnormality if medical intervention is required or if it leads to hospitalization or persists for >1 week (5) gr 3 or 4 febrile neutropenia (6) gr 3 or 4 alanine aminotransferase, aspartate aminotransferase and/or bilirubin laboratory value (7) treatment related adverse event (AE) causing study intervention discontinuation during the first 21 days (8) treatment related AE causing intervention administration delay for >14 days during the first 21 days (9) gr 5 toxicity. The number of participants who experience one or more DLTs in the efficacy phase will be presented.	Up to ~21 days
Efficacy Phase: Number of participants who experience one or more AEs	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experience one or more AEs in the efficacy phase will be presented.	Up to ~43 months
Efficacy Phase: Number of participants who discontinue study treatment due to an AE	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who discontinue study treatment due to an AE in the efficacy phase will be presented.	Up to ~43 months
Efficacy Phase: Objective response rate (ORR)	ORR is defined as the percentage of participants in the analysis population who have a complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters). Responses are according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR).	Up to ~43 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy Phase: Duration of response (DOR)	For participants in the analysis population who demonstrate a confirmed CR (disappearance of all target lesions) or confirmed PR (at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters), DOR is defined as the time from first documented evidence of CR or PR until progressive disease or death due to any cause, whichever occurs first. Responses are according to RECIST 1.1 by BICR.	Up to ~43 months
Efficacy Phase: Progression-free survival (PFS)	PFS is defined as the time from randomization to the first documented progressive disease or death due to any cause, whichever occurs first. Responses are according to RECIST 1.1 by BICR.	Up to ~43 months
Efficacy Phase: Overall survival (OS)	OS is defined as the time from randomization to death due to any cause.	Up to ~43 months
Efficacy Phase: Clinical benefit rate (CBR)	CBR is defined as the percentage of participants who have achieved CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters) or stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease) of ≥6 months. Responses are according to RECIST 1.1 by BICR.	Up to ~43 months

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Suarez C, Rojas C, Shin SJ, Yanez Weber P, Albiges L, Motzer R, Hammers H, Peer A, Lee JL, Miller WH, Waddell T, Neiman V, Keizman D, Zwenger Kloster A, Weickhardt A, Dziadziuszko R, Suttner L, Sharma M, Burgents JE, Powles T. Novel pembrolizumab-based treatments as first-line therapy in advanced clear-cell renal cell carcinoma: substudy 03A of the open-label, umbrella platform, phase I/II KEYMAKER-U03 trial. Ann Oncol. 2026 Feb;37(2):229-240. doi: 10.1016/j.annonc.2025.10.010. Epub 2025 Oct 18.

Helpful Links

• Merck Oncology Clinical Trials Information
• Plain Language Summary

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2020
• Primary Completion (Estimated): July 17, 2026
• Study Completion (Estimated): July 17, 2026

Study Registration Dates

• First Submitted: November 10, 2020
• First Submitted That Met QC Criteria: November 10, 2020
• First Posted (Actual): November 12, 2020

Study Record Updates

• Last Update Posted (Actual): May 18, 2026
• Last Update Submitted That Met QC Criteria: May 15, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: receptor tyrosine kinase inhibitor; programmed cell death 1 (PD-1, PD1); programmed cell death ligand 1 (PD-L1, PDL1)
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Urologic Neoplasms; Carcinoma; Kidney Neoplasms; Carcinoma, Renal Cell; Parkinson Disease 4, Autosomal Dominant Lewy Body; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; pembrolizumab; belzutifan; lenvatinib
• Other Study ID Numbers: 3475-03A; MK-3475-03A (Other Identifier: MSD); 2019-003609-84 (EudraCT Number); 2023-506838-68-00 (Registry Identifier: EU CT); U1111-1294-4527 (Registry Identifier: UTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No