Substudy 02B: Safety and Efficacy of Pembrolizumab in Combination With Investigational Agents or Pembrolizumab Alone in Participants With First Line (1L) Advanced Melanoma (MK-3475-02B/KEYMAKER-U02)

A Phase 1/2 Open-Label Rolling-Arm Umbrella Platform Design of Investigational Agents With or Without Pembrolizumab or Pembrolizumab Alone in Participants With Melanoma (KEYMAKER-U02): Substudy 02B

Substudy 02B is part of a larger research study where researchers are looking for new ways to treat advanced melanoma that has not been treated before. The larger study is the umbrella study. Researchers want to know if adding other treatments to pembrolizumab can treat advanced melanoma. The goals of this study are to learn:

• About the safety and how well people tolerate pembrolizumab given with other treatments
• How many people have melanoma that responds (gets smaller or goes away) to treatment

Study Overview

• Status: Completed
• Conditions: Melanoma
• Intervention / Treatment: Biological: Pembrolizumab; Biological: Pembrolizumab/Quavonlimab; Drug: Lenvatinib; Biological: Vibostolimab; Biological: Favezelimab/Pembrolizumab; Drug: ATRA

Detailed Description

With Amendment 6, all arms are closed to enrollment. Participants in arms 2 (pembrolizumab), 3 (coformulation pembrolizumab/quavonlimab), and 4 (coformulation pembrolizumab/quavonlimab + lenvatinib) who complete study treatment or otherwise meet end of treatment (EOT) criteria will be discontinued from the study after completing the EOT visit and any required safety follow-up visits. Participants in arm 6 (coformulation favezelimab/pembrolizumab + All-trans Retinoic Acid [ATRA]) will discontinue ATRA and participants in arms 5 and 6 can continue on coformulation favezelimab/pembrolizumab or pembrolizumab.

• Study Type: Interventional
• Enrollment (Actual): 335
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1187AAN
    • Sanatorio Finochietto ( Site 2245)
  • Buenos Aires
    • Caba., Buenos Aires, Argentina, C1430EGF
      • Clinica Adventista Belgrano-Oncology ( Site 2242)
  • Buenos Aires F.D.
    • Buenos Aires, Buenos Aires F.D., Argentina, 1426ANZ
      • Instituto Alexander Fleming-Alexander Fleming ( Site 2243)
• Australia
  • New South Wales
    • Waratah, New South Wales, Australia, 2298
      • Calvary Mater Newcastle-Medical Oncology ( Site 2404)
    • Wollstonecraft, New South Wales, Australia, 2065
      • Melanoma Institute Australia ( Site 2402)
  • Queensland
    • Southport, Queensland, Australia, 4120
      • Tasman Oncology Research Pty Ltd ( Site 2403)
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Fiona Stanley Hospital ( Site 2401)
• Chile
  • Araucania
    • Temuco, Araucania, Chile, 4810218
      • CIDO SpA-Oncology ( Site 2256)
  • Coquimbo Region
    • La Serena, Coquimbo Region, Chile, 1720430
      • IC La Serena Research ( Site 2254)
  • Region M. de Santiago
    • Santiago, Region M. de Santiago, Chile, 7500921
      • FALP-UIDO ( Site 2251)
    • Santiago, Region M. de Santiago, Chile, 7500994
      • Oncovida ( Site 2257)
    • Santiago, Region M. de Santiago, Chile, 8420383
      • Bradfordhill ( Site 2252)
• Colombia
  • Bogota D.C.
    • Bogotá, Bogota D.C., Colombia, 111321
      • Clinica Colsanitas S.A, Sede Clínica Universitaria Colombia-Center Investigator ( Site 2261)
  • Valle del Cauca Department
    • Cali, Valle del Cauca Department, Colombia, 760032
      • Fundación Valle del Lili ( Site 2265)
• France
  • Paris, France, 75010
    • A.P.H. Paris, Hopital Saint Louis ( Site 2107)
  • Bouches-du-Rhone
    • Marseille, Bouches-du-Rhone, France, 13005
      • Hopital La Timone ( Site 2103)
  • Gironde
    • Bordeaux, Gironde, France, 33075
      • CHU de Bordeaux- Hopital Saint Andre ( Site 2108)
  • Haute-Garonne
    • Toulouse, Haute-Garonne, France, 31059
      • Institut Claudius Regaud ( Site 2105)
  • Rhone
    • Pierre-Bénite, Rhone, France, 69495
      • C.H. Lyon Sud ( Site 2102)
  • Île-de-France Region
    • Villejuif, Île-de-France Region, France, 94805
      • Gustave Roussy ( Site 2101)
• Greece
  • Thessaloniki, Greece, 570 01
    • European Interbalkan Medical Center-Oncology Department ( Site 2211)
  • Attica
    • Athens, Attica, Greece, 115 26
      • General Hospital of Athens "Laiko"-First Department of Internal Medicine ( Site 2212)
• Hungary
  • Csongrád megye
    • Szeged, Csongrád megye, Hungary, 6720
      • Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ ( Site 2221)
• Israel
  • Afula, Israel, 1834111
    • HaEmek Medical Center ( Site 2703)
  • Haifa, Israel, 3109601
    • Rambam Health Care Campus-Oncology ( Site 2704)
  • Jerusalem, Israel, 9112001
    • Hadassah Ein Karem Jerusalem ( Site 2702)
  • Petah Tikva, Israel, 4941492
    • Rabin Medical Center-Oncology ( Site 2705)
  • Ramat Gan, Israel, 5265601
    • Chaim Sheba Medical Center ( Site 2701)
• Italy
  • Milan, Italy, 20133
    • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano ( Site 2399)
  • Milan, Italy, 20141
    • Istituto Europeo di Oncologia ( Site 2301)
  • Naples, Italy, 80131
    • Istituto Nazionale Tumori Fondazione Pascale ( Site 2302)
  • Padova, Italy, 35128
    • Istituto Oncologico Veneto IRCCS ( Site 2355)
  • Siena, Italy, 53100
    • Policlinico Le Scotte - A.O. Senese ( Site 2377)
• Poland
  • Masovian Voivodeship
    • Warsaw, Masovian Voivodeship, Poland, 02-781
      • Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy w Warszawie ( Site 2233)
  • Pomeranian Voivodeship
    • Gdansk, Pomeranian Voivodeship, Poland, 80-952
      • Uniwersyteckie Centrum Kliniczne-Early Clinical Trials Unit ( Site 2231)
• South Africa
  • Eastern Cape
    • Port Elizabeth, Eastern Cape, South Africa, 6055
      • CANCERCARE LANGENHOVEN DRIVE ONCOLOGY CENTRE ( Site 2865)
  • Gauteng
    • Pretoria, Gauteng, South Africa, 0181
      • LIFE GROENKLOOF-Mary Potter Cancer Centre ( Site 2861)
    • Pretoria, Gauteng, South Africa, 0002
      • Steve Biko Academic Hospital-Medical Oncology ( Site 2862)
    • Sandton, Gauteng, South Africa, 2196
      • Sandton Oncology Medical Group (Pty) Ltd-Research ( Site 2863)
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7570
      • Cape Town Oncology Trials ( Site 2864)
• Spain
  • Catalonia
    • Barcelona, Catalonia, Spain, 08036
      • HOSPITAL CLÍNIC DE BARCELONA-ICHMO- Clinic Institut of Haematological and Oncological diseases ( Site 2801)
  • Madrid, Comunidad de
    • Madrid, Madrid, Comunidad de, Spain, 28034
      • Hospital Universitario Ramón y Cajal ( Site 2802)
• Switzerland
  • Canton of Geneva
    • Geneva, Canton of Geneva, Switzerland, 1211
      • Hôpitaux Universitaires de Genève (HUG)-Oncology ( Site 2603)
  • Canton of Vaud
    • Lausanne, Canton of Vaud, Switzerland, 1011
      • CHUV Centre Hospitalier Universitaire Vaudois ( Site 2602)
  • Canton of Zurich
    • Zuerich Flughafen, Canton of Zurich, Switzerland, 8058
      • Universitaetsspital Zuerich ( Site 2601)
• United States
  • California
    • Los Angeles, California, United States, 90025
      • The Angeles Clinic and Research Institute ( Site 2009)
    • Los Angeles, California, United States, 90095
      • UCLA Hematology & Oncology ( Site 2004)
    • Santa Monica, California, United States, 90404
      • Providence Saint John's Health Center ( Site 2010)
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado, Anschutz Cancer Pavilion ( Site 2012)
  • Florida
    • Gainesville, Florida, United States, 32608
      • University of Florida College of Medicine-UF Health Cancer Center/Clinical Trials Office ( Site 2026)
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins ( Site 2022)
  • New York
    • Lake Success, New York, United States, 11042
      • R.J. Zuckerberg Cancer Center ( Site 2032)
    • New York, New York, United States, 10016
      • NYU Clinical Cancer Center ( Site 2002)
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Cancer Institute ( Site 2005)
  • Ohio
    • Columbus, Ohio, United States, 43221
      • Martha Morehouse Tower ( Site 2020)
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University ( Site 2013)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Abramson Cancer Center ( Site 2008)
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • West Cancer Center - East Campus ( Site 2014)
  • Texas
    • San Antonio, Texas, United States, 78229
      • Mays Cancer Center ( Site 2025)
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Inova Schar Cancer Institute ( Site 2011)

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Has histologically or cytologically confirmed melanoma
• Has unresectable Stage III or Stage IV melanoma, not amenable to local therapy
• Has been untreated for advanced disease.
• Has provided a tumor biopsy

• If capable of producing sperm, male participants agree to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention (7 days):

  • Abstains from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent OR
  • Uses contraception unless confirmed to be azoospermic

• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:

  • Is not a WOCBP OR
  • Is a WOCBP and Uses a contraceptive method that is highly effective, with low user dependency, or be abstinent from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is:
  • MK-4280A: 120 days
  • MK-1308A: 120 days
  • MK-7684: 50 days
  • MK-3475: 120 days
  • Lenvatinib: 30 days
  • ATRA: 30 days
• Has adequate organ function
• Has resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia and Grade 2 neuropathy)

Exclusion Criteria:

• Has a diagnosis of immunodeficiency or is receiving immunosuppressive therapy within 7 days before the first dose of study intervention
• Has a known additional malignancy that is progressing or requires active treatment within the past 2 years
• Has known central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has ocular or mucosal melanoma
• Has an active autoimmune disease that has required systemic treatment in the past 2 years
• Has an active infection requiring systemic therapy
• Has known history of human immunodeficiency virus (HIV)
• Has history of Hepatitis B or known Hepatitis C virus infection
• Has a history of (noninfectious) pneumonitis
• Has a history of active tuberculosis (TB)
• Has received prior systemic anticancer therapy within 4 weeks prior to randomization
• Has received prior radiotherapy within 2 weeks of first dose of study intervention
• Has had major surgery <3 weeks prior to first dose of study intervention
• Has received a live vaccine within 30 days before the first dose of study intervention
• Has participated in a study of an investigational agent within 4 weeks prior to the first dose of study intervention
• Has had an allogeneic tissue/solid organ transplant
• Has a known psychiatric or substance abuse disorder that would interfere with requirements of the study

• Participants who receive lenvatinib have the following additional exclusion criteria:

  • Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula
  • Has radiographic evidence of encasement of invasion of a major blood vessel, or of intratumoral cavitation
  • Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study intervention
  • Has clinically significant cardiovascular disease within 12 months from first dose of study intervention
  • Has urine protein ≥1 g/24-hour.
  • Has presence of gastrointestinal condition including malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib

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

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pembrolizumab + Vibostolimab; Participants will receive pembrolizumab intravenously (IV) plus vibostolimab IV at specified doses on specified days for a total treatment duration of up to approximately 2 years.	Biological: Pembrolizumab; Administered via IV infusion at a specified dose on specified days; Other Names: MK-3475; KEYTRUDA®; Biological: Vibostolimab; Administered via IV infusion at a specified dose on specified days; Other Names: MK-7684
Active Comparator: Pembrolizumab; Participants will receive pembrolizumab IV at a specified dose on specified days for a total treatment duration of up to approximately 2 years.	Biological: Pembrolizumab; Administered via IV infusion at a specified dose on specified days; Other Names: MK-3475; KEYTRUDA®
Experimental: Coformulation Pembrolizumab/Quavonlimab; Participants will receive coformulation of pembrolizumab and quavonlimab (MK-1308A) IV at a specified dose on specified days for a total treatment duration of up to approximately 2 years.	Biological: Pembrolizumab; Administered via IV infusion at a specified dose on specified days; Other Names: MK-3475; KEYTRUDA®; Biological: Pembrolizumab/Quavonlimab; Administered via IV infusion at a specified dose on specified days; Other Names: MK-1308A
Experimental: Coformulation Pembrolizumab/Quavonlimab + Lenvatinib; Participants will receive coformulation of pembrolizumab and quavonlimab IV plus lenvatinib orally at specified doses on specified days for a total treatment duration of up to approximately 2 years.	Biological: Pembrolizumab; Administered via IV infusion at a specified dose on specified days; Other Names: MK-3475; KEYTRUDA®; Biological: Pembrolizumab/Quavonlimab; Administered via IV infusion at a specified dose on specified days; Other Names: MK-1308A; Drug: Lenvatinib; Administered via oral capsule at a specified dose on specified days; Other Names: E7080; MK-7902; LENVIMA®
Experimental: Coformulation Favezelimab/Pembrolizumab; Participants will receive cofomulation of favezelimab + pembrolizumab (MK-4280A) IV at specified dose on specified days every 3 weeks (Q3W) for up to approximately 2 years	Biological: Favezelimab/Pembrolizumab; Administered via IV infusion at a specified dose on specified days; Other Names: MK-4280A
Experimental: Coformulation Favezelimab/Pembrolizumab + All-trans Retinoic Acid (ATRA); Participants will receive coformulation of favezelimab and pembrolizumab IV Q3W for up to 35 cycles, plus ATRA orally (for 3 days surrounding each infusion of MK-4280A, including Days 1, 2, and 3 of Cycle 1 and on Days -1, 1, and 2 of all subsequent cycles).	Drug: ATRA; Administered via oral capsule at a specified dose on specified days
Experimental: Coformulation Favezelimab/Pembrolizumab + Vibostolimab; Participants will receive coformulation of favezelimab and pembrolizumab (MK-4280A) IV and vibostolimab IV at specified doses on specified days for a total treatment duration of up to approximately 2 years.	Biological: Vibostolimab; Administered via IV infusion at a specified dose on specified days; Other Names: MK-7684; Biological: Favezelimab/Pembrolizumab; Administered via IV infusion at a specified dose on specified days; Other Names: MK-4280A

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of participants who experience an adverse event (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 percentage of participants who experience an AE will be reported.	Up to ~28 months
Percentage 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 percentage of participants who discontinue study treatment due to an AE will be reported.	Up to ~24 months
Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1)	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 RECIST 1.1 as assessed by blinded independent central review (BICR). RECIST 1.1 has been modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.	Up to ~30 months
Percentage of participants who experience a dose-limiting toxicity (DLT): Safety lead-in phase	The percentage of participants who experience 1 or more protocol-defined DLTs during the safety lead-in period will be reported.	Up to ~3 weeks
Percentage of participants who experience an adverse event (AE): Safety lead-in	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 percentage of participants who experience an AE during the safety lead-in period will be reported.	Up to ~3 weeks
Percentage of participants who discontinue study treatment due to an AE: Safety lead-in	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 percentage of participants who discontinue study treatment due to an AE during the safety lead-in will be reported.	Up to ~3 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response (DOR) per RECIST 1.1	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 (PD) or death due to any cause, whichever occurs first. Responses are according to RECIST 1.1 as assessed by BICR. RECIST 1.1 has been modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.	Up to ~30 months

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• Merck Clinical Trials Information
• Plain Language Summary

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2020
• Primary Completion (Actual): May 18, 2026
• Study Completion (Actual): May 18, 2026

Study Registration Dates

• First Submitted: March 9, 2020
• First Submitted That Met QC Criteria: March 9, 2020
• First Posted (Actual): March 12, 2020

Study Record Updates

• Last Update Posted (Actual): May 28, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: programmed cell death 1 (PD-1, PD1); programmed cell death ligand 1 (PD-L1, PDL1); T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine receptor motif domains (TIGIT); Cytotoxic T lymphocyte associated protein 4 (CTLA4)
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Skin and Connective Tissue Diseases; Melanoma; Parkinson Disease 4, Autosomal Dominant Lewy Body; Diabetes Mellitus, Insulin-Dependent, 12; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; pembrolizumab; lenvatinib
• Other Study ID Numbers: 3475-02B; KEYMAKER-U02 (Other Identifier: MSD); MK-3475-02B (Other Identifier: MSD); 2019-003977-24 (EudraCT Number); U1111-1293-5644 (Registry Identifier: UTN); 2023-506313-21-00 (Registry Identifier: EU CT)

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