Pembrolizumab Plus Lenvatinib for First-line Advanced/Metastatic Non-clear Cell Renal Cell Carcinoma (1L nccRCC) (MK-3475-B61) (KEYNOTE-B61)

A Phase 2, Single-arm, Open-label Clinical Trial of Pembrolizumab Plus Lenvatinib in Participants With First-line Advanced/Metastatic Non-clear Cell Renal Cell Carcinoma (nccRCC) (KEYNOTE-B61)

This study is being performed as a single-arm open-label study in order to rapidly provide information on the potential benefits of the combination of pembrolizumab and lenvatinib in participants with previously untreated advanced/metastatic non-clear cell renal cell carcinoma.

Study Overview

• Status: Completed
• Conditions: Renal Cell Carcinoma
• Intervention / Treatment: Biological: Pembrolizumab; Drug: Lenvatinib

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Macquarie Park, New South Wales, Australia, 2109
      • Macquarie University-MQ Health Clinical Trials Unit ( Site 0405)
    • Waratah, New South Wales, Australia, 2298
      • Calvary Mater Newcastle ( Site 0403)
  • Queensland
    • Brisbane, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital-Medical Oncology Clinical Trials Unit, Cancer Care Services ( Si
  • South Australia
    • Kurralta Park, South Australia, Australia, 5037
      • Ashford Cancer Centre Research ( Site 0404)
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Health ( Site 0400)
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Fiona Stanley Hospital ( Site 0402)
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BC Cancer Vancouver-Clinical Trials Unit ( Site 1500)
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre ( Site 1501)
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre ( Site 1504)
  • Quebec
    • Québec, Quebec, Canada, G1R 3S1
      • CHU de Quebec - Université Laval - Hotel Dieu de Quebec ( Site 1502)
• France
  • Alsace
    • Strasbourg, Alsace, France, 67200
      • Institut de cancérologie Strasbourg Europe (ICANS) ( Site 1007)
  • Calvados
    • Caen, Calvados, France, 14076
      • Centre François Baclesse ( Site 1000)
  • Languedoc-Roussillon
    • Montpellier, Languedoc-Roussillon, France, 34070
      • Centre de Cancérologie du Grand Montpellier ( Site 1005)
  • Rhone
    • Pierre-Bénite, Rhone, France, 69310
      • centre hospitalier lyon sud ( Site 1003)
  • Val-de-Marne
    • Villejuif, Val-de-Marne, France, 94800
      • Gustave Roussy ( Site 1002)
• Hungary
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem Klinikai Kozpont-Onkológiai Klinika ( Site 0300)
  • Borsod-Abauj Zemplen county
    • Miskolc, Borsod-Abauj Zemplen county, Hungary, 3526
      • Borsod-Abaúj-Zemplén Megyei Központi Kórház és Egyetemi Okta-Klinikai Onkológiai és Sugárterápiás C
  • Jász-Nagykun-Szolnok
    • Szolnok, Jász-Nagykun-Szolnok, Hungary, 5000
      • Jász-Nagykun-Szolnok Megyei Hetényi Géza Kórház-Onkologiai Kozpont ( Site 0303)
  • Pest County
    • Budapest, Pest County, Hungary, 1122
      • Országos Onkológiai Intézet-Urogenital Tumors Department and Clinical Pharmacology ( Site 0304)
• Ireland
  • Dublin, Ireland, D24 NR0A
    • Tallaght University Hospital ( Site 1600)
• Italy
  • Terni, Italy, 05100
    • Azienda Ospedaliera Santa Maria Terni-SC Oncologia ( Site 0900)
  • Lazio
    • Rome, Lazio, Italy, 00168
      • Fondazione Policlinico Universitario Agostino Gemelli-Medical Oncology ( Site 0901)
  • Lombardy
    • Milan, Lombardy, Italy, 20133
      • Fondazione IRCCS Istituto Nazionale dei Tumori-Struttura Complessa Oncologia Medica 1 ( Site 0903)
  • Veneto
    • Verona, Veneto, Italy, 37134
      • Azienda Ospedaliera Universitaria Integrata Verona - Ospedale Borgo Roma-Oncology Unit ( Site 0902)
• Poland
  • Greater Poland Voivodeship
    • Poznan, Greater Poland Voivodeship, Poland, 60-569
      • Szpital Kliniczny im. Przemienienia Panskiego Uniwersytetu M-chemotherapy department ( Site 0800)
  • Masovian Voivodeship
    • Warsaw, Masovian Voivodeship, Poland, 02-781
      • Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy w Warszawie (
    • Warsaw, Masovian Voivodeship, Poland, 01-748
      • Luxmed Onkologia sp. z o. o. ( Site 0802)
• Russia
  • Saint Petersburg, Russia, 188663
    • SHBI Leningrad Regional Clinical Oncology Dispensary-Clinical Trials Department ( Site 0607)
  • Moscow
    • Moscow, Moscow, Russia, 117485
      • Russian Scientific Center of Radiology-Russian Scientific Center of Radiology ( Site 0602)
  • Nizhny Novgorod Oblast
    • Nizhny Novgorod, Nizhny Novgorod Oblast, Russia, 603074
      • Volga District Medical Center-Urology Department ( Site 0604)
    • Nizhny Novgorod, Nizhny Novgorod Oblast, Russia, 603081
      • Nizhegorodsky Regional Oncology Dispensary, Branch #2-chemotherapy ( Site 0605)
• South Korea
  • Seoul, South Korea, 06351
    • Samsung Medical Center ( Site 1301)
  • Seoul, South Korea, 03722
    • Severance Hospital, Yonsei University Health System-Medical oncology ( Site 1302)
  • Seoul, South Korea, 05505
    • Asan Medical Center-Department of Oncology ( Site 1300)
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron-Departamento de Oncologia- VHIO ( Site 0201)
  • Madrid, Comunidad de
    • Madrid, Madrid, Comunidad de, Spain, 28034
      • Hospital Universitario Ramón y Cajal-Medical Oncology ( Site 0200)
  • Valenciana, Comunitat
    • Valencia, Valenciana, Comunitat, Spain, 46009
      • Fundación Instituto Valenciano de Oncología-Oncologico ( Site 0202)
• Turkey (Türkiye)
  • Ankara, Turkey (Türkiye), 06100
    • Ankara University Hospital Cebeci ( Site 1105)
  • Ankara, Turkey (Türkiye), 06230
    • Hacettepe Universitesi-oncology hospital ( Site 1101)
  • Istanbul, Turkey (Türkiye), 34722
    • Göztepe Prof. Dr. Süleyman Yalçın Şehir Hastanesi-oncology ( Site 1103)
  • Istanbul
    • Istanbul- Fatih, Istanbul, Turkey (Türkiye), 34098
      • Istanbul Universitesi Cerrahpasa ( Site 1104)
  • İzmir
    • Bornova, İzmir, Turkey (Türkiye), 35100
      • Ege University Medicine of Faculty ( Site 1102)
• Ukraine
  • Cherkasy Oblast
    • Cherkassy, Cherkasy Oblast, Ukraine, 18009
      • Cherkasy Regional Oncology Dispensary ( Site 0504)
  • Chernihiv Oblast
    • Chernihiv, Chernihiv Oblast, Ukraine, 14029
      • Chernihiv Medical Center of Modern Oncology ( Site 0509)
  • Dnipropetrovsk Oblast
    • Dnipro, Dnipropetrovsk Oblast, Ukraine, 49005
      • Dnepropetrovsk Regional Clinical Hospital Mechnikov-Department of urology ( Site 0508)
  • Kharkivs’ka Oblast’
    • Kharkiv, Kharkivs’ka Oblast’, Ukraine, 61070
      • CNPE "Regional Center of Oncology"-oncourology department ( Site 0502)
• United Kingdom
  • Manchester, United Kingdom, M20 4BX
    • The Christie ( Site 1205)
  • England
    • Cambridge, England, United Kingdom, CB2 0QQ
      • Cambridge University Hospital ( Site 1200)
• United States
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • Georgetown University Medical Center ( Site 0001)
  • Montana
    • Billings, Montana, United States, 59102
      • St. Vincent Frontier Cancer Center ( Site 0004)
  • Nevada
    • Las Vegas, Nevada, United States, 89169
      • Comprehensive Cancer Centers of Nevada ( Site 0010)
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center ( Site 0015)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center ( Site 0011)
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center ( Site 0008)
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance ( Site 0014)
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • MEDICAL COLLEGE OF WISCONSIN ( Site 0006)

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Must have a histologically confirmed diagnosis of nccRCC.
2. Has locally advanced/metastatic disease (ie, Stage IV per the American Joint Committee on Cancer).
3. Has received no prior systemic therapy for advanced nccRCC. Note: Prior neoadjuvant/adjuvant therapy for nccRCC is acceptable if completed >12 months prior to allocation.
4. Male participants agree to use approved contraception during the treatment period for at least 7 days after the last dose of study medication, or refrain from heterosexual intercourse during this period.
5. Female participants are not pregnant or breastfeeding, and are not a woman of childbearing potential (WOCBP), OR are a WOCBP that agrees to use contraception during the treatment period and for at least 120 days post pembrolizumab, or 30 days post lenvatinib, whichever occurs last.
6. Has measurable disease per RECIST 1.1 as assessed by BICR. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
7. Has submitted an archival tumor tissue sample or newly obtained core or incisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
8. Has Karnofsky Performance Status (KPS) ≥70% as assessed within 10 days prior to the start of study intervention.
9. Has adequately controlled blood pressure with or without antihypertensive medications
10. Have adequate organ function.

Exclusion Criteria:

1. Has collecting duct histology.
2. A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study intervention.
3. Has a left ventricular ejection fraction below the institutional (or local laboratory) normal range.
4. Has radiographic encasement or invasion of a major blood vessel, or of intratumoral cavitation.
5. Has clinically significant cardiovascular disease within 12 months from first dose of study intervention.
6. Has gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib.
7. Has active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug.
8. Has had major surgery within 3 weeks prior to first dose of study intervention.
9. Has received prior therapy with an anti-programmed cell-death 1 (PD-1), anti-programmed cell-death ligand 1 (PD-L1), or anti-programmed cell-death ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137).
10. Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to allocation.
11. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
12. Has received a live or attenuated vaccine within 30 days before the first dose of study intervention.
13. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
14. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention.

15. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.

    Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.

16. Has known active CNS metastases and/or carcinomatous meningitis.
17. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, lenvatinib and/or any of their excipients.
18. Has an active autoimmune disease that has required systemic treatment in past 2 years
19. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
20. Has an active infection requiring systemic therapy.
21. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
22. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus.
23. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
24. Has had an allogenic tissue/solid organ transplant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pembrolizumab + Lenvatinib; Pembrolizumab 400 mg, every 6 weeks (Q6W) intravenous (IV) up to 18 infusions or up to progressive disease or discontinuation PLUS Lenvatinib 20 mg, daily (QD), oral, until progressive disease or discontinuation.	Biological: Pembrolizumab; Pembrolizumab 400 mg, every 6 weeks (Q6W) intravenous (IV) up to 18 infusions or up to progressive disease or discontinuation.; Other Names: MK-3475; KEYTRUDA®; Drug: Lenvatinib; Lenvatinib 20 mg, daily (QD), oral, until progressive disease or discontinuation.; Other Names: E7080; MK-7902; LENVIMA®; Kisplyx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR was defined as the percentage of participants who had a best overall response of either 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 as assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). The percentage of participants who experienced a CR or PR as assessed per RECIST 1.1 by blinded independent central review (BICR) is presented.	Up to approximately 47 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response (DOR)	For participants who demonstrate a confirmed 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) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), DOR was defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. Duration of response per RECIST 1.1 by Blinded Independent Central Review (BICR) is presented.	Up to approximately 47 months
Progression Free Survival (PFS)	PFS was defined as the time from date of study treatment to the first documented progressive disease (PD) based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The percentage of participants who experienced PFS per RECIST 1.1 by Blinded Independent Central Review (BICR) is presented.	Up to approximately 47 months
Overall Survival (OS)	OS was defined as the time from the date of study treatment to the date of death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. The OS for all participants is presented.	Up to approximately 47 months
Clinical Benefit Rate (CBR)	CBR is defined as the percentage of participants who have achieved 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 or Stable Disease (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm]) of ≥6 months per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR).	Up to approximately 47 months
Disease Control Rate (DCR)	DCR was defined per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as the percentage of participants 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) or Stable Disease (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm]). The appearance of one or more new lesions is also considered PD]). Disease Control rate per RECIST 1.1 by Blinded Independent Central Review (BICR) is presented.	Up to approximately 47 months
Number of Participants With One or More Adverse Events (AEs)	An AE was defined as 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants with at least one or more AE is presented.	Up to approximately 56 months
Number of Participants Who Discontinued From Study Treatment Due to an AE	An AE was defined as 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants with at least one or more AE is presented.	Up to approximately 56 months

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Collaborators: Eisai Inc.
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Albiges L, Gurney H, Atduev V, Suarez C, Climent MA, Pook D, Tomczak P, Barthelemy P, Lee JL, Stus V, Ferguson T, Wiechno P, Gokmen E, Lacombe L, Gedye C, Perini RF, Sharma M, Peng X, Lee CH. Pembrolizumab plus lenvatinib as first-line therapy for advanced non-clear-cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2023 Aug;24(8):881-891. doi: 10.1016/S1470-2045(23)00276-0. Epub 2023 Jul 11.
• Voss MH, Gurney H, Atduev V, Suarez C, Climent MA, Pook D, Tomczak P, Barthelemy P, Lee JL, Nalbandian T, Stus V, Ferguson T, Wiechno P, Gokmen E, Lacombe L, Gedye C, Cornell J, Sharma M, Burgents JE, Albiges L. First-line Pembrolizumab Plus Lenvatinib for Advanced Non-clear-cell Renal Cell Carcinoma: Updated Results from the Phase 2 KEYNOTE-B61 Trial. Eur Urol. 2025 Jul 23:S0302-2838(25)00297-0. doi: 10.1016/j.eururo.2025.05.019. Online ahead of print.

Helpful Links

• Merck Clinical Trials Information
• Plain Language Summary

Study record dates

Study Major Dates

• Study Start (Actual): February 23, 2021
• Primary Completion (Actual): January 27, 2025
• Study Completion (Actual): October 21, 2025

Study Registration Dates

• First Submitted: January 7, 2021
• First Submitted That Met QC Criteria: January 7, 2021
• First Posted (Actual): January 11, 2021

Study Record Updates

• Last Update Posted (Estimated): December 3, 2025
• Last Update Submitted That Met QC Criteria: November 19, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Pembrolizumab; Lenvatinib; Programmed Cell Death-1 (PD1, PD-1); Programmed Death-Ligand 1 (PDL1, PD-L1)
• 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; lenvatinib
• Other Study ID Numbers: 3475-B61; MK-3475-B61 (Other Identifier: MSD); 2020-004087-26 (EudraCT Number); 2023-504944-32-00 (Registry Identifier: EU CT); U1111-1290-4553 (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