A Clinical Study of Belzutifan (MK-6482) and Zanzalintinib in People With Renal Cell Carcinoma (RCC) (LITESPARK-034/LS-034/MK-6482-034)

A Phase 3, Randomized, Double-blind, Study of Belzutifan + Zanzalintinib Versus Belzutifan + Placebo in Participants With Advanced RCC Who Have Progressed on or After Both PD-1/L1 and VEGF-TKI Therapies in Sequence or in Combination (LITESPARK-034)

Researchers are looking for new ways to treat advanced renal cell carcinoma (RCC).

A standard (usual) treatment for certain people with RCC is belzutifan (a study medicine), which is a targeted therapy. Targeted therapy is a treatment that works to control how specific types of cancer cells grow and spread. Researchers want to learn if adding another targeted therapy called zanzalintinib (another study medicine) can treat more people with advanced RCC than belzutifan alone.

The goal of this study is to learn if people who receive belzutifan and zanzalintinib live longer overall and without the cancer getting worse compared to people who receive belzutifan and placebo.

Study Overview

• Status: Recruiting
• Conditions: Carcinoma, Renal Cell
• Intervention / Treatment: Drug: Belzutifan; Drug: Zanzalintinib; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 758
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Toll Free Number; Phone Number: 1-888-577-8839; Email: Trialsites@msd.com

Study Locations

• Argentina
  • La Rioja, Argentina, X5004BAL
    • Recruiting
    • Centro Oncológico Riojano Integral ( Site 0256)
    • Contact: Study Coordinator; Phone Number: +543804436443X108
  • Buenos Aires
    • CABA, Buenos Aires, Argentina, C1426AHB
      • Recruiting
      • Centro Oncologico Korben ( Site 0254)
      • Contact: Study Coordinator; Phone Number: +541159507952
    • Mar del Plata, Buenos Aires, Argentina, B7600FZO
      • Recruiting
      • Instituto de Investigaciones Clinicas Mar del Plata ( Site 0250)
      • Contact: Study Coordinator; Phone Number: +542234963224
  • Córdoba Province
    • Río Cuarto, Córdoba Province, Argentina, X5800ALB
      • Recruiting
      • Centro Privado de RMI Río Cuarto S.A. II ( Site 0255)
      • Contact: Study Coordinator; Phone Number: +543584620273
  • Santa Fe Province
    • Rosario, Santa Fe Province, Argentina, S2000DSV
      • Recruiting
      • Sanatorio Parque ( Site 0251)
      • Contact: Study Coordinator; Phone Number: +5493416955611
• Australia
  • New South Wales
    • Macquarie University, New South Wales, Australia, 2109
      • Suspended
      • Macquarie University ( Site 2700)
• Czechia
  • Brno-mesto
    • Brno, Brno-mesto, Czechia, 656 53
      • Recruiting
      • Masarykuv onkologicky ustav ( Site 0903)
      • Contact: Study Coordinator; Phone Number: +420543132216
• Denmark
  • Capital Region
    • Herlev, Capital Region, Denmark, 2730
      • Recruiting
      • Herlev Hospital ( Site 1002)
      • Contact: Study Coordinator; Phone Number: 00 45 38689191
  • Central Jutland
    • Aarhus, Central Jutland, Denmark, 8200
      • Recruiting
      • Aarhus Universitetshospital, Skejby ( Site 1001)
      • Contact: Study Coordinator; Phone Number: +4591167472
• Greece
  • Attica
    • Athens, Attica, Greece, 185 47
      • Recruiting
      • Metropolitan Hospital ( Site 1402)
      • Contact: Study Coordinator; Phone Number: +302104809667
• Israel
  • Haifa, Israel, 3109601
    • Recruiting
    • Rambam Health Care Campus ( Site 1600)
    • Contact: Study Coordinator; Phone Number: +97247772688
  • Petah Tikva, Israel, 4941492
    • Recruiting
    • Rabin Medical Center ( Site 1602)
    • Contact: Study Coordinator; Phone Number: 97239378074
  • Ramat Gan, Israel, 5265601
    • Recruiting
    • Sheba Medical Center ( Site 1601)
    • Contact: Study Coordinator; Phone Number: 97235303030
• Netherlands
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1066 CX
      • Recruiting
      • Nederlands Kanker Instituut Antoni van Leeuwenhoek (NKI AVL) ( Site 1900)
      • Contact: Study Coordinator; Phone Number: +3120 512 9111
• Poland
  • Greater Poland Voivodeship
    • Skórzewo, Greater Poland Voivodeship, Poland, 60-185
      • Recruiting
      • AIDPORT Sp. z o.o. ( Site 2118)
      • Contact: Study Coordinator; Phone Number: +48570783100
  • Masovian Voivodeship
    • Warsaw, Masovian Voivodeship, Poland, 02-172
      • Recruiting
      • MTZ Clinical Research Powered by Pratia ( Site 2107)
      • Contact: Study Coordinator; Phone Number: +48225725959
• South Korea
  • Seoul, South Korea, 05505
    • Recruiting
    • Asan Medical Center ( Site 2901)
    • Contact: Study Coordinator; Phone Number: +82-2-3010-5977
  • Seoul, South Korea, 06351
    • Recruiting
    • Samsung Medical Center ( Site 2902)
    • Contact: Study Coordinator; Phone Number: +82-2-3410-1767
  • Seoul, South Korea, 03722
    • Recruiting
    • Severance Hospital, Yonsei University Health System ( Site 2903)
    • Contact: Study Coordinator; Phone Number: +82-2-2228-8138
• Spain
  • Madrid, Comunidad de
    • Madrid, Madrid, Comunidad de, Spain, 28007
      • Recruiting
      • HOSPITAL GENERAL UNIVERSITARIO GREGORIO MARAÑON ( Site 2301)
      • Contact: Study Coordinator; Phone Number: +34914269393

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

• Has a histologically confirmed diagnosis of unresectable, advanced renal cell carcinoma (RCC) with clear cell component (with or without sarcomatoid features) ie, Stage IV RCC per American Joint Committee on Cancer (8th Edition)
• Has measurable disease per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1)
• Has received no more than 3 prior systemic regimens for RCC, including only 1 prior anti-Programmed Cell Death-1/Programmed Cell Death 1 Ligand 1 therapy

Exclusion Criteria:

For exclusion criteria: The main exclusion criteria include but are not limited to the following:

• Has any of the following: a pulse oximeter reading <92% at rest, requires intermittent supplemental oxygen, or required chronic supplemental oxygen
• Has clinically significant cardiovascular disease within 12 months from first dose of study intervention
• Has deep vein thrombosis within 3 months before randomization unless stable, asymptomatic, and treated with therapeutic anticoagulation for at least 4 weeks before randomization
• Has a left ventricular ejection fraction ≤50% or below the institutional (or local laboratory) normal range as determined by multigated acquisition or echocardiogram
• Has had major surgery within 8 weeks before randomization
• Has current pneumonitis/interstitial lung disease
• Has a history of human immunodeficiency virus infection
• Has Hepatitis B or Hepatitis C virus infection
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
• Has a history of solid organ transplant
• Has not adequately recovered from major surgery or has ongoing surgical complications

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Belzutifan + Zanzalintinib; Participants will receive 120 mg belzutifan orally and 60 mg zanzalintinib once daily for approximately 24 months.	Drug: Belzutifan; Tablet for oral administration.; Other Names: MK-6482; PT2977; WELIREG; Drug: Zanzalintinib; Tablet for oral administration.; Other Names: XL092
Active Comparator: Belzutifan + Placebo; Participants will receive 120 mg belzutifan orally and zanzalintinib-matching placebo once daily for approximately 24 months.	Drug: Belzutifan; Tablet for oral administration.; Other Names: MK-6482; PT2977; WELIREG; Drug: Placebo; Zanzalintinib-matching placebo tablet for oral administration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS)	PFS is defined as the time from randomization to the first documented disease progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) based on blinded independent central review (BICR) or death due to any cause, whichever occurs first.	Up to approximately 30 months
Overall Survival (OS)	OS is defined as the time from randomization to death due to any cause.	Up to approximately 50 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR is defined as the percentage of participants who have achieved confirmed Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by BICR.	Up to approximately 30 months
Duration of Response (DOR)	DOR is defined as the interval from the first documented evidence of a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 until Progressive Disease (PD) or death due to any cause, whichever occurs first, in participants demonstrating a best confirmed response of CR or PR. 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.	Up to approximately 30 months
Number of Participants Who Experience One or More Adverse Events (AEs)	An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. The number of participants who experience an AE will be reported.	Up to approximately 25 months
Number of Participants who Discontinue Study Treatment Due to an AE	An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. The number of participants who discontinue study treatment due to an AE will be reported.	Up to approximately 24 months
Change from Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score	EORTC QLQ-C30 is a questionnaire to assess the overall quality of life (QoL) of cancer patients. Participant responses to questions regarding Global Health Status (GHS; "How would you rate your overall health during the past week?") and QoL ("How would you rate your overall quality of life during the past week?") are scored on a 7-point scale (1= Very poor to 7=Excellent). The combined score of GHS (Item 29) and QoL (Item 30) is computed by averaging the raw scores of the 2 items and then applying a linear transformation to standardize the average score, so that the combined scores range from 0-100. A higher score indicates a better outcome. The change from baseline in GHS and QoL combined score will be presented.	Baseline and up to approximately 25 months
Change from Baseline in the EORTC QLQ-C30 Physical Functioning (Items 1-5) Combined Score	EORTC QLQ-C30 is a questionnaire to assess the overall QoL of cancer patients. Participant responses to 5 questions about their physical functioning (Items 1 to 5) are scored on a 4-point scale (1=Not at All to 4=Very Much). The combined score of items 1 to 5 was computed by averaging the raw scores of the 5 items and then applying a linear transformation to standardize the average score, so that the combined scores range from 0-100. A higher score indicates a better outcome. The change from baseline in EORTC QLQ-C30 physical functioning (Items 1-5) combined score will be presented.	Baseline and up to approximately 25 months
Change from Baseline in the EORTC QLQ-C30 Role Functioning (Items 6 and 7) Combined Score	The EORTC QLQ-C30 is a cancer specific health-related quality of life questionnaire. The role functioning score is based on participant responses to questions scored on a 4-point scale (1=Not at All to 4=Very Much). The combined score was computed by averaging the raw scores of Items 6 and 7 and then applying a linear transformation to standardize the average score, so that the combined scores range from 0-100. Higher scores indicate better role functioning. The change from baseline in EORTC QLQ-C30 Role Functioning (Items 6 and 7) combined score will be reported.	Baseline and up to approximately 25 months
Change From Baseline in Disease Symptoms Using the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-related Symptoms (FKSI-DRS) (Items 1-9) Score	The FKSI-DRS index consists of a 9-item questionnaire that assesses the extent of participant symptoms from kidney cancer. Each item is scored on a 5-point scale (0=not at all to 4=very much). FKSI-DRS total score ranged from 0 (most severe symptoms) to 36 (no symptoms) with a higher score indicating a better outcome.	Baseline and up to approximately 25 months
Time to Deterioration (TTD) in EORTC QLQ-C30 Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score	EORTC QLQ-C30 is a questionnaire to assess QoL of cancer patients. Participant responses to questions on GHS ("How would you rate your overall health during the past week?") and QoL ("How would you rate your overall QoL during the past week?") were scored on a 7-point scale (1= Very poor to 7=Excellent). The combined score of GHS (Item 29) and QoL (Item 30) was computed by averaging raw scores of the 2 items and applying a linear transformation to standardize the average score, so that the combined scores range from 0-100. A higher score indicates a better outcome. TTD was defined as the time from baseline to first onset of ≥10-point negative change (decrease) from baseline in GHS-QoL combined score. A longer TTD indicates a better outcome.	Up to approximately 25 months
TTD in EORTC QLQ-C30 Physical Functioning (Items 1-5) Score	EORTC QLQ-C30 is a questionnaire to assess the overall QoL of cancer patients. Participant responses to 5 questions about their physical functioning (Items 1 to 5) are scored on a 4-point scale (1=Not at All to 4=Very Much). The combined score of items 1 to 5 was computed by averaging the raw scores of the 5 items and then applying a linear transformation to standardize the average score, so that the combined scores range from 0-100. A higher score indicates a better outcome. TTD was defined as the time from baseline to first onset of ≥10-point negative change (decrease) from baseline in physical functioning (Items 1 to 5). A longer TTD indicates a better outcome.	Up to approximately 25 months
TTD in EORTC QLQ-C30 Role Functioning (Items 6 and 7) Score	EORTC QLQ-C30 is a questionnaire to assess the overall QoL of cancer patients. Participant responses to questions about their role functioning (Items 6 and 7) are scored on a 4-point scale (1=Not at All to 4=Very Much). The combined score of Items 6 and 7 was computed by averaging the raw scores of the items and then applying a linear transformation to standardize the average score, so that the combined scores range from 0-100. A higher score indicates a better outcome. TTD was defined as the time from baseline to first onset of ≥10-point negative change (decrease) from baseline in role functioning (Items 6 and 7). A longer TTD indicates a better outcome.	Up to approximately 25 months
TTD in Disease Symptoms Using the FKSI-DRS (Items 1-9) Score	TTD is defined as time from the first dose of study treatment to the date of deterioration of FKSI-DRS score. The FKSI-DRS index consists of a 9-item questionnaire that assesses the extent of participant symptoms from kidney cancer. Each item is scored on a 5-point scale (0=not at all to 4=very much). FKSI-DRS total score ranged from 0 (most severe symptoms) to 36 (no symptoms) with a higher score indicating a better outcome. Deterioration is defined as a 3-point decrease (i.e. lower score) in symptom score and the time to true deterioration is the time to first onset of 3 or more decreases from baseline with confirmation under right-censoring rule (the last observation). A longer TTD indicates a better outcome.	Up to approximately 25 months

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• Merck Clinical Trials Information

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2026
• Primary Completion (Estimated): November 27, 2030
• Study Completion (Estimated): November 27, 2030

Study Registration Dates

• First Submitted: March 20, 2026
• First Submitted That Met QC Criteria: March 20, 2026
• First Posted (Actual): March 24, 2026

Study Record Updates

• Last Update Posted (Actual): May 29, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• 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; belzutifan
• Other Study ID Numbers: 6482-034; U1111-1311-4692 (Registry Identifier: UTN); 2024-516993-31-00 (Registry Identifier: EU CT); LITESPARK-034 (Other Identifier: MSD); MK-6482-034 (Other Identifier: MSD); LS-034 (Other Identifier: MSD)

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