A Study of Belzutifan (MK-6482) Versus Everolimus in Participants With Advanced Renal Cell Carcinoma (MK-6482-005)

Phase 3

Active, not recruiting

• Conditions: Carcinoma, Renal Cell
• Interventions: Drug: Belzutifan; Drug: Everolimus

• Registration Number: NCT04195750
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

The primary objective of this study is to compare belzutifan to everolimus with respect to progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR) and to compare everolimus with respect to overall survival (OS). The hypothesis is that belzutifan is superior to everolimus with respect to PFS and OS.

Detailed Description

Per protocol, all participants enrolled in the Safety Run-In were not randomized and not included in the protocol-specified analyses for any of the outcome measures.

Study Timeline

• Study First Submitted: 2019-12-10
• Study First Submitted QC: 2019-12-10
• Study First Posted: 2019-12-12
• Study Start: 2020-02-27
• Primary Completion: 2024-04-15
• Status Verified: 2025-04
• Results First Submitted: 2025-04-09
• Results First Submitted QC: 2025-04-09
• Last Update Submitted: 2025-04-09
• Results First Posted: 2025-04-29
• Last Update Posted: 2025-04-29
• Study Completion: 2026-09-17

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 755

Inclusion Criteria

• Has unresectable, locally advanced or metastatic clear cell renal cell carcinoma (RCC)
• Has had disease progression on or after having received systemic treatment for locally advanced or metastatic RCC with both Programmed cell death 1 ligand 1 (PD-1/L1) checkpoint inhibitor and a vascular endothelial growth factor - tyrosine kinase inhibitor (VEGF-TKI) in sequence or in combination
• Has received no more than 3 prior systemic regimens for locally advanced or metastatic RCC
• A male participant is eligible to participate if he is abstinent from heterosexual intercourse or agrees to use contraception during the intervention period and for at least 7 days after the last dose of study intervention
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: Not a woman of childbearing potential (WOCBP) OR a WOCBP who agrees to follow the contraceptive guidance during the intervention period and for at least 30 days after the last dose of study intervention for those randomized to belzutifan and for at least 8 weeks after the last dose of study intervention for those randomized to everolimus
• The participant (or legally acceptable representative if applicable) has provided documented informed consent for the study
• Has adequate organ function

Exclusion Criteria

• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. (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)
• Has known central nervous system (CNS) metastases and/or carcinomatous meningitis. (Participants with previously treated brain metastases may participate provided they are radiologically stable for at least 4 weeks (28 days) by repeat imaging)
• Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study medication administration, or New York Heart Association Class III or IV congestive heart failure. (Medically controlled arrhythmia stable on medication is permitted)
• Has poorly controlled hypertension defined as systolic blood pressure (SBP) ≥150 mm Hg and/or diastolic blood pressure (DBP) ≥90 mm Hg
• Has moderate to severe hepatic impairment (Child-Pugh B or C)
• Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
• Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (e.g., gastrectomy, partial bowel obstruction, malabsorption)
• Has known hypersensitivity or allergy to the active pharmaceutical ingredient or any component of the study intervention (belzutifan or everolimus) formulations
• Has received prior treatment with belzutifan or another hypoxia inducible factor 2α (HIF-2α inhibitor)
• Has received prior treatment with everolimus or any other specific or selective target of rapamycin complex 1 (TORC1)/ phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) inhibitor (e.g., temsirolimus) in the advanced disease setting
• Has received any type of systemic anticancer antibody (including investigational antibody) within 4 weeks before randomization
• Has received prior radiotherapy within 2 weeks prior to randomization
• Has had major surgery within 3 weeks prior to randomization
• Has received a live vaccine within 30 days prior to randomization. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines are live attenuated vaccines and are not allowed
• Is currently receiving either strong (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 3A4 (CYP3A4) that cannot be discontinued for the duration of the study
• Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate (e.g., bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study
• Is currently participating in a study of an investigational agent or is currently using an investigational device
• Has an active infection requiring systemic therapy
• Has active bacillus tuberculosis (TB)
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization
• Has a known history of human immunodeficiency virus (HIV) infection. (Testing for HIV at screening is only required if mandated by local health authority
• Has a known history of Hepatitis B virus (HBV) (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (HCV) (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Belzutifan	Belzutifan	Randomized participants received 120 mg of belzutifan orally once daily (QD), until disease progression or discontinuation.
Everolimus	Everolimus	Randomized participants received 10 mg of Everolimus orally QD, until disease progression or discontinuation.
Safety Run-In	Belzutifan	Non-Randomized participants enrolled into the Safety Run-in received up to 120 mg of belzutifan QD.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS) Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)	Up to approximately 39 months	PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥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 ≥5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by blinded independent central review is presented here.
Overall Survival (OS)	Up to approximately 49 months	OS is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up.

Secondary Outcome Measures

Name	Time	Method
Time to True Deterioration (TTD) in Health-Related Quality-of-Life (HRQoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Combined Score	Up to approximately 39 months	The EORTC QLQ-C30 is a cancer specific health-related quality-of life (QoL) questionnaire. Participant responses to the questions regarding Global Health Status (GHS; "How would you rate your overall health during the past week?") and Quality of Life (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), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in Items 29 and 30 scale scores. If the first deterioration is at the last PRO assessment timepoint at the time of analysis, then no confirmation is required. A longer TTD indicates a better outcome. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data.
TTD in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score	Up to approximately 39 months	The EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD was defined as the time from baseline to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in physical functioning Items 1 to 5 scale scores. If the first deterioration is at the last PRO assessment timepoint at the time of analysis, then no confirmation is required. A longer TTD indicates a better outcome. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data.
TTD in Disease Symptoms Using the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-related Symptoms (FKSI-DRS) Items 1-9 Score	Up to approximately 39 months	The FKSI-DRS was a questionnaire that asked the participant to rate 9 kidney cancer-related symptoms: lack of energy, fatigue, weight loss, pain, bone pain, shortness of breath, cough, fever, or blood in the urine. Each item was 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. TTD was defined as the time to first onset of a ≥3-point decrease in symptom score from baseline with confirmation by the subsequent visit of a ≥3-point deterioration from baseline under right-censoring rule. If the first deterioration is at the last PRO assessment timepoint at the time of analysis, then no confirmation is required. A longer TTD indicates a better outcome. TTD is reported based on the product-limit (Kaplan-Meier) method for censored data.
Change From Baseline to Week 17 in the HRQoL Using the EORTC QLQ-C30 Items 29 and 30 Combined Score	Baseline (Day 1) and week 17	The EORTC-QLQ-C30 is a 30-item questionnaire to assess the quality of life of cancer patients. Participant responses to the Global Health Status (GHS) question "How would you rate your overall health during the past week?" (Item 29) and the Quality of Life (QoL) question "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100; a higher score indicating a better overall outcome. Change from baseline to Week 17 in EORTC QLQ-C30 Items 29 and 30 combined scores was calculated based on a constrained longitudinal data analysis (cLDA) model with scores as response variable with covariates for treatment by time interaction, stratification factors (IMDC Risk Category, and Number of Prior VEGF/VEGF-Receptor Targeted Therapies for RCC) as covariates.
Change From Baseline to Week 17 in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score	Baseline (Day 1) and week 17	The EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much), then summed. Summed raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. The change from baseline to Week 17 in physical functioning (EORTC QLQ-C30 Items 1-5) score was calculated based on a constrained longitudinal data analysis (cLDA) model with scores as response variable with covariates for treatment by time interaction, stratification factors (IMDC Risk Category, and Number of Prior VEGF/VEGF-Receptor Targeted Therapies for RCC) as covariates.
Change From Baseline to Week 17 in Disease Symptoms Using the FKSI-DRS Items 1-9 Score	Baseline (Day 1) and week 17	The FKSI-DRS was a questionnaire that asked the participant to rate 9 kidney cancer-related symptoms: lack of energy, fatigue, weight loss, pain, bone pain, shortness of breath, cough, fever, or blood in the urine. Each item was 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. The change from baseline to Week 17 in Disease Symptoms using the FKSI-DRS Items 1-9 score was calculated based on a constrained longitudinal data analysis (cLDA) model with the PRO scores as response variable with covariates for treatment by time interaction, stratification factors (IMDC Risk Category, and Number of Prior VEGF/VEGF-Receptor Targeted Therapies for RCC) as covariates.
Change From Baseline to Week 17 in Visual Analogue Scale (VAS) Score on the European Quality of Life 5 Dimension, 5-level Questionnaire (EQ-5D-5L) Health Utility Score	Baseline (Day 1) and week 17	The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/ depression. Each dimension has 5 response options that reflect increasing levels of difficulty, which are coded on a scale from 1 (no problems) to 5 (extreme problems). The VAS is a component of EQ-5D-5L that asks participants to rate their overall health on a vertical visual analogue scale, with the scale's ends labelled 'The best health you can imagine' (equivalent to a score of 0) and 'The worst health you can imagine' (equivalent to a score of 100). The change from baseline to Week 17 in Health Utility using the EQ-5D-5L VAS score was calculated based on a constrained longitudinal data analysis (cLDA) model with the PRO scores as response variable with covariates for treatment by time interaction, stratification factors (IMDC Risk Category, and Number of Prior VEGF/VEGF-Receptor Targeted Therapies for RCC) as covariates.
Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR	Up to approximately 31 months	ORR is defined as the percentage of participants who have a 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. The percentage of participants who experience a CR or PR as assessed by blinded independent central review based on RECIST 1.1 is presented here.
Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR	Up to approximately 49 months	For participants who demonstrate a confirmed complete response (CR: Disappearance of all target lesions) or confirmed partial response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death. The DOR as assessed by blinded independent central review is presented here. The Median DOR was analyzed by the Kaplan-Meier method for censored data.
Number of Participants Who Experience One or More Adverse Events (AEs)	Up to approximately 78 months	An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Number of Participants Who Discontinue Study Treatment Due to an AE	Up to approximately 78 months	An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The number of participants who discontinue study treatment due to an AE will be presented.

Trial Locations

Locations (172)

University of Alabama - Birmingham ( Site 1538); 🇺🇸 Birmingham, Alabama, United States

University of California San Diego Moores Cancer Center ( Site 1546); 🇺🇸 La Jolla, California, United States

St Joseph Heritage Healthcare ( Site 1531); 🇺🇸 Santa Rosa, California, United States

University Of Colorado ( Site 1540); 🇺🇸 Aurora, Colorado, United States

UCHealth Highlands Ranch Hospital ( Site 1560); 🇺🇸 Highlands Ranch, Colorado, United States

Sibley Memorial Hospital ( Site 1559); 🇺🇸 Washington, District of Columbia, United States

Northwest Georgia Oncology Centers PC ( Site 1520); 🇺🇸 Marietta, Georgia, United States

The University of Chicago Medical Center ( Site 1539); 🇺🇸 Chicago, Illinois, United States

Ochsner Medical Center ( Site 1522); 🇺🇸 New Orleans, Louisiana, United States

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins ( Site 1514); 🇺🇸 Baltimore, Maryland, United States

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