Phase 3 Randomized Open-label Study of Belzutifan and Zanzalintinib Versus Cabozantinib in Advanced Renal Cell Carcinoma Post Anti-PD-1/L1 Therapy
- Trial ID
- 2024-517136-21-00
- Protocol
- MK-6482-033
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the efficacy of belzutifan plus zanzalintinib against cabozantinib in patients with advanced renal cell carcinoma who have experienced disease recurrence following prior adjuvant anti-PD-1/L1 therapy. Clinical efficacy is primarily evaluated through progression-free survival (PFS) as determined by RECIST 1.1 criteria and blinded independent central review (BICR), alongside overall survival (OS). Secondary objectives include the assessment of objective response rate (ORR) and duration of response (DOR). Additionally, the study evaluates the safety and tolerability of the combination therapy, as well as impacts on health-related quality of life (HRQoL) and disease-related symptoms, specifically measuring mean changes from baseline and time to deterioration (TTD) using the EORTC-QLQ-C30 and FKSI-DRS instruments.
Participants
This study involves 506 participants diagnosed with advanced renal cell carcinoma. The population includes both male and female patients within specific age categories. Eligible individuals must have a histologically confirmed diagnosis of unresectable, advanced disease with a clear cell component, classified as Stage IV according to the AJCC 8th Edition. Participants are required to have measurable disease as defined by RECIST 1.1. The cohort consists of patients experiencing disease recurrence during or within 24 months following the conclusion of adjuvant anti-PD-1/L1 therapy. Inclusion is limited to those who have received no other prior systemic therapy for their condition except for the aforementioned adjuvant treatment.
Plans and Procedures
This Phase 3, randomized, open-label study is designed to compare the efficacy and safety of belzutifan and zanzalintinib against cabozantinib in participants with advanced renal cell carcinoma. The research methodology focuses on evaluating progression-free survival as the primary endpoint, assessed via RECIST 1.1 by blinded independent central review, alongside overall survival. The study involves participants who have experienced disease recurrence during or within 24 months of completing adjuvant anti-PD-1/L1 therapy and have not received other systemic treatments for their condition. The estimated duration of the study spans from December 2025 to December 2031. Secondary endpoints include objective response rate, duration of response, and various measures of health-related quality of life using validated questionnaires. Participant involvement includes a screening period to confirm eligibility based on histological diagnosis and measurable disease, followed by treatment and subsequent follow-up assessments. Early termination of study participation may occur due to adverse events or other predefined clinical conditions.
Treatment
The experimental treatment consists of belzutifan and XL092 (N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide). Both substances are administered via the oral route. XL092 is provided in tablet form.
The comparator treatment is cabozantinib, which is administered as film-coated tablets through the oral route. Available strengths include 20 mg and 60 mg doses.
Efficacy
The efficacy of the investigational therapy will be evaluated using several clinical endpoints in participants with advanced renal cell carcinoma. The primary endpoints consist of progression-free survival, assessed according to RECIST 1.1 by blinded independent central review, and overall survival.
Secondary efficacy parameters include the following:
- Objective response rate
- Duration of response
- Change from baseline in European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire 30 (EORTC QLQ-C30) global health/health-related quality of life (HRQoL) score
- Change from baseline in EORTC QLQ-C30 physical functioning score
- Change from baseline in EORTC QLQ-C30 role functioning score
- Change from baseline in Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-related Symptoms (FKSI-DRS) score
- Time from baseline to first deterioration in EORTC QLQ-C30 global health/HRQoL score
- Time from baseline to first deterioration in EORTC QLQ-C30 physical functioning score
- Time from baseline to first deterioration in EORTC QLQ-C30 role functioning score
- Time from baseline to first deterioration in FKSI-DRS score
Inclusion and Exclusion Criteria
Inclusion Criteria
- Has a histologically confirmed diagnosis of unresectable, advanced renal cell cancer (RCC) with clear cell component (with or without sarcomatoid features) ie, Stage IV renal cell cancer per AJCC (8th Edition).
- Has measurable disease per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1).
- Has disease recurrence during adjuvant anti-programmed cell death 1/programmed cell death ligand 1 (PD-1/L1) therapy or recurrence ≤24 months following the last dose of adjuvant anti-PD-1/L1 therapy.
- Has received no other prior systemic therapy for their RCC except for their adjuvant anti-PD-1/L1 therapy.
Exclusion Criteria
- Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, new-onset angina, pulmonary embolism, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability.
- Had 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 or has not adequately recovered from major surgery or has ongoing surgical complications.
- Has not adequately recovered from major surgery or has ongoing surgical complications.
- Has current pneumonitis/interstitial lung disease.
- Has symptomatic pleural effusion (for example cough, dyspnea, pleuritic chest pain), ascites, or pericardial fluid requiring drainage within 4 weeks prior to randomization.
- Has a gastrointestinal disorder including those associated with a high risk of perforation or fistula formation.
- Has a serious active nonhealing wound/ulcer/bone fracture.
- Has a requirement for hemodialysis or peritoneal dialysis.
- Has history of human immunodeficiency virus infection.
- Has hepatitis B or hepatitis C virus.
- Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 31 Dec 2025 | 17 |
 Belgium | Recruiting | 31 Dec 2025 | 22 |
 Croatia | Recruiting | 31 Dec 2025 | 17 |
 Czechia | Recruiting | 31 Dec 2025 | 38 |
 Denmark | Recruiting | 31 Dec 2025 | 17 |
 France | Recruiting | 31 Dec 2025 | 67 |
 Germany | Recruiting | 31 Dec 2025 | 52 |
 Greece | Recruiting | 31 Dec 2025 | 12 |
 Ireland | Recruiting | 31 Dec 2025 | 17 |
 Italy | Recruiting | 31 Dec 2025 | 50 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Cabozantinib Ipsen 60 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL | 00 | 1 | PRD12195253 |
XL092 | Test | TABLET | ORAL | 00 | 1 | PRD10205697 |
XL092 | Test | TABLET | ORAL | 00 | 1 | PRD10205698 |
XL092 | Test | TABLET | ORAL | 00 | 1 | PRD10205699 |
BELZUTIFAN | Test | — | ORAL | 00 | 1 | SUB207909 |
Cabozantinib Ipsen 20 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL | 00 | 1 | PRD12195252 |
XL092 | Test | TABLET | ORAL | 00 | 1 | PRD10205739 |