Phase 3 Randomized Study of Belzutifan Plus Zanzalintinib Versus Belzutifan Plus Placebo in Advanced Renal Cell Carcinoma After PD-1/L1 and VEGF-TKI Therapy

The primary objective of this study is to compare the efficacy of belzutifan plus zanzalintinib versus belzutifan plus placebo in patients with advanced renal cell carcinoma who have progressed on or after sequential or combined PD-1/L1 and VEGF-TKI therapies. Clinical relevance is established by evaluating progression-free survival per RECIST 1.1 as assessed by blinded independent central review and comparing overall survival.

Secondary objectives include:

• Comparison of overall response rate per RECIST 1.1 as assessed by blinded independent central review.
• Evaluation of duration of response for both treatment arms.
• Assessment of safety and tolerability of the belzutifan and zanzalintinib combination.
• Evaluation of health-related quality of life and disease-related symptoms via mean change from baseline and time to deterioration using the EORTC QLQ-C30 and FKSI-DRS instruments.

This clinical trial involves 437 participants diagnosed with advanced renal cell carcinoma. The study population includes both male and female individuals within specific age categories. Participants must have a histologically confirmed diagnosis of unresectable disease with a clear cell component. Inclusion requires the presence of measurable disease according to RECIST 1.1. Eligible subjects have received no more than three prior systemic regimens for this condition, with a limitation of one prior anti-PD-1/PD-L1 therapy. The primary objectives are:

• To compare the combination of belzutifan and zanzalintinib to belzutifan and placebo regarding progression-free survival as assessed by blinded independent central review.
• To compare the combination of belzutifan and zanzalintinib to belzutifan and placebo regarding overall survival.

This Phase 3, randomized, double-blind, controlled study evaluates the efficacy and safety of combining belzutifan and zanzalintinib versus belzutifan and a placebo in participants with advanced renal cell carcinoma. The research methodology aims to compare the treatment groups regarding progression-free survival as assessed by blinded independent central review and overall survival. Secondary objectives include assessing the objective response rate, duration of response, and various quality of life metrics. The trial is expected to conclude by November 2030. The study sequence involves an initial screening visit to confirm eligibility based on histological diagnosis and prior systemic regimens, followed by treatment periods and subsequent follow-up assessments. Participant involvement continues until the end-of-study visit. Termination from the study may occur due to the occurrence of adverse events or other predefined clinical conditions.

The experimental medication XL092, also known as zanzalintinib, is administered as an oral tablet. The active substance is N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide.

The experimental medication belzutifan is administered via the oral route at a dosage of 120 mg.

A placebo to zanzalintinib is utilized in the study design.

The efficacy of the investigational combination in participants with advanced renal cell carcinoma will be evaluated using several clinical endpoints. The primary endpoints include progression-free survival (PFS), determined according to RECIST 1.1 criteria and assessed by blinded independent central review (BICR), and overall survival (OS).

Secondary efficacy parameters consist of the following:

• Objective response rate (ORR) and duration of response (DOR).
• Changes from baseline in the EORTC QLQ-C30 combined scores for global health status and quality of life, physical functioning, and role functioning.
• Changes from baseline in disease symptoms as measured by the FKSI-DRS score.
• Time to deterioration (TTD) in the EORTC QLQ-C30 global health status and quality of life, physical functioning, and role functioning scores, as well as in the FKSI-DRS disease symptoms score.