Phase 3 Randomized, Double-Blind Study of Belzutifan and Pembrolizumab Versus Placebo and Pembrolizumab in Adjuvant Treatment of Clear Cell Renal Cell Carcinoma

The primary objective of this study is to compare **disease-free survival** (DFS) as assessed by the investigator for participants treated with belzutifan plus pembrolizumab versus those receiving placebo plus pembrolizumab. This objective is clinically relevant as it evaluates the efficacy of the combination therapy in preventing the recurrence of renal cell carcinoma (RCC) post-nephrectomy, which is crucial for improving patient outcomes and prolonging survival.

Secondary objectives include:

• Comparing overall survival (OS) for participants treated with belzutifan plus pembrolizumab versus those receiving placebo plus pembrolizumab.
• Comparing the safety and tolerability profiles for participants treated with belzutifan plus pembrolizumab versus those receiving placebo plus pembrolizumab.
• Comparing measures of disease recurrence-specific survival (DRSS) as assessed by the investigator, in participants treated with belzutifan plus pembrolizumab versus those receiving placebo plus pembrolizumab.
• Comparing participants treated with belzutifan plus pembrolizumab versus those receiving placebo plus pembrolizumab with respect to mean change from baseline in health-related quality of life (HRQoL) and symptoms using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life 30 Questionnaire (QLQ-C30) and the Functional Assessment of Cancer Therapy – Kidney Symptom Index Disease-related Symptoms (FKSI-DRS).

The clinical trial involves a total of **1253 participants** diagnosed with **renal cell carcinoma**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on specific inclusion criteria, such as having a histologically or cytologically confirmed diagnosis of renal cell carcinoma with a clear cell component, and having undergone complete resection of the primary tumor. The trial does not include a vulnerable population. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Lifestyle considerations such as diet and physical activity are not specified, but participants must have adequate organ function and adhere to contraception requirements. The trial aims to compare disease-free survival between those treated with belzutifan plus pembrolizumab and those receiving placebo plus pembrolizumab.

The clinical trial is a **randomized**, **double-blind**, controlled Phase 3 study designed to evaluate the efficacy and safety of **Belzutifan** plus **Pembrolizumab** compared to a placebo plus Pembrolizumab in the adjuvant treatment of **renal cell carcinoma** (RCC) post-nephrectomy. The trial aims to assess **disease-free survival** (DFS) as the primary endpoint, with secondary endpoints including overall survival, adverse events, and changes in health-related quality of life. The study is expected to conclude by January 25, 2030, with recruitment having commenced on April 12, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of RCC, specific risk categories, and adequate organ function. Following randomization, participants will receive either the investigational treatment or placebo. The trial includes regular follow-up visits to monitor treatment effects, adverse events, and overall health status. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any long-term effects of the treatment.

The expected duration of participant involvement is up to 54 weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial is structured to ensure rigorous assessment of the investigational treatment's safety and efficacy, contributing valuable data to the understanding of adjuvant therapies in RCC.

The clinical trial involves the administration of **Belzutifan**, a chemical compound provided in the form of a film-coated tablet. The active substance in Belzutifan is chemically synthesized and is known by the synonyms MK-6482 and PT-2977. The pharmaceutical form is a film-coated tablet, and the medication is administered orally. The maximum daily dose is 120 mg, with a total maximum dose of 45,360 mg over a treatment period of up to 54 weeks. Participant compliance with the dosing schedule will be monitored throughout the trial.

**Pembrolizumab**, marketed as KEYTRUDA, is a biological agent used in this study. It is provided as a 25 mg/mL concentrate for solution for infusion. The active substance, Pembrolizumab, is a protein-based therapeutic agent, also known by the synonyms Lambrolizumab and MK-3475. The administration route is intravenous infusion, with a maximum daily dose of 400 mg and a total maximum dose of 3,600 mg over a treatment period of up to 54 weeks. The infusion schedule and participant adherence will be closely monitored during the trial.

The study also includes a **placebo** for MK6482, which serves as a comparator treatment. The placebo is designed to match the experimental medication in appearance and administration route but does not contain any active pharmaceutical ingredients. The placebo is administered orally, following the same schedule as the active treatment, to maintain the double-blind nature of the trial. Compliance with the placebo administration will be monitored to ensure the integrity of the study results.

The efficacy of the clinical trial will be assessed primarily through **Disease-Free Survival (DFS)**, as evaluated by investigators. This primary endpoint will compare the DFS of participants treated with belzutifan plus pembrolizumab against those receiving placebo plus pembrolizumab. Secondary endpoints include **Overall Survival (OS)**, the number of participants experiencing at least one adverse event (AE), the number of participants discontinuing study treatment due to an AE, and various measures of disease recurrence-specific survival (DRSS1 and DRSS2). Additionally, changes from baseline in health-related quality of life (HRQoL) will be measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) for items 29 and 30, as well as changes in physical and role functioning and disease symptoms using the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-related Symptoms (FKSI-DRS) for items 1-9.