An Open-label, Randomized Phase 3 Study to Evaluate Efficacy and Safety of Pembrolizumab (MK-3475) in Combination with Belzutifan (MK-6482) and Lenvatinib (MK-7902), or MK-1308A in Combination with Lenvatinib, versus Pembrolizumab and Lenvatinib, as First-line Treatment in Participants with Advanced Clear Cell Renal Cell Carcinoma (ccRCC)

The primary objective of this study is to evaluate the efficacy of different treatment arms in patients with advanced **clear cell renal cell carcinoma** (ccRCC). Specifically, the study aims to compare Arm A to Arm C with respect to **Progression-Free Survival** (PFS) as assessed by the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and Overall Survival (OS). Additionally, Arm B will be compared to Arm C regarding PFS and OS. These comparisons are clinically relevant as they aim to determine the most effective first-line treatment regimen for improving survival outcomes in ccRCC patients.

Secondary objectives include:

• Comparing Arm A and Arm B to Arm C with respect to Objective Response Rate (ORR) per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR).
• Evaluating the Duration of Response (DOR) as assessed by BICR according to RECIST 1.1.
• Assessing the safety and tolerability of Arm A and Arm B compared to Arm C.

The clinical trial involves a total of **1191 participants** diagnosed with **clear cell renal cancer**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of renal cell carcinoma with a clear cell component and no prior systemic therapy for advanced clear cell renal cell carcinoma. The trial includes individuals with adequately controlled blood pressure and adequate organ function. Both male and female participants are required to adhere to contraceptive guidelines to prevent pregnancy during and after the study period. The trial population also includes individuals receiving bone resorptive therapy, provided it was initiated at least two weeks prior to randomization. The study considers vulnerable populations, ensuring comprehensive ethical oversight. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as an open-label, randomized, Phase 3 study to evaluate the efficacy and safety of **pembrolizumab** in combination with **belzutifan** and **lenvatinib**, or MK-1308A in combination with **lenvatinib**, versus **pembrolizumab** and **lenvatinib** as first-line treatment in participants with advanced clear cell renal cell carcinoma (ccRCC). The trial will involve multiple arms to compare progression-free survival (PFS) and overall survival (OS) among different treatment combinations. The study is expected to run from April 2021 to June 2027, with participants involved for varying durations depending on the treatment arm, with a maximum treatment period of 72 weeks for some interventions.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of renal cell carcinoma with a clear cell component and no prior systemic therapy for advanced ccRCC. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, including assessments of PFS and OS according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR). The end-of-study visit will conclude the participant's involvement, with final assessments conducted to evaluate the overall outcomes of the trial.

Participant involvement may be terminated early if they experience unacceptable adverse events, fail to comply with study procedures, or if the investigator deems it in the participant's best interest. The trial's primary endpoints include PFS and OS, while secondary endpoints focus on objective response rate, duration of response, and the incidence of adverse events. The study aims to provide comprehensive data on the safety and efficacy of the treatment combinations, contributing to the understanding of therapeutic options for advanced ccRCC.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Pembrolizumab**, marketed as Keytruda, is provided as a 25 mg/mL concentrate for solution for infusion. It is administered via **intravenous infusion** with a maximum daily dose of 400 mg and a total dose limit of 7200 mg over a treatment period of 24 weeks. This biologic agent is produced by Merck Sharp & Dohme BV and is not a pediatric formulation.

**Lenvatinib** is administered in capsule form, with a maximum daily dose of 20 mg and a total dose limit of 42800 mg over a 72-week treatment period. The route of administration is **oral**, and it is classified as a chemical medicinal product. Lenvatinib is produced by Merck & Co. Inc. and is also not formulated for pediatric use.

**Belzutifan** is provided as a film-coated tablet, with a maximum daily dose of 120 mg and a total dose limit of 262800 mg over a 72-week treatment period. It is administered **orally** and is classified as a chemical medicinal product. This medication is produced by Merck & Co. Inc. and is not intended for pediatric use.

Another formulation of **Lenvatinib** is also included in the trial, with a maximum daily dose of 120 mg and a total dose limit of 262800 mg over a 72-week treatment period. This formulation is administered **orally** in capsule form and is classified as a chemical medicinal product. It is produced by Merck & Co. Inc. and is not a pediatric formulation.

**MK-1308A** is a combination product containing pembrolizumab and quavonlimab, provided as a solution for infusion. It is administered via **intravenous infusion** with a maximum daily dose of 425 mg and a total dose limit of 7650 mg over a 28-week treatment period. This biologic agent is produced by Merck & Co. Inc. and is not formulated for pediatric use.

Throughout the trial, participant compliance with dosing schedules is monitored to ensure adherence to the prescribed treatment regimens. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression-Free Survival (PFS)** and **Overall Survival (OS)**. PFS will be evaluated according to the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and assessed by Blinded Independent Central Review (BICR). OS will also be compared across different treatment arms. Secondary endpoints include Objective Response Rate (ORR) and Duration of Response (DOR), both assessed per RECIST 1.1 by BICR, as well as the number of participants who experience at least one adverse event (AE) and those who discontinue study treatment due to an AE.

The trial involves a comparison of different treatment combinations in participants with advanced clear cell renal cell carcinoma (ccRCC). The efficacy parameters will be measured and collected at specified intervals throughout the study duration, with assessments conducted by independent reviewers to ensure objectivity. The trial is designed to provide comprehensive data on the efficacy of the treatment regimens, contributing to the understanding of their potential benefits in the target patient population.