Phase 3 Randomized Study of Belzutifan and Lenvatinib Versus Cabozantinib in Advanced Renal Cell Carcinoma Post Anti-PD-1/L1 Therapy

The primary objective of this study is to compare the combination of **belzutifan** and **lenvatinib** to **cabozantinib** in terms of progression-free survival (PFS) as per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, assessed by blinded independent central review (BICR). Additionally, the study aims to compare overall survival (OS) between the two treatment regimens. These objectives are clinically relevant as they address the efficacy of the treatment options in managing advanced renal cell carcinoma (RCC) with a clear cell component, particularly in patients who have progressed following prior anti-PD-1/L1 therapy.

Secondary objectives include:

• Comparing the objective response rate (ORR) of belzutifan+lenvatinib to cabozantinib based on RECIST 1.1 as assessed by BICR.
• Evaluating the duration of response (DOR) as assessed by BICR according to RECIST 1.1.
• Assessing the safety and tolerability of belzutifan+lenvatinib compared to cabozantinib.

The clinical trial involves a total of **347 participants** diagnosed with **advanced renal cell carcinoma (RCC)** with a clear cell component. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including having unresectable, locally advanced, or metastatic clear cell RCC, adequate organ function, and disease progression following anti-PD-1/L1 therapy. The trial excludes vulnerable populations. Participants are required to have a Karnofsky performance status score of at least 70% and must have received no more than two prior systemic regimens. Lifestyle considerations such as contraceptive use are mandated for both male and female participants to prevent pregnancy during and after the trial period. The trial does not impose specific dietary or physical activity requirements. The sponsor has not provided additional information regarding the general health status or lifestyle habits of the participants.

The clinical trial is designed as an open-label, randomized, Phase 3 study to evaluate the efficacy and safety of **belzutifan** in combination with **lenvatinib** compared to **cabozantinib** in participants with advanced renal cell carcinoma (RCC) who have progressed after prior anti-PD-1/L1 therapy. The trial aims to assess progression-free survival (PFS) and overall survival (OS) as primary endpoints, with secondary endpoints including objective response rate (ORR), duration of response (DOR), and the incidence of adverse events (AEs). The study is expected to run from February 25, 2021, to December 23, 2024, with a maximum treatment period of 46 weeks for participants.

Participants will be randomly assigned to receive either the combination of belzutifan and lenvatinib or cabozantinib, with all medications administered orally. The trial will include several key visits: an initial screening visit to confirm eligibility based on criteria such as unresectable, locally advanced, or metastatic clear cell RCC, adequate organ function, and disease progression following anti-PD-1/L1 therapy. Follow-up visits will be conducted to monitor treatment response and safety, with assessments based on RECIST 1.1 criteria by a blinded independent central review. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Participant involvement is expected to last up to 46 weeks, with conditions for early termination including significant adverse events, disease progression, or withdrawal of consent. The trial's methodology ensures rigorous evaluation through its randomized, controlled design, providing robust data on the comparative effectiveness of the treatment regimens. The study's findings will contribute to understanding the therapeutic potential of belzutifan and lenvatinib in this patient population.

The clinical trial involves the administration of **Lenvatinib**, a chemical compound provided in **capsule** form. The pharmaceutical product is identified by the sponsor product code MK-7902 and is manufactured by Merck & Co. Inc. The maximum daily dose of Lenvatinib is 20 mg, with a total maximum dose of 27,780 mg over a treatment period of 46 weeks. The route of administration is oral, and the medication is not formulated for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the trial.

**Belzutifan** is another experimental medication used in this study, provided as a **film-coated tablet**. It is also manufactured by Merck & Co. Inc. and identified by the sponsor product code MK-6482. The maximum daily dose for Belzutifan is 120 mg, with a total maximum dose of 166,680 mg over the same 46-week treatment period. The administration route is oral, and the formulation is not intended for pediatric use. Compliance with the dosing regimen will be closely monitored.

The comparator treatment in this trial is **Cabozantinib**, a chemical compound administered in a pharmaceutical form denoted as PHF00006MIG. The maximum daily dose for Cabozantinib is 60 mg, with a total maximum dose of 83,340 mg over 46 weeks. This medication is also administered orally and is not formulated for pediatric use. As with the experimental treatments, participant adherence to the dosing schedule will be monitored.

Efficacy in this clinical trial will be assessed using the primary endpoints of **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 a Blinded Independent Central Review (BICR). OS will also be compared between the treatment groups. Secondary endpoints include the Objective Response Rate (ORR) and Duration of Response (DOR), both assessed per RECIST 1.1 by BICR, as well as the number of participants experiencing adverse events and those discontinuing treatment due to adverse events.