A Phase 3, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Pembrolizumab (MK-3475) as Monotherapy in the Adjuvant Treatment of Renal Cell Carcinoma Post Nephrectomy (KEYNOTE-564)

The primary objective of this Phase 3, randomized, double-blind, placebo-controlled clinical trial is to compare **disease-free survival (DFS)** as assessed by the investigator for participants treated with **pembrolizumab** versus those receiving placebo in the adjuvant treatment of **renal cell carcinoma** post-nephrectomy. This objective is clinically relevant as it aims to determine the efficacy of pembrolizumab in prolonging the period during which patients remain free from cancer recurrence, which is crucial for improving long-term outcomes in renal cell carcinoma patients.

Secondary objectives include:

• Comparing overall survival (OS) for participants treated with pembrolizumab versus those receiving placebo.
• Comparing the safety and tolerability profiles for participants treated with pembrolizumab versus those receiving placebo.
• Comparing measures of disease recurrence-specific survival (DRSS), as assessed by the investigator, for participants treated with pembrolizumab versus those receiving placebo.
• Comparing event-free survival (EFS) as assessed by the blinded independent radiology review for participants treated with pembrolizumab versus those receiving placebo.
• Comparing DFS and OS according to participants’ PD-L1 expression status (Positive, Negative) for participants treated with pembrolizumab versus those receiving placebo.
• Evaluating patient-reported outcomes (PROs) with the EORTC-QLQ-C30 and the FKSI-DRS.

The clinical trial involves a total of **652 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 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, an Eastern Cooperative Oncology Group Performance Status score of 0 or 1, and adequate organ function. The trial includes individuals who have undergone nephrectomy and/or metastasectomy within a specified timeframe and are tumor-free as assessed by imaging techniques. The study population is characterized by intermediate-high risk, high risk, or M1 no evidence of disease renal cell carcinoma, with no prior systemic therapy for advanced RCC. Both male and female participants of childbearing potential are required to use adequate contraception during the study and for a period after the last dose of treatment. The trial also considers vulnerable populations, ensuring comprehensive representation within the study cohort.

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of **pembrolizumab** as monotherapy in the adjuvant treatment of **renal cell carcinoma** post-nephrectomy. The primary objective is to compare disease-free survival (DFS) as assessed by the investigator for participants treated with pembrolizumab versus those receiving placebo. The trial is expected to conclude by December 2025, with recruitment having commenced in June 2017. Participants will be randomly assigned to receive either pembrolizumab or a placebo, both administered via **intravenous infusion**.

The study involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of renal cell carcinoma, adequate organ function, and a recent nephrectomy. Participants must also have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1. Following the screening, participants will undergo regular follow-up visits to monitor their health status, assess treatment efficacy, and record any adverse events. 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 12 months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include the occurrence of significant adverse events, disease progression, or withdrawal of consent by the participant. The trial will also evaluate secondary endpoints such as overall survival, the number of participants experiencing adverse events, and changes in quality of life scores. The study is not classified as low intervention, given its Phase III status and the need to confirm safety and efficacy in the target population.

The clinical trial involves the administration of **Sodium Chloride Intravenous Infusion BP 0.9% w/v** as a non-experimental treatment. This solution is utilized as a placebo in the study. It is a **solution for infusion** with the active substance being **sodium chloride**, originating from a chemical source. The pharmaceutical form is a solution for infusion, and it is administered via **intravenous infusion**. The maximum daily dose is 200 mg, with a total maximum dose of 2400 mg over a treatment period of up to 12 months. The product is manufactured by Baxter Healthcare Ltd. and is not a pediatric formulation.

The experimental medication in this trial is **KEYTRUDA 25 mg/mL concentrate for solution for infusion**, with the active substance **pembrolizumab**, a protein-based therapeutic. This medication is administered as a **solution for infusion** through **intravenous infusion**. The maximum daily dose is 200 mg, with a total maximum dose of 3400 mg over a treatment period of up to 12 months. Pembrolizumab is provided by Merck Sharp & Dohme BV and is not formulated for pediatric use. The trial aims to evaluate the efficacy of pembrolizumab as a monotherapy in the adjuvant treatment of renal cell carcinoma post-nephrectomy, comparing disease-free survival (DFS) against the placebo group.

The efficacy of the clinical trial will be assessed primarily through **Disease-Free Survival (DFS)** as evaluated by the investigator. This primary endpoint will compare the DFS of participants treated with pembrolizumab against those receiving a placebo. Secondary endpoints include **Overall Survival (OS)**, the number of participants experiencing an **Adverse Event (AE)**, and the number of participants who discontinued the study drug due to an AE. Additional secondary endpoints involve specific survival metrics such as **First Local Disease Recurrence-Specific Survival (DRSS1)** and **Visceral Disease Recurrence-Specific Survival (DRSS2)**, both assessed by the investigator. Event-Free Survival (EFS) will be evaluated by a Blinded Independent Central Review (BICR).

Further assessments will include DFS and OS according to participant **Programmed Cell Death-Ligand 1 (PD-L1)** expression status, categorized as positive or negative. Patient-reported outcomes will be measured using changes from baseline in the **European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30)** total score and the **Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS)** index score. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial duration, ensuring a comprehensive evaluation of the treatment's impact on renal cell carcinoma post-nephrectomy.