Adjuvant Therapy with Pembrolizumab versus Placebo in Resected Highrisk Stage II Melanoma: A Randomized, Double-blind Phase 3 Study (KEYNOTE 716)

The primary objective of this study is to compare **Recurrence-free Survival (RFS)** between treatment arms in patients with resected high-risk Stage II melanoma. This is clinically relevant as RFS is a critical endpoint in evaluating the efficacy of adjuvant therapies, providing insights into the potential of pembrolizumab to delay or prevent melanoma recurrence post-surgery.

Secondary objectives include:

• To compare **Distant Metastasis-Free Survival (DMFS)** between treatment arms, which is important for understanding the treatment's impact on the spread of melanoma to distant sites.
• To compare **Overall Survival (OS)** between treatment arms, offering a comprehensive measure of the treatment's effect on patient longevity.
• To assess the safety and tolerability of pembrolizumab compared to placebo in terms of the proportion of **Adverse Events (AEs)**, which is crucial for evaluating the risk-benefit profile of the treatment.

The clinical trial involves a total of **485 participants** diagnosed with **Resected High-Risk Stage II Melanoma**. The study population includes both male and female subjects aged **12 years and older**, encompassing a range of age categories. Participants were selected based on specific criteria, including having a surgically resected and histologically/pathologically confirmed new diagnosis of Stage IIB or IIC cutaneous melanoma, as per the American Joint Committee on Cancer (AJCC) 8th edition guidelines. The trial includes individuals who have not received prior treatment for melanoma beyond complete surgical resection and have no evidence of metastatic disease on imaging. Participants are required to have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale or equivalent scales for younger age groups. The trial population is characterized by a general good health status, having adequately recovered from surgery-related toxicity or complications. Female participants of childbearing potential must adhere to contraception guidelines during and after the treatment period. The trial also includes vulnerable populations, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographic groups.

The clinical trial is designed to evaluate the efficacy and safety of **pembrolizumab** as an adjuvant therapy compared to a placebo in patients with resected high-risk Stage II melanoma. This is a randomized, double-blind, controlled Phase III study. The primary objective is to compare recurrence-free survival (RFS) between the treatment arms, with secondary endpoints including distant metastasis-free survival (DMFS), overall survival (OS), and the incidence of adverse events (AEs). The trial is expected to run from September 2018 to October 2033, with a maximum treatment period of 36 months for each participant.

Participants will be randomly assigned to receive either pembrolizumab or a placebo, administered via intravenous infusion. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to be 12 years or older, have a confirmed diagnosis of Stage IIB or IIC cutaneous melanoma, and meet specific health and recovery benchmarks post-surgery. Exclusion criteria are not specified in the provided data.

Participant involvement is expected to last up to 36 months, with conditions for early termination including the occurrence of unacceptable adverse events or disease progression. The study aims to ensure rigorous monitoring and data collection to support the evaluation of pembrolizumab's potential benefits in preventing melanoma recurrence. The trial's design and methodology adhere to high standards to ensure the reliability and validity of the results.

The clinical trial involves the administration of **KEYTRUDA** (pembrolizumab), a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 25 mg/mL and is administered via **intravenous infusion**. The maximum daily dose is 200 mg, with a total maximum dose of 10,400 mg over a treatment period of up to 36 months. Pembrolizumab is a biological product, specifically a protein of other origin, and is manufactured by Merck Sharp & Dohme BV. The medication is not formulated for pediatric use and is identified by the sponsor product code MK-3475. The primary objective of the trial is to compare recurrence-free survival between treatment arms in patients with resected high-risk stage II melanoma.

The study also includes a **placebo** treatment, which is normal saline, serving as a comparator to KEYTRUDA. The placebo is administered in a manner consistent with the experimental treatment to maintain the double-blind nature of the trial. The placebo does not contain any active pharmaceutical ingredients and is used to assess the efficacy of pembrolizumab by providing a baseline for comparison. The administration schedule and route for the placebo are designed to mimic those of the experimental drug to ensure blinding and consistency in the trial protocol.

Efficacy in the clinical trial titled "Adjuvant Therapy with Pembrolizumab versus Placebo in Resected High-risk Stage II Melanoma: A Randomized, Double-blind Phase 3 Study (KEYNOTE 716)" will be assessed primarily through **Recurrence-free Survival (RFS)**. This primary endpoint will compare the time from randomization to the first occurrence of melanoma recurrence or death from any cause between the treatment arms. Secondary endpoints include **Distant Metastasis-free Survival (DMFS)**, **Overall Survival (OS)**, the number of participants who experienced at least one adverse event (AE), and the number of participants who discontinued study treatment due to an AE.

The trial will utilize a randomized, double-blind design to ensure unbiased assessment of efficacy. The efficacy parameters will be collected and analyzed at predefined intervals throughout the study duration, which is estimated to conclude by October 12, 2033. The study will involve the administration of Pembrolizumab, a biological product, as a concentrate for solution for infusion, with a maximum treatment period of 36 months. The trial aims to confirm the safety and efficacy of Pembrolizumab in the target population, which includes patients with surgically resected and histologically/pathologically confirmed Stage IIB or IIC cutaneous melanoma.