A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate Pembrolizumab Versus Placebo as Adjuvant Therapy Following Surgery and Radiation in Participants with High-risk Locally Advanced Cutaneous Squamous Cell Carcinoma (LA cSCC) (KEYNOTE-630).

The primary objective of this study is to compare the **recurrence-free survival** (RFS) in individuals with resectable high-risk locally advanced cutaneous squamous cell carcinoma (LA cSCC) who receive pembrolizumab versus those who receive a placebo as adjuvant therapy. This objective is clinically relevant as it aims to determine the efficacy of pembrolizumab in preventing cancer recurrence, which is crucial for improving long-term outcomes in patients with high-risk LA cSCC.

Secondary objectives include:

• Comparing overall survival (OS) between individuals receiving pembrolizumab and those receiving placebo as adjuvant therapy, which is important for assessing the long-term benefits of pembrolizumab on patient survival.
• Comparing the mean change from baseline in health-related quality of life (HRQoL) scores, using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30, between the two groups. This objective evaluates the impact of pembrolizumab on patients' quality of life, an essential aspect of cancer treatment.
• Determining the safety and tolerability of pembrolizumab as adjuvant therapy, which is critical for understanding the risk-benefit profile of the treatment.

The clinical trial involves a total of **269 participants** diagnosed with **resectable high-risk Locally Advanced Cutaneous Squamous Cell Carcinoma (LA cSCC)**. 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 inclusion criteria, such as having histologically confirmed cutaneous squamous cell carcinoma as the primary site of malignancy and a life expectancy of more than three months. The trial population is characterized by a good general health status, as indicated by an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. All participants have undergone complete macroscopic resection of known cSCC disease and completed adjuvant radiotherapy. The study does not include pregnant or breastfeeding individuals, nor persons of childbearing potential. The trial also involves a vulnerable population, ensuring comprehensive representation in the study. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy of **pembrolizumab** versus placebo as adjuvant therapy in participants with high-risk locally advanced cutaneous squamous cell carcinoma (LA cSCC) following surgery and radiation. The primary objective is to compare the recurrence-free survival (RFS) between the two groups, as assessed by the investigator and confirmed by biopsy. Secondary endpoints include overall survival, changes in quality of life scores, and the percentage of participants experiencing adverse events or discontinuing treatment due to adverse events.

The trial is expected to run from April 2019 to August 2028, with participant involvement lasting up to 36 months. Participants will be randomly assigned to receive either pembrolizumab or a placebo, both administered via intravenous infusion. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor health and treatment response, and an end-of-study visit to assess final outcomes. Participants must have histologically confirmed LA cSCC with at least one high-risk feature, have completed adjuvant radiotherapy, and be disease-free as assessed by the investigator. Conditions for early termination from the study include significant adverse events or withdrawal of consent.

The clinical trial involves the administration of **KEYTRUDA** (pembrolizumab), a **concentrate for solution for infusion**. Pembrolizumab is an active substance classified under the ATC code L01FF02. It is provided as a 25 mg/mL concentrate and is administered via **intravenous infusion**. The maximum daily dose is 400 mg, with a total maximum dose of 10,800 mg over a treatment period of up to 36 months. Pembrolizumab is produced by Merck Sharp & Dohme BV and is used as an adjuvant therapy in this study to evaluate its efficacy in improving recurrence-free survival in participants with high-risk locally advanced cutaneous squamous cell carcinoma (LA cSCC).

The study also includes a **placebo** treatment, which is a normal saline solution designed to mimic the administration of KEYTRUDA. The placebo is administered in the same pharmaceutical form and route as pembrolizumab, ensuring the double-blind nature of the trial. The placebo serves as a comparator to assess the efficacy of pembrolizumab in the study population. Both treatments are administered under controlled conditions, with participant compliance monitored throughout the trial to ensure adherence to the dosing schedule and protocol requirements.

Efficacy in this clinical trial will be assessed primarily through **Recurrence-Free Survival (RFS)**, as evaluated by the investigator and confirmed by biopsy. This endpoint is designed to measure the time from randomization until the recurrence of cutaneous squamous cell carcinoma (cSCC) or death from any cause, whichever occurs first. Secondary endpoints include **Overall Survival (OS)**, changes from baseline in the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) score, changes in physical functioning using EORTC QLQ-C30 items 1-5 score, and the percentage of participants experiencing adverse events (AEs) or discontinuing study treatment due to AEs.

The efficacy parameters will be collected and analyzed at various timepoints throughout the study, with specific intervals determined by the study protocol. The EORTC QLQ-C30 is a validated tool used to assess the quality of life in cancer patients, providing a comprehensive evaluation of the participants' well-being and physical functioning. The study will employ rigorous methods to ensure the accuracy and reliability of the data collected, with all assessments conducted in accordance with standardized procedures. The trial is designed to provide robust evidence on the efficacy of pembrolizumab as an adjuvant therapy in participants with high-risk locally advanced cutaneous squamous cell carcinoma following surgery and radiation.