A Randomized, Double-blind, Placebo-controlled Phase 3 Trial of Pembrolizumab (MK-3475) Versus Placebo in Participants with Esophageal Carcinoma Receiving Concurrent Definitive Chemoradiotherapy (KEYNOTE 975)

The primary objective of this Phase 3 trial is to compare the efficacy of concurrent definitive chemoradiotherapy (**dCRT**) combined with **pembrolizumab** versus dCRT combined with placebo in participants with **esophageal carcinoma**. The comparison focuses on event-free survival (EFS) as assessed by investigators through radiological evaluation or histopathological confirmation. This assessment is conducted in participants whose tumors express programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥10, CPS ≥1, and across all participants. Additionally, the trial aims to compare overall survival (OS) between the two treatment groups within the same PD-L1 expression subgroups. These objectives are clinically relevant as they aim to determine the potential benefit of pembrolizumab in improving survival outcomes in esophageal carcinoma, a malignancy with significant morbidity and mortality.

Secondary objectives include evaluating the safety and tolerability profile of the combination of dCRT and pembrolizumab. This is crucial for understanding the risk-benefit ratio of the treatment regimen and ensuring patient safety during therapy.

The clinical trial involves a total of **493 participants** diagnosed with **esophageal carcinoma**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, indicating adult and elderly participants. The trial population was selected based on specific inclusion criteria, such as having a histologically or cytologically confirmed diagnosis of esophageal carcinoma with certain staging and metastasis characteristics, being deemed suitable for definitive chemoradiotherapy (dCRT), and having an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Participants are required to have adequate organ function and must not be eligible for curative surgery. Both male and female participants are required to adhere to strict contraceptive measures during the study. The trial includes a vulnerable population, and lifestyle considerations such as diet and physical activity are not specified. The study aims to compare the efficacy of dCRT combined with pembrolizumab versus dCRT with placebo in terms of event-free survival (EFS) and overall survival (OS) across different PD-L1 expression levels.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** Phase 3 study to evaluate the efficacy and safety of **pembrolizumab** in combination with definitive chemoradiotherapy (dCRT) compared to dCRT with placebo in participants with **esophageal carcinoma**. The trial aims to assess overall survival (OS) and event-free survival (EFS) as primary endpoints, with secondary endpoints including the number of participants experiencing adverse events and those discontinuing treatment due to adverse events. The trial is expected to run from January 24, 2020, to February 21, 2026.

Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically or cytologically confirmed diagnosis, suitability for dCRT, and adequate organ function. Following the screening, participants will be randomized to receive either pembrolizumab or placebo in conjunction with dCRT. The treatment period will last up to 12 months, with regular follow-up visits to monitor safety, efficacy, and any adverse events. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected length of participant involvement is approximately 12 months, with conditions for early termination including significant adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. Participants are required to adhere to contraceptive guidelines during the study and for a specified period after the last dose of chemotherapy or pembrolizumab. The trial is conducted under strict regulatory and ethical standards to ensure participant safety and data integrity.

The clinical trial involves the administration of **KEYTRUDA** (pembrolizumab), a concentrate for solution for infusion, with a concentration of 25 mg/mL. The pharmaceutical form is a solution for infusion, and it is administered intravenously. The maximum daily dose is 400 mg, with a total maximum dose of 3600 mg over a treatment period of up to 12 months. Pembrolizumab is a protein-based therapeutic agent, specifically a monoclonal antibody, and is used as the test treatment in this study.

Participants in the trial may also receive a **placebo** to Keytruda, which is a saline solution. The placebo is administered in the same manner as Keytruda, as a solution for infusion, to maintain the double-blind nature of the study. The placebo serves as a control to evaluate the efficacy and safety of pembrolizumab.

**FOLINIC ACID** is included as an auxiliary treatment in the trial. It is provided as a solution for injection, with a maximum daily dose of 400 mg and a total maximum dose of 2400 mg over a 6-month period. Folinic acid is a chemically derived substance used to mitigate the side effects of certain chemotherapy drugs.

**CALCIUM FOLINATE** is another auxiliary treatment, available as a solution for injection or infusion. The dosing schedule allows for a maximum daily dose of 400 mg and a total maximum dose of 2400 mg over 6 months. Calcium folinate is chemically similar to folinic acid and serves a similar protective role during chemotherapy.

**CISPLATIN** is administered as a solution for infusion, with a maximum daily dose of 75 mg/m² and a total maximum dose of 300 mg/m² over a 4-month period. Cisplatin is a platinum-based chemotherapy agent used to treat various types of cancer, including esophageal carcinoma.

**FLUOROURACIL** is provided as a solution for infusion, with a maximum daily dose of 800 mg and a total maximum dose of 4800 mg over 6 months. Fluorouracil is a chemotherapy drug that interferes with the growth of cancer cells.

**OXALIPLATIN** is also administered as a solution for infusion, with a maximum daily dose of 85 mg and a total maximum dose of 510 mg over 6 months. Oxaliplatin is a platinum-based chemotherapy drug used in combination with other agents to treat cancer.

**CALCIUM LEVOFOLINATE** is included as an auxiliary treatment, provided as a solution for infusion. The dosing schedule allows for a maximum daily dose of 400 mg and a total maximum dose of 2400 mg over 6 months. Calcium levofolinate is chemically related to folinic acid and is used to reduce the toxic effects of chemotherapy.

Efficacy in this clinical trial will be assessed using the primary endpoints of **Overall Survival (OS)** and **Event-free Survival (EFS)**. These endpoints will be evaluated to compare the efficacy of pembrolizumab in combination with definitive chemoradiotherapy (dCRT) versus placebo with dCRT in participants with esophageal carcinoma. The assessment of OS will involve measuring the time from randomization to death from any cause, while EFS will be determined by the time from randomization to the first occurrence of disease progression, as assessed by radiological methods or histopathologic confirmation, or death from any cause.

The trial will also include secondary endpoints, which focus on safety parameters such as the number of participants experiencing an adverse event (AE) and the number of participants discontinuing study treatment due to an AE. These efficacy and safety parameters will be collected and analyzed throughout the trial duration, with specific timepoints for assessment not explicitly detailed in the provided data. The trial aims to provide a comprehensive evaluation of the treatment's impact on survival and safety in the target population.