A Phase 3, Randomized Study to Evaluate the Efficacy and Safety of Pembrolizumab (MK-3475) + Lenvatinib (E7080/MK-7902) + Chemotherapy Compared with Standard of Care as First-line Intervention in Participants with Metastatic Esophageal Carcinoma

The primary objective of this Phase 3, randomized study is to compare **overall survival** (OS) between treatment arms in participants with metastatic **esophageal carcinoma**. This objective is clinically relevant as it directly assesses the efficacy of the treatment regimens in prolonging the life of patients, which is a critical endpoint in oncology trials.

Secondary objectives include:

• Comparing **progression-free survival** (PFS) per RECIST 1.1, as determined by blinded independent central review (BICR), between treatment arms.
• Comparing **objective response rate** (ORR) per RECIST 1.1, as determined by BICR, between treatment arms.
• Evaluating **duration of response** (DOR) per RECIST 1.1, as determined by BICR, between treatment arms.
• Comparing OS, PFS, ORR, and DOR per RECIST 1.1 assessed by BICR between treatment arms in participants whose tumors are PD-L1 CPS ≥10.
• Evaluating the safety and tolerability profile of lenvatinib + pembrolizumab in combination with chemotherapy versus pembrolizumab + chemotherapy.
• Comparing lenvatinib + pembrolizumab in combination with chemotherapy compared with pembrolizumab + chemotherapy with respect to mean change from baseline in health-related quality of life (HRQoL) using the EORTC QLQ-C30 and QLQ-OES18.
• Comparing lenvatinib + pembrolizumab in combination with chemotherapy compared with pembrolizumab + chemotherapy with respect to time to deterioration (TTD) in HRQoL using the EORTC QLQ-C30 and QLQ-OES18.

The clinical trial involves a total of **629 participants** diagnosed with **esophageal carcinoma**, specifically metastatic squamous cell carcinoma of the esophagus. 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 inclusion criteria, including a confirmed diagnosis and adequate organ function. The trial population is characterized by a requirement for controlled blood pressure, with or without antihypertensive medications, and adherence to contraceptive measures for both genders during and after the intervention period. The study does not exclude vulnerable populations, indicating a diverse participant base. Lifestyle considerations such as diet and physical activity are not specified, but participants must maintain certain health standards to ensure safety and efficacy during the trial.

The clinical trial is a **Phase 3**, randomized, double-blind, controlled study designed to evaluate the efficacy and safety of a combination therapy involving **pembrolizumab**, **lenvatinib**, and chemotherapy compared to the standard of care in participants with metastatic **esophageal carcinoma**. The trial is structured into two parts: Part 1 focuses on the safety and tolerability of the treatment combination, while Part 2 aims to compare overall survival between treatment arms. The trial is expected to run from August 2021 to May 2027, with participant involvement potentially lasting up to 108 weeks, depending on individual response and treatment tolerance.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of metastatic squamous cell carcinoma of the esophagus and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment effects, assess safety, and evaluate efficacy endpoints such as progression-free survival and objective response rate. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted.

Participant involvement may be terminated early due to conditions such as the occurrence of dose-limiting toxicities, adverse events leading to discontinuation, or withdrawal of consent. The trial's primary endpoints include the number of participants with dose-limiting toxicities and overall survival, while secondary endpoints focus on progression-free survival, objective response rate, and health-related quality of life changes. The study employs a rigorous methodology to ensure the reliability and validity of the results, with assessments conducted by blinded independent central review.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Levoleucovorin disodium**, also known as disodium levofolinate, is administered as an intravenous infusion. The pharmaceutical form is coded as PHF675, with a maximum daily dose of 200 mg/m² and a total maximum dose of 1200 mg/m² over a treatment period of 12 weeks.

**Cisplatin**, known by synonyms such as cis-diamminedichloroplatinum, is also administered via intravenous infusion. It is provided in the pharmaceutical form PHF00230MIG, with a maximum daily dose of 80 mg/m² and a total maximum dose of 480 mg/m² over 18 weeks.

**Lenvatinib** is administered orally in capsule form. The maximum daily dose is 20 mg, with a total maximum dose of 14600 mg over a 24-week period. This medication is identified by the sponsor product code MK-7902.

**Anhydrous calcium folinate** is delivered through intravenous infusion, with a pharmaceutical form coded as PHF00169MIG. The maximum daily dose is 400 mg/m², and the total maximum dose is 2400 mg/m² over 12 weeks.

**Fluorouracil**, also known as 5-FU, is administered via intravenous infusion in the form PHF00230MIG. The maximum daily dose is 2400 mg/m², with a total maximum dose of 140000 mg/m² over a 105-week period.

**Pembrolizumab**, marketed as Keytruda, is administered as an intravenous infusion. It is provided as a concentrate for solution for infusion, with a maximum daily dose of 400 mg and a total maximum dose of 7200 mg over 108 weeks. It is identified by the sponsor product code MK-3475.

**Oxaliplatin** is administered via intravenous infusion in the pharmaceutical form PHF00230MIG. The maximum daily dose is 85 mg/m², with a total maximum dose of 1020 mg/m² over a 24-week period.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy and safety of these medications in combination with standard chemotherapy as a first-line intervention in participants with metastatic esophageal carcinoma.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint for Part 2 of the main study is **Overall Survival (OS)** in all participants. Secondary endpoints include **Progression-free Survival (PFS)**, **Objective Response Rate (ORR)**, and **Duration of Response (DOR)**, all evaluated per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR). Additionally, OS, PFS, ORR, and DOR will be specifically assessed in participants with a Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10.

Other secondary endpoints involve the number of participants experiencing adverse events (AEs) and those who discontinue study treatment due to AEs. Health-related quality of life (HRQoL) will be measured using the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) and the EORTC Quality of Life Questionnaire-Oesophageal Module (QLQ-OES18). Changes from baseline in HRQoL scores and time to deterioration (TTD) in these scores will also be evaluated.