A Phase 3, Randomized, Double-Blind Study of Pembrolizumab versus Placebo in Combination With Adjuvant Chemotherapy With or Without Radiotherapy for the Treatment of Newly Diagnosed High-Risk Endometrial Cancer After Surgery With Curative Intent (KEYNOTE-B21 / ENGOT-en11 / GOG-3053)

The primary objective of this Phase 3, randomized, double-blind study is to compare **pembrolizumab** with placebo, both in combination with adjuvant chemotherapy with or without radiotherapy, in terms of **disease-free survival** (DFS) and **overall survival** (OS) in patients with newly diagnosed high-risk **endometrial cancer** following surgery with curative intent. This evaluation is clinically relevant as it aims to determine the efficacy of pembrolizumab in prolonging survival and preventing disease recurrence, which are critical outcomes for improving patient prognosis in high-risk endometrial cancer.

Secondary objectives include:

• Comparing pembrolizumab with placebo regarding DFS assessed radiographically by blinded independent central review or by histopathologic confirmation of disease recurrence.
• Comparing pembrolizumab with placebo concerning OS and DFS assessed radiographically by the investigator or by histopathologic confirmation of disease recurrence, stratified by PD-L1 status and tumor mutation burden (TMB) status.
• Evaluating the safety and tolerability of pembrolizumab in combination with adjuvant chemotherapy with or without radiotherapy.
• Comparing pembrolizumab with placebo in terms of changes from baseline in the EORTC Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status/Quality of Life (QoL) scale and Physical Function subscale, and the EORTC endometrial cancer-specific QoL module (EORTC QLQ-EN24).

The clinical trial involves a total of **795 participants** who are exclusively female, reflecting the study's focus on **endometrial cancer**. The participants are selected based on specific criteria, including a histologically confirmed new diagnosis of Endometrial Carcinoma or Carcinosarcoma, and have undergone curative intent surgery. The age range of the participants spans from adults to older adults, specifically categorized as age groups 3 and 4. Participants are required to be disease-free with no evidence of loco-regional disease or distant metastasis post-operatively and on imaging. They must not have received any prior radiation or systemic therapy for endometrial cancer. The trial population is characterized by an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Additionally, participants must have adequate organ function and provide a tumor tissue sample for histology and mismatch repair status determination. The trial does not include male subjects and involves a vulnerable population, emphasizing the need for careful ethical considerations in the study design and execution.

The clinical trial is a **Phase 3, randomized, double-blind, controlled study** designed to evaluate the efficacy and safety of **pembrolizumab** in combination with adjuvant chemotherapy, with or without radiotherapy, compared to a placebo in patients with newly diagnosed high-risk **endometrial cancer** following surgery with curative intent. The trial aims to assess **disease-free survival (DFS)** and **overall survival (OS)** as primary endpoints, with secondary endpoints including DFS and OS assessed by various criteria, as well as the incidence of adverse events and changes in quality of life scores.

The trial is expected to last until March 2026, with participant recruitment having commenced in January 2021. Participants will be involved in the study for a maximum treatment period of 54 weeks, during which they will receive **intravenous infusions** of the investigational products. The study includes 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. Participants must meet specific inclusion criteria, such as having a histologically confirmed diagnosis of endometrial carcinoma or carcinosarcoma and having undergone surgery with curative intent. They must also be disease-free post-operatively and have not received prior systemic therapy for endometrial cancer.

Conditions that may lead to early termination from the study include the occurrence of unacceptable adverse events, withdrawal of consent, or any significant protocol deviations. The trial is conducted under strict regulatory guidelines to ensure the safety and well-being of participants, with all investigational products administered as per the study protocol. The trial's design and methodology are structured to provide robust data on the potential benefits of pembrolizumab in this patient population, contributing to the understanding of its role in the treatment of high-risk endometrial cancer.

The clinical trial involves the administration of several **experimental medications** and a placebo. **Carboplatin** is administered as an intravenous infusion. It is a chemical substance with the ATC code L01XA02. The pharmaceutical form is designated as PHF00230MIG. The maximum daily dose is 900 mg, with a total maximum dose of 5400 mg over a treatment period of 18 weeks. The dosing schedule and participant compliance are monitored throughout the trial.

**Anhydrous Docetaxel** is also administered via intravenous infusion. It is a chemical substance with the ATC code L01CD02. The pharmaceutical form is PHF00230MIG. The maximum daily dose is 75 mg/m², with a total maximum dose of 450 mg/m² over 18 weeks. The administration and dosing are carefully monitored to ensure adherence to the protocol.

**Cisplatin** is another chemical substance used in the trial, administered through intravenous infusion. It has the ATC code L01XA01 and is provided in the pharmaceutical form PHF00230MIG. The maximum daily dose is 75 mg/m², with a total maximum dose of 450 mg/m² over the course of 18 weeks. Compliance with the dosing schedule is closely observed.

**Paclitaxel** is administered as an intravenous infusion, classified under the ATC code L01CD01. The pharmaceutical form is PHF00016MIG. The maximum daily dose is 175 mg/m², with a total maximum dose of 1050 mg/m² over 18 weeks. Participant adherence to the dosing regimen is monitored throughout the study.

The trial includes a **placebo** for Pembrolizumab, which serves as a comparator treatment. The placebo is not associated with any active substance and is used to maintain the double-blind nature of the study.

**Pembrolizumab**, marketed as Keytruda, is administered as a concentrate for solution for infusion. It is a biologic substance with the ATC code L01FF02. The pharmaceutical form is a solution for infusion, with a concentration of 25 mg/mL. The maximum daily dose is 400 mg, with a total maximum dose of 3600 mg over a treatment period of 54 weeks. The administration is conducted via intravenous infusion, and participant compliance is rigorously monitored.

The efficacy of the clinical trial will be assessed using primary and secondary endpoints. The primary endpoints include **Disease-Free Survival (DFS)**, as assessed radiographically by the investigator or through histopathologic confirmation of suspected disease recurrence, and **Overall Survival (OS)**. Secondary endpoints will further evaluate DFS and OS, incorporating assessments by Blinded Independent Central Review (BICR) and analyses based on Combined Positivity Score (CPS)-determined Programmed Cell Death 1 Ligand 1 (PD-L1) status and Tumor Mutation Burden (TMB) status. Additionally, the trial will monitor the number of participants experiencing adverse events (AEs) and those discontinuing treatment due to AEs. Changes from baseline in quality of life will be measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the symptom-specific scale for endometrial cancer (EORTC QLQ-EN24).

These efficacy parameters will be collected and analyzed at various timepoints throughout the trial, with specific methods for radiographic and histopathologic assessments. The trial is designed to compare pembrolizumab with placebo, both in combination with adjuvant chemotherapy, with or without radiotherapy, in patients with newly diagnosed high-risk endometrial cancer following surgery with curative intent. The trial is expected to conclude by March 2026, with recruitment having started in January 2021.