A Randomized, Phase 3, Double-Blind Study of Chemoradiotherapy With or Without Pembrolizumab for the Treatment of High-risk, Locally Advanced Cervical Cancer (KEYNOTE-A18 / ENGOT-cx11/GOG-3047)

The primary objective of this study is to evaluate the efficacy of **pembrolizumab** in combination with concurrent chemoradiotherapy compared to chemoradiotherapy plus placebo in patients with high-risk, locally advanced cervical cancer. This will be assessed by comparing progression-free survival per RECIST 1.1, as determined by the investigator or through histopathologic confirmation of suspected disease progression, in the absence of radiographic disease progression. Additionally, the study aims to compare overall survival between the two treatment groups. These objectives are clinically relevant as they address the potential of pembrolizumab to improve survival outcomes in a high-risk patient population.

Secondary objectives include:

• Comparing progression-free survival at 2 years and overall survival at 3 years.
• Evaluating complete and objective response rates at 12 weeks post-treatment.
• Assessing progression-free survival after next-line treatment and changes in quality of life and symptom experience using EORTC QLQ-C30 and CX24 scales.
• Evaluating the safety and tolerability of pembrolizumab in combination with chemoradiotherapy.

The clinical trial involves a total of **439 participants** diagnosed with **locally advanced cervical cancer**. The study population is exclusively female, with an age range that includes adults and older adults. Participants were selected based on specific criteria, including having high-risk locally advanced cervical cancer as defined by the International Federation of Gynecology and Obstetrics (FIGO) 2014 Stages IB2-IIB with node-positive disease or Stages III-IVA. All participants have histologically confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix and have not previously received any definitive surgical, radiation, or systemic therapy for cervical cancer. The trial excludes male subjects and does not involve a vulnerable population. Participants are required to have 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 radiographically evaluable disease. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy and safety of concurrent chemoradiotherapy with or without **pembrolizumab** in patients with high-risk, locally advanced cervical cancer. The trial aims to compare progression-free survival and overall survival between the two treatment groups. Participants will be randomly assigned to receive either chemoradiotherapy plus pembrolizumab or chemoradiotherapy plus a placebo. The study is expected to last until December 2025, with recruitment having started in March 2020.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as having high-risk locally advanced cervical cancer and adequate organ function. Following the screening, eligible participants will be enrolled and randomized into one of the treatment arms. The treatment period will involve regular follow-up visits to monitor the participants' health status, assess treatment efficacy, and record any adverse events. These visits will include clinical assessments, imaging studies, and laboratory tests as per the study protocol.

The end-of-study visit will occur after the completion of the treatment period or upon early termination from the study. Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The expected length of participant involvement in the study is approximately 105 weeks, depending on individual response and tolerance to the treatment. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of **Cisplatin**, a chemical compound known for its antineoplastic properties. Cisplatin is administered in the form of an intravenous infusion. The dosage is calculated based on body surface area, with a maximum daily dose of 40 mg/m² and a total maximum dose of 240 mg/m² over a treatment period of 56 days. The pharmaceutical form of Cisplatin is denoted as PHF00015MIG, and it is not a pediatric formulation. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

In addition to Cisplatin, the trial includes the administration of **Pembrolizumab**, marketed under the name Keytruda. Pembrolizumab is a biological agent classified as a protein, specifically a monoclonal antibody, and is provided as a 25 mg/mL concentrate for solution for infusion. The maximum daily dose of Pembrolizumab is 400 mg, with a total maximum dose of 7000 mg over a treatment period of 105 days. The route of administration is also intravenous infusion. Pembrolizumab is produced by Merck Sharp & Dohme B.V. and is not intended for pediatric use. The dosing schedule and participant compliance are closely monitored to ensure the integrity of the trial data.

The study also employs a **placebo** to Pembrolizumab, which serves as a comparator treatment to evaluate the efficacy of Pembrolizumab in combination with chemoradiotherapy. The placebo is designed to mimic the administration of Pembrolizumab without containing the active substance. The placebo is administered in a manner consistent with the active treatment to maintain the double-blind nature of the trial. Participant adherence to the placebo regimen is monitored to ensure the validity of the comparative analysis.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression-Free Survival (PFS)** as per the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), assessed by the investigator, and **Overall Survival (OS)**. Secondary endpoints encompass a range of measures, including PFS assessed by Blinded Independent Central Review (BICR), PFS at Month 24, OS at Month 36, and Complete Response (CR) Rate at Week 12, all evaluated using RECIST 1.1 criteria. Additionally, Objective Response Rate (ORR) and PFS in Programmed Cell Death 1 Ligand 1 (PD-L1) positive participants will be assessed both by the investigator and BICR.

Further secondary endpoints include changes from baseline in quality of life scores using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and the Symptom Specific Scale for Cervical Cancer (EORTC QLQ-CX24). The number of participants experiencing adverse events and those discontinuing treatment due to adverse events will also be recorded. Efficacy assessments will be conducted at specified timepoints, including Week 12 and Month 24, with overall survival evaluated at Month 36. These assessments will be performed using validated scales and criteria to ensure accuracy and reliability in measuring the trial's outcomes.