A Phase 3, Randomized, Double-blind Study to Evaluate Perioperative Pembrolizumab (MK-3475) + Neoadjuvant Chemotherapy versus Perioperative Placebo + Neoadjuvant Chemotherapy in Cisplatin-eligible Participants with Muscle-invasive Bladder Cancer (KEYNOTE-866)

The primary objective of this Phase 3, randomized, double-blind study is to compare **event-free survival (EFS)** between two treatment arms in patients with cisplatin-eligible muscle-invasive bladder cancer. Arm A involves perioperative pembrolizumab combined with neoadjuvant chemotherapy, radical cystectomy (RC), and pelvic lymph node dissection (PLND), while Arm B involves a perioperative placebo with the same treatment regimen. Evaluating EFS is clinically relevant as it provides insights into the effectiveness of pembrolizumab in preventing cancer recurrence or progression, which is crucial for improving patient outcomes.

Secondary objectives include:

• Comparing **pathologic complete response (pCR)** rates between the two arms to assess the efficacy of pembrolizumab in achieving complete tumor eradication.
• Comparing **overall survival (OS)** to determine the long-term survival benefits of pembrolizumab.
• Assessing **disease-free survival (DFS)** to evaluate the duration patients remain free from cancer post-treatment.
• Comparing the rate of **pathologic downstaging (pDS)** to evaluate the extent of tumor reduction before surgery.
• Evaluating the **safety and tolerability** of the pembrolizumab regimen to ensure patient safety during treatment.
• Assessing changes in **patient-reported outcomes** and time to deterioration using the Functional Assessment of Cancer Therapy-Bladder-Cystectomy (FACT-BI-Cys) and the European Quality of Life Questionnaire (EQ-5D-5L) to understand the impact on quality of life.

The clinical trial involves a total of **404 participants** diagnosed with **muscle-invasive bladder cancer**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their histologically confirmed diagnosis of urothelial carcinoma with predominant urothelial histology and clinically non-metastatic bladder cancer, as determined by imaging. All participants are required to be eligible for Radical Cystectomy and Pelvic Lymph Node Dissection, and must have an Eastern Cooperative Oncology Group Performance Status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Adequate organ function is a prerequisite for inclusion. The trial population includes individuals who are part of a vulnerable population, and all participants must agree to use contraception as per the study protocol. 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 study designed to evaluate the efficacy of perioperative **pembrolizumab** combined with neoadjuvant chemotherapy compared to a placebo with neoadjuvant chemotherapy in participants eligible for **cisplatin** with muscle-invasive bladder cancer. The primary objective is to compare event-free survival between the two study arms. The trial is expected to commence recruitment on November 17, 2023, and conclude by June 15, 2025, with an estimated duration of 19 months.

Participants will be randomly assigned to one of two groups: Arm A will receive perioperative pembrolizumab plus neoadjuvant chemotherapy, while Arm B will receive a placebo plus neoadjuvant chemotherapy. Both groups will undergo radical cystectomy and pelvic lymph node dissection. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and adverse events, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to have a histologically confirmed diagnosis of muscle-invasive bladder cancer, be eligible for radical cystectomy, and have adequate organ function, among other criteria.

The expected length of participant involvement is up to 24 months, depending on individual treatment response and tolerability. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or disease progression. The primary endpoint is event-free survival, with secondary endpoints including pathologic complete response rate, overall survival, and disease-free survival, among others. The study aims to provide comprehensive data on the safety and efficacy of pembrolizumab in combination with chemotherapy for this patient population.

**Gemcitabine** is utilized in this clinical trial as a **powder for solution for infusion**. The active substance, gemcitabine, is administered via **intravenous infusion**. The dosage is calculated based on body surface area, with a maximum daily dose of 1000 mg/m² and a total maximum dose of 8000 mg/m² over a treatment period of up to 5 weeks. This medication is classified as a chemical compound and is not a pediatric formulation.

**Cisplatin** is another experimental medication used in the study, provided as a **concentrate for solution for infusion**. The active substance, cisplatin, is also administered through **intravenous infusion**. The maximum daily dose is 70 mg, with a total maximum dose of 280 mg over a 5-week treatment period. Cisplatin is a chemical compound and is not formulated for pediatric use.

The study includes a **placebo** treatment, specifically a **normal saline solution** serving as a placebo to Keytruda. This placebo is used to maintain the double-blind nature of the trial, ensuring unbiased results when comparing the efficacy of the experimental treatments.

**Keytruda** (pembrolizumab) is administered as a **25 mg/mL concentrate for solution for infusion**. The active substance, pembrolizumab, is delivered via **intravenous infusion**. The maximum daily dose is 200 mg, with a total maximum dose of 3400 mg over a treatment period of up to 24 weeks. Keytruda is a biological product and is not intended for pediatric use. The administration of Keytruda is monitored to ensure participant compliance with the dosing schedule.

The efficacy of the clinical trial will be assessed primarily through **Event-Free Survival (EFS)**, which serves as the primary endpoint. Secondary endpoints include **Pathologic Complete Response (pCR) Rate**, **Overall Survival (OS)**, **Disease-Free Survival (DFS)**, and **Pathologic Downstaging (pDS) Rate**. Additionally, the trial will evaluate the number of participants who experienced an adverse event (AE), those who discontinued study treatment due to an AE, and those who experienced perioperative complications. Patient-reported outcomes will also be measured, including changes from baseline in the total score of the Functional Assessment of Cancer Therapy – General (FACT-G), FACT-Bladder (FACT-BI-Cys), FACT-BI-Cys-Trial Outcome Index (TOI), and the European Quality of Life Questionnaire (EQ-5D-5L) Visual Analog Score (VAS). Time to deterioration (TTD) in the total score of FACT-G and EQ-5D-5L VAS will also be assessed.

The trial is designed to compare the efficacy of perioperative pembrolizumab combined with neoadjuvant chemotherapy against a placebo combined with neoadjuvant chemotherapy in participants with muscle-invasive bladder cancer. The study will utilize a randomized, double-blind methodology to ensure unbiased results. The efficacy parameters will be collected and analyzed at various timepoints throughout the trial, with the estimated end date set for June 15, 2025. The trial aims to confirm the safety and efficacy of the treatment regimen in the target population, contributing to the understanding of therapeutic outcomes in muscle-invasive bladder cancer.