Efficacy and Safety of Pembrolizumab with Chemoradiotherapy versus Chemoradiotherapy Alone in Muscle-Invasive Bladder Cancer: A Phase III Randomized Trial

The primary objective of this Phase 3, randomized, double-blind, placebo-controlled clinical trial is to compare **bladder intact event-free survival** in participants with **muscle-invasive bladder cancer** (MIBC) between two treatment arms: Arm A, which receives pembrolizumab in combination with chemoradiotherapy, and Arm B, which receives a placebo with chemoradiotherapy. This objective is clinically relevant as it aims to determine the efficacy of pembrolizumab in maintaining bladder integrity and delaying disease progression, which is crucial for improving patient outcomes and quality of life.

Secondary objectives include:

• Comparing overall survival between the two treatment arms.
• Evaluating the rate of metastasis-free survival.
• Assessing the time to occurrence of non–muscle-invasive bladder cancer (NMIBC).
• Evaluating the safety and tolerability of pembrolizumab combined with chemoradiotherapy.
• Assessing changes from baseline in health-related quality of life and time to deterioration using general and disease-specific instruments.
• Evaluating the time to cystectomy.

The clinical trial involves a total of **348 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 specific criteria, including a histologically confirmed initial diagnosis of muscle-invasive bladder cancer with predominant urothelial histology and clinically nonmetastatic status. All participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, indicating they are ambulatory and capable of self-care. The trial includes individuals who are eligible to receive chemoradiotherapy and one of the protocol-specified radiosensitizing chemotherapy regimens. Participants must demonstrate adequate organ function and adhere to specific lifestyle considerations regarding contraception and reproductive health during and after the intervention period. The trial population includes a vulnerable population, ensuring comprehensive representation in the study.

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of **pembrolizumab** in combination with chemoradiotherapy (CRT) compared to CRT alone in participants with muscle-invasive bladder cancer (MIBC). The trial aims to assess the primary endpoint of bladder intact event-free survival (BI-EFS) and secondary endpoints including overall survival, metastasis-free survival, and quality of life measures. The study is expected to run from May 2020 to November 2031, with participant involvement lasting up to 12 months, depending on the treatment arm and individual response.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of MIBC, nonmetastatic status, and adequate organ function. Following randomization, participants will receive either pembrolizumab plus CRT or placebo plus CRT. Study visits will include regular assessments through cystoscopy, biopsy, urine cytology, and radiographic evaluations to monitor disease progression and treatment response. Follow-up visits will occur at specified intervals to ensure ongoing safety and efficacy monitoring.

The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to evaluate the long-term effects of the treatment. Participants may be withdrawn from the study early if they experience unacceptable adverse events, disease progression, or if they withdraw consent. The trial's design ensures rigorous monitoring and data collection to provide comprehensive insights into the treatment's impact on MIBC.

The clinical trial involves the administration of several **experimental medications** and a placebo. **Fluorouracil** is provided as a solution for injection/infusion, with a maximum daily dose of 500 mg/m² and a total dose not exceeding 5000 mg/m² over a treatment period of up to 10 days. The route of administration is via **intravenous infusion**. This chemical agent is used as an auxiliary treatment in the trial.

**Pembrolizumab**, marketed as Keytruda, is a biological agent provided as a 25 mg/mL concentrate for solution for infusion. The maximum daily dose is 400 mg, with a total dose limit of 3600 mg over a 12-week period. It is administered through intravenous infusion and serves as the primary test medication in the study.

**Gemcitabine Hydrochloride** is administered as a concentrate for solution for infusion, with a maximum daily dose of 27 mg/m² and a total dose of 324 mg/m² over a 6-week period. The administration route is intravenous infusion, and it is used as an auxiliary chemical treatment in the trial.

**Cisplatin** is provided in a similar pharmaceutical form as gemcitabine, with a maximum daily dose of 35 mg/m² and a total dose of 210 mg/m² over a 6-week period. It is also administered via intravenous infusion and serves as an auxiliary chemical agent in the study.

**Mitomycin** is administered as a solution for injection/infusion, with a maximum daily and total dose of 12 mg/m² over a single day. The route of administration is intravenous infusion, and it is used as an auxiliary chemical treatment in the trial.

The **placebo** used in the trial is normal saline, serving as a comparator to pembrolizumab. It is administered in a manner consistent with the active treatment to maintain the double-blind nature of the study. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is **Bladder Intact Event-Free Survival (BI-EFS)**, which will be evaluated by comparing participants in Arm A (pembrolizumab + chemoradiotherapy) with those in Arm B (placebo + chemoradiotherapy). This assessment will be based on cystoscopy, biopsy with central pathology review (if applicable), urine cytology, and radiographic assessment by a blinded independent central review.

Secondary endpoints include Overall Survival (OS), Metastasis-Free Survival (MFS), and Time to Occurrence of Non–Muscle-Invasive Bladder Cancer (NMIBC). Additionally, the trial will measure the number of participants who experienced an adverse event (AE) and those who discontinued the study intervention due to an AE. Patient-reported outcomes will be evaluated using validated instruments such as the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and the Bladder Cancer Index (BCI). Changes from baseline in global health status, physical functioning, and specific domains of the BCI will be assessed, along with the Visual Analog Score (VAS) of the European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L). Time to Deterioration (TTD) in these scores and Time to Cystectomy will also be analyzed.