Evaluation of Perioperative Pembrolizumab and Enfortumab Vedotin with Cystectomy Versus Cystectomy Alone in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer

The primary objective of this study is to compare **event-free survival** (EFS) between Arm C, which involves perioperative enfortumab vedotin in combination with pembrolizumab and radical cystectomy plus pelvic lymph node dissection (RC+PLND), and Arm B, which involves RC+PLND alone. This comparison is clinically relevant as it aims to determine the efficacy of adding enfortumab vedotin and pembrolizumab to the standard surgical treatment in patients with muscle-invasive bladder cancer who are ineligible for or decline cisplatin.

Secondary objectives include:

• Comparing EFS between Arm A (perioperative pembrolizumab and RC+PLND) and Arm B.
• Comparing overall survival (OS) between Arm C and Arm B, and between Arm A and Arm B.
• Comparing pathologic complete response (pCR) rates between Arm C and Arm B, and between Arm A and Arm B, based on central pathologic review.
• Assessing disease-free survival (DFS) in participants from Arm A, Arm B, and Arm C who are disease-free after surgery.
• Comparing the rates of pathologic downstaging (pDS) between Arm A and Arm B, and between Arm C and Arm B.
• Evaluating the safety and tolerability of perioperative pembrolizumab with RC+PLND and perioperative enfortumab vedotin in combination with pembrolizumab with RC+PLND.

The clinical trial involves a total of **384 participants** diagnosed with **Muscle Invasive Bladder Cancer**. The study population includes both male and female subjects, with age categories ranging from adults to older adults. Participants were selected based on specific inclusion criteria, such as having a histologically confirmed diagnosis of urothelial carcinoma with predominant urothelial histology, being clinically nonmetastatic, and being eligible for radical cystectomy plus pelvic lymph node dissection. The trial does not include a vulnerable population. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, and adequate organ function. Lifestyle considerations include the use of contraception for male and female participants during the intervention period and for a specified duration after the last dose of the study drugs. The trial does not specify any particular dietary or physical activity requirements.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy and safety of perioperative **pembrolizumab** and **enfortumab vedotin** in combination with radical cystectomy and pelvic lymph node dissection (RC+PLND) compared to RC+PLND alone in participants with muscle-invasive bladder cancer who are ineligible for or decline cisplatin. The trial aims to assess event-free survival (EFS) as the primary endpoint, with secondary endpoints including overall survival (OS), pathological complete response (pCR) rate, disease-free survival (DFS), and the incidence of adverse events (AEs).

The trial is expected to span from June 2019 to December 2027, with participant involvement lasting up to 27 months, depending on the treatment arm. Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as histologically confirmed diagnosis, nonmetastatic status, and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, with assessments including imaging, laboratory tests, and physical examinations. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Participants may be withdrawn from the study early due to reasons such as disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision based on clinical judgment. The trial's design ensures rigorous monitoring and data collection to evaluate the therapeutic potential of the investigational treatments in improving outcomes for patients with muscle-invasive bladder cancer.

The clinical trial involves the administration of **pembrolizumab**, marketed under the name Keytruda, which is provided as a 25 mg/mL concentrate for solution for infusion. This experimental medication is classified as a biological product and is administered via **intravenous infusion**. The maximum daily dose of pembrolizumab is 200 mg, with a total maximum dose of 3400 mg over a treatment period of up to 12 months. Pembrolizumab is a protein-based therapeutic agent, specifically an immune checkpoint inhibitor, and is not formulated for pediatric use. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

Another experimental medication used in the trial is **enfortumab vedotin**, which is also administered as a solution for infusion. This biological/vaccine product is delivered through intravenous infusion, with a maximum daily dose of 125 mg and a total maximum dose of 2250 mg over a treatment period of up to 27 weeks. Enfortumab vedotin is a protein-based agent, functioning as an antibody-drug conjugate, and is not intended for pediatric formulations. The dosing schedule is carefully monitored to maintain participant compliance and ensure the integrity of the trial results.

In this study, the experimental treatments are compared against a standard-of-care therapy, which involves radical cystectomy plus pelvic lymph node dissection (RC+PLND) in participants with muscle-invasive bladder cancer who are ineligible for or decline cisplatin treatment. The trial aims to evaluate the event-free survival between the experimental arms and the standard-of-care arm, with rigorous monitoring of drug administration and participant adherence to the treatment protocols.

The efficacy of the clinical trial will be assessed primarily through the measurement of **Event-Free Survival (EFS)** between Arm C, which involves perioperative enfortumab vedotin in combination with pembrolizumab and radical cystectomy plus pelvic lymph node dissection (RC+PLND), and Arm B, which involves RC+PLND alone. Secondary endpoints include EFS between Arm A and Arm B, **Overall Survival (OS)** between Arm C and Arm B, OS between Arm A and Arm B, **Pathological Complete Response (pCR) Rate** between Arm C and Arm B, pCR Rate between Arm A and Arm B, **Disease-Free Survival (DFS)**, **Pathologic Downstaging (pDS) Rate** between Arm A and Arm B, and pDS Rate between Arm C and Arm B. Additionally, the trial will monitor the number of participants experiencing an adverse event (AE), the number of participants discontinuing study treatment due to an AE, and the number of participants experiencing perioperative complications.