Phase 3 Randomized Study of Perioperative Enfortumab Vedotin and Pembrolizumab Versus Neoadjuvant Gemcitabine and Cisplatin in Cisplatin-Eligible Muscle-Invasive Bladder Cancer

The primary objective of this study is to compare **event-free survival** (EFS) between two treatment arms in patients with **muscle-invasive bladder cancer**. Arm A involves perioperative administration of enfortumab vedotin plus pembrolizumab, followed by radical cystectomy and pelvic lymph node dissection. Arm B involves neoadjuvant treatment with gemcitabine and cisplatin, followed by the same surgical procedures. EFS is a critical endpoint as it reflects the time until disease progression, recurrence, or death, providing a comprehensive measure of treatment efficacy in this patient population.

Secondary objectives include:

• Comparing pathologic complete response (pCR) rates between the two arms, which is important for assessing the immediate impact of the treatment on tumor eradication.
• Comparing overall survival (OS) to determine the long-term benefits of the treatment regimens.
• Assessing disease-free survival (DFS) in participants who are disease-free post-surgery, which is crucial for understanding the durability of the treatment response.
• Evaluating the rate of pathologic downstaging (pDS), which indicates the treatment's ability to reduce tumor burden before surgery.
• Evaluating the safety and tolerability of the perioperative regimen in Arm A, ensuring that the treatment is not only effective but also manageable for patients.
• Assessing changes in health-related quality of life (HRQoL) and time to deterioration using validated instruments, which provides insight into the treatment's impact on patients' daily lives and well-being.

The clinical trial involves a total of **415 participants** diagnosed with **Muscle Invasive Bladder Cancer**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of urothelial carcinoma with predominant urothelial histology, clinically non-metastatic bladder cancer, eligibility for Radical Cystectomy and Pelvic Lymph Node Dissection, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. The trial includes a vulnerable population, indicating that special considerations are in place to ensure their safety and well-being. Lifestyle factors such as diet, physical activity, and habits were not specified by the sponsor.

The clinical trial is a **Phase 3**, randomized, open-label study designed to evaluate the efficacy and safety of **enfortumab vedotin** plus **pembrolizumab** compared to neoadjuvant **gemcitabine** and **cisplatin** in participants with muscle-invasive bladder cancer. The trial aims to compare event-free survival (EFS) between the two treatment arms. Participants will be randomly assigned to either Arm A, receiving perioperative enfortumab vedotin and pembrolizumab, or Arm B, receiving neoadjuvant gemcitabine and cisplatin. The study is expected to run from April 2021 to July 2028, with the primary endpoint being EFS and secondary endpoints including pathologic complete response rate, overall survival, and disease-free survival.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of muscle-invasive bladder cancer, non-metastatic status, eligibility for radical cystectomy, and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events. The end-of-study visit will assess the final outcomes and any long-term effects of the treatments. The expected length of participant involvement varies depending on the treatment arm, with a maximum treatment period of 51 weeks for pembrolizumab and 27 weeks for enfortumab vedotin. Conditions that may lead to early termination from the study include significant adverse events or withdrawal of consent.

**Enfortumab Vedotin** is an experimental medication used in this clinical trial. It is administered as an **intravenous infusion** with a pharmaceutical form designated as PHF00230MIG. The dosage is calculated based on body weight, with a maximum daily dose of 1.25 mg/kg and a total maximum dose of 22.5 mg/kg over a treatment period of up to 27 weeks. Enfortumab Vedotin is classified as a biological medicinal product and is not a pediatric formulation.

**Pembrolizumab**, marketed as Keytruda, is another experimental medication in this study. It is provided as a 25 mg/mL concentrate for solution for infusion and is administered 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 51 weeks. Pembrolizumab is also a biological product and is not formulated for pediatric use.

**Cisplatin** is used as a comparator treatment in this trial. It is administered as an **intravenous infusion** in the pharmaceutical form PHF00230MIG. The dosage is based on body surface area, with a maximum daily dose of 70 mg/m² and a total maximum dose of 280 mg/m² over a 12-week treatment period. Cisplatin is classified as a chemical medicinal product and is not a pediatric formulation.

**Gemcitabine** is another comparator treatment in the study. It is administered via **intravenous infusion** in the pharmaceutical form PHF00230MIG. The dosage is also 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 12-week treatment period. Gemcitabine is classified as a chemical medicinal product and is not formulated for pediatric use.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is **Event-Free Survival (EFS)**, which will be compared between Arm A (perioperative Enfortumab Vedotin plus Pembrolizumab and Radical Cystectomy with Pelvic Lymph Node Dissection) and Arm B (neoadjuvant Gemcitabine plus Cisplatin and Radical Cystectomy with Pelvic Lymph Node Dissection). 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) and those who discontinued study treatment due to an AE in Arm A only.

Patient-reported outcomes will be measured using validated instruments such as the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) and the EuroQoL-5 Dimensions, 5-level Questionnaire (EQ-5D-5L). Changes from baseline in global health status, physical functioning, and specific domains related to bladder cancer will be assessed. Time to deterioration (TTD) in these domains will also be evaluated. The schedule for measuring these endpoints will be aligned with the trial's treatment and follow-up periods, ensuring comprehensive data collection and analysis to determine the efficacy of the treatment regimens.