e-Poster Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2021

KEYNOTE-905/EV-303: A Phase 3 Study of Perioperative Pembrolizumab or Pembrolizumab + Enfortumab Vedotin and Cystectomy Versus Cystectomy Alone in Cisplatin-Ineligible Patients With Muscle-Invasive Bladder Cancer (#408)

Tammy Hennika 1 , Matthew D. Galsky 2 , Andrea Necchi 3 , Neal D. Shore 4 , Elizabeth Plimack 5 , Calvin Jia 1 , Blanca Homet Moreno 1 , J. Alfred Witjes 6
  1. Merck & Co., Inc., Kenilworth, NJ, United States
  2. Icahn School of Medicine at Mount Sinai, New York, NY, United States
  3. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
  4. Carolina Urologic Research Center, Myrtle Beach, SC, United States
  5. Fox Chase Cancer Center, Philadelphia, PA, United States
  6. Radboud University, Nijmegen, Netherlands

Aims: Standard of care for cisplatin-ineligible patients with muscle-invasive bladder cancer (MIBC) is radical cystectomy + pelvic lymph node dissection (RC+PLND), but patients experience high rates of disease recurrence and poor overall survival (OS). The PD-1 inhibitor pembrolizumab has shown promising antitumor activity in MIBC as monotherapy in the neoadjuvant setting and in combination with the nectin 4–directed antibody-drug conjugate enfortumab vedotin (EV) in metastatic urothelial carcinoma. KEYNOTE‑905/EV‑303, a randomized phase 3 study (NCT03924895), will investigate the efficacy and safety of perioperative pembrolizumab monotherapy with RC+PLND versus perioperative EV+pembrolizumab with RC+PLND versus RC+PLND alone for cisplatin-ineligible patients with MIBC.

Methods: Cisplatin-ineligible adults with confirmed treatment-naive MIBC (T2-T4aN0M0 or T1-T4aN1M0), ECOG PS score 0-2, and predominant (≥50%) urothelial histology are eligible to enroll. Patients will be stratified by PD-L1 status (combined positive score [CPS] ≥10 vs <10), region (United States vs Europe vs most of the world), and disease stage (T2N0 vs T3/T4N0 vs T1-T4aN1). Approximately 836 patients will be randomly assigned 1:1:1 to receive neoadjuvant pembrolizumab (3 cycles) before RC+PLND and adjuvant pembrolizumab (14 cycles) in arm A, RC+PLND alone followed by observation in arm B, or neoadjuvant EV+pembrolizumab (3 cycles) before RC+PLND and adjuvant EV+pembrolizumab (6 cycles) and adjuvant pembrolizumab (8 cycles) in arm C. Pembrolizumab 200 mg IV Q3W will be administered in both the neoadjuvant and the adjuvant phases of arm A and the adjuvant phase of arm C. In arm C, pembrolizumab 200 mg IV Q3W will be administered on day 1 of each cycle, and EV 1.25 mg/kg will be administered on days 1 and 8 of each cycle in both phases. Coprimary end points are event-free survival and pathologic complete response in all patients and in patients with PD-L1 CPS ≥10. Secondary end points are OS, disease-free survival, pathologic downstaging, and safety.