Introduction:

Cisplatin-ineligible patients with muscle-invasive bladder cancer (MIBC) experience high rates of recurrence and poor overall survival (OS) after standard-of-care treatment with radical cystectomy + pelvic lymph node dissection (RC+PLND). The PD-1 inhibitor pembrolizumab has shown antitumor activity in patients with non-MIBC or MIBC, and the nectin 4–directed antibody-drug conjugate enfortumab vedotin (EV) is approved for locally advanced or metastatic urothelial cancer (UC) after PD-1/PD-L1 therapy. Furthermore, neoadjuvant pembrolizumab monotherapy has shown promising antitumor activity in MIBC and in combination with EV in metastatic UC. Therefore, further investigation of EV+pembrolizumab is warranted. The randomized phase 3 KEYNOTE‑905/EV‑303 study (NCT03924895) will be conducted to assess the efficacy and safety of perioperative pembrolizumab monotherapy with RC+PLND versus perioperative EV+pembrolizumab with RC+PLND versus RC+PLND alone for patients with MIBC.

Methods:

Treatment-naive, cisplatin-ineligible adults with confirmed MIBC (T2-T4aN0M0 or T1-T4aN1M0), predominant (≥50%) urothelial histology, and ECOG PS 0-2 will be enrolled. 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 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±EV 1.25 mg/kg will be administered on days 1 and 8 Q3W in the neoadjuvant and adjuvant phases. Patients will be stratified by PD-L1 status (CPS ≥10 vs <10), disease stage (T2N0 vs T3/T4N0 vs T1-T4aN1), and region (United States vs Europe vs most of the world). Coprimary end points are pathologic complete response and event-free survival in all patients and patients with PD-L1 CPS ≥10. Secondary end points include overall survival, pathologic downstaging, and safety.

Results:

Conclusion:

Funding: Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA