Multinational phase 3 trial of perioperative enfortumab vedotin and pembrolizumab for muscle-invasive bladder cancer

Patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy proceed directly to radical cystectomy with pelvic lymph-node dissection. The multinational phase 3 KEYNOTE-905/EV-303 trial evaluated perioperative enfortumab vedotin (EV) plus pembrolizumab for these patients. Patients were randomized to 9 cycles of EV plus17 cycles of pembrolizumab, with surgery after 3 cycles (EV-pembro group; n=170) or surgery alone (control group; n=174). The primary endpoint was event-free survival. At data cutoff, median follow-up was 25.6 months (range 11.8-53.7). Surgery was performed in 87.6% of patients in the EV-pembro group and 89.7% in the control group. Pathologic complete response was observed in 57.1% of participants in the EV-pembro group and 8.6% in the control group (p<0.001). At two years, estimated event-free survival was 74.7% in the EV-pembro group and 39.4% in the control group (HR 0.40; p<0.001), with estimated overall survival 79.7% versus 63.1% (HR 0.50; p<0.001). Adverse events occurred in all participants in the EV-pembro group (grade ≥3: 71.3%) and in 64.8% in the control group (grade ≥3: 45.9%). The authors conclude that perioperative EV-pembro plus surgery resulted in significantly improved event-free survival and overall survival compared with surgery alone among patients with predominantly cisplatin-ineligible MIBC.