Multinational phase 3 trial of perioperative enfortumab vedotin plus pembrolizumab in cisplatin-eligible muscle-invasive bladder cancer

Neoadjuvant cisplatin-based chemotherapy is a standard therapy for muscle-invasive bladder cancer (MIBC). The multinational phase 3 KEYNOTE-B15/EV-304 trial compared the perioperative combination of enfortumab vedotin (EV) plus pembrolizumab versus neoadjuvant cisplatin-gemcitabine for MIBC. Adult cisplatin-eligible patients were randomized to 4 cycles of neoadjuvant EV-pembrolizumab followed by cystectomy and 5 cycles of EV and 13 cycles of pembrolizumab (n=405) or neoadjuvant cisplatin-gemcitabine followed by cystectomy (n=403). The primary endpoint was event-free survival (EFS). The median time from randomization to data-cutoff date was 33.6 months (range 22.5-53.6). A total of 86.7% of the participants in the EV-pembrolizumab group and 89.6% of those in the cisplatin-gemcitabine group underwent cystectomy. At two years, the EFS rate was 79.4% with EV-pembrolizumab and 66.2% with cisplatin-gemcitabine (HR 0.53; p<0.001) and the overall survival rate was 86.9% and 81.3%, respectively (HR 0.65; p=0.006). Pathological complete response occurred in 55.8% and 32,5%,respectively (p<0.001). The incidence of grade 3 or higher adverse events of any cause was 75.7% with EV-pembrolizumab and 67.2% with cisplatin-gemcitabine. The authors conclude that among patients with MIBC eligible for cisplatin-based chemotherapy, perioperative EV-pembrolizumab led to significant better EFS and OS outcomes than neoadjuvant cisplatin-gemcitabine, but with more adverse events of grade 3 and higher (quick take video summary).