Enfortumab vedotin (Nectin-4 ADC) + pembrolizumab (PD-1) delivers ~57% pCR and halves death risk in cisplatin-ineligible MIBC

Enfortumab vedotin (a Nectin-4–directed MMAE antibody–drug conjugate) plus pembrolizumab (anti–PD-1) was evaluated as perioperative (neoadj-adj) therapy in the Phase 3 KEYNOTE-905/EV-303 randomized trial (NCT03924895) in cisplatin-ineligible or cisplatin-declining MIBC (T2–T4aN0M0 or T1–T4aN1M0; n=344; data cutoff June 6, 2025; median follow-up 25.6 months). Across clinically relevant subgroups by baseline stage, EV+pembro improved EFS and deepened pathologic response vs radical cystectomy + pelvic lymph node dissection (RC+PLND) alone: T3–T4aN0 had EFS HR 0.43 with mEFS NR vs 17.2mo, OS HR 0.54 with mOS NR vs 41.7mo, and pCR 57.1% vs 6.8%; smaller cohorts also favored EV+pembro (T2N0 EFS HR 0.26; pCR 60.0% vs 18.8%; T1–4aN1 mEFS 36.7 vs 7.2mo; pCR 42.9% vs 0%), though some OS reads are immature (<10 events). As a practical benchmark, neoadjuvant cisplatin-based chemo (for eligible patients) typically yields pT0 rates in the ~20–40% range, so the ~57% pCR here is above historical chemo expectations—while also addressing the cisplatin-ineligible population where RC alone has low pCR (8.6% in this trial).