Enfortumab vedotin (Nectin-4 ADC) + pembrolizumab (PD-1) sustains 33.6-mo OS and high CR conversion vs platinum chemo in 1L la/mUC

Enfortumab vedotin is a Nectin-4–directed antibody–drug conjugate (MMAE payload) combined with pembrolizumab, a PD-1 inhibitor; in the randomized Phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), previously untreated locally advanced/metastatic urothelial carcinoma patients received EV+P (n=442) vs gemcitabine + cisplatin/carboplatin (n=444). With 42.8 months median follow-up (data cutoff Oct 6, 2025), EV+P maintained a large OS advantage (median OS 33.6 vs 15.9 months; 42-month OS 44.0% vs 24.6%; HR 0.53 [95% CI 0.45–0.63]) and “no new safety signals”—an absolute OS gain that clearly exceeds historical platinum/gemcitabine outcomes (median OS typically ~13–16 months in 1L mUC trials). In exploratory response-depth analyses, 45.1% of responders achieved CR on EV+P vs 32.8% on chemo, and among confirmed EV+P CRs, 66.2% converted from an initial PR to CR after a median ~5 additional EV cycles; in this PR→CR subgroup (n=88), median OS was not estimable and ~82% were alive at 42 months, with longer duration not creating new safety concerns (a reminder that “time on therapy” may matter when chasing maximal response). After EV+P, the most common next therapy was platinum chemo (30.5%), with a 20.7% investigator-assessed response rate to subsequent platinum in evaluable patients—suggesting some chemo sensitivity remains even after frontline EV+P.