Neoadjuvant and adjuvant (neoadj-adj) enfortumab vedotin (EV) plus pembrolizumab (pembro) in participants with cisplatin-ineligible muscle-invasive bladder cancer (MIBC): An analysis of clinically relevant subgroups in KEYNOTE-905.

Abstract

4613 Background: Results from the phase 3 KEYNOTE-905/EV-303 study (NCT03924895) showed that neoadj-adj EV + pembro and radical cystectomy with pelvic lymph node dissection (RC + PLND) led to superior event-free survival (EFS; HR 0.40; 95% CI 0.28-0.57), overall survival (OS; HR 0.50; 95% CI 0.33-0.74), and pathological complete response (pCR) rate (57.1% vs 8.6%) vs RC + PLND alone in participants (pts) with MIBC who were ineligible for or declined cisplatin. We report efficacy in subgroups of clinical interest, including advanced age, ECOG PS, cisplatin eligibility status, and baseline clinical tumor stage. Methods: Adults with stage T2-T4aN0M0 or T1-T4aN1M0 MIBC by central review who were cisplatin-ineligible or declined cisplatin were randomly assigned 1:1 to neoadj-adj EV + pembro and RC + PLND vs RC + PLND alone (control). EFS by BICR, OS, and pCR (pT0N0) rate by central review were analyzed in subgroups by age (≥65 to <75 vs ≥75 yr), ECOG PS (0-1 vs 2), cisplatin-ineligibility status (ineligible vs declined), and clinical stage (T2N0 vs T3-T4aN0 vs T1-4aN1). The analyses were exploratory; no formal statistical testing was performed. Results: 170 pts were assigned to EV + pembro and 174 to control. Median follow-up at data cutoff (Jun 6, 2025) was 25.6 mo (range 11.8-53.7). 30 pts in the EV + pembro arm and 32 in the control arm had stage T2N0 MIBC; 133 and 132 pts had stage T3-T4aN0; 7 and 10 had stage T1-4aN1. In pts with T2N0 MIBC, median EFS was not reached (NR) with EV + pembro vs NR with control (HR 0.26; 95% CI 0.08-0.80), and pCR rate was 60.0% vs 18.8%. In pts with T3-T4aN0 MIBC, median EFS was NR with EV + pembro vs 17.2 mo with control (HR 0.43; 95% CI 0.29-0.63); median OS was NR vs 41.7 mo (HR 0.54; 95% CI 0.35-0.82); pCR rate was 57.1% vs 6.8%. In pts with T1-4aN1 MIBC, median EFS was 36.7 vs 7.2 mo (HR 0.35; 95% CI 0.09-1.40); pCR rate was 42.9% vs 0%. OS for T2N0 and T1-4aN1 will be assessed after additional follow-up (currently <10 events). Outcomes by age, ECOG PS, and cisplatin eligibility are shown in the Table. Conclusions: An efficacy benefit was observed with neoadj-adj EV + pembro added to RC + PLND vs RC + PLND alone across clinically relevant subgroups, consistent with the ITT population. Results further support EV + pembro as a potential new standard treatment for pts with cisplatin-ineligible MIBC. Clinical trial information: NCT03924895 . Age ≥65 to <75 yr Age ≥75 yr ECOG 0-1 ECOG 2 Cisplatin-ineligible EV+P C EV+P C EV+P C EV+P C EV+P C N 63 77 78 68 149 148 21 26 142 139 EFS, median, mo NR 13.1 NR 18.8 NR 17.2 NR 9.3 NR 14.2 EFS HR(95% CI) 0.41(0.24-0.70) 0.50(0.30-0.84) 0.44(0.30-0.64) 0.19(0.07-0.52) 0.37(0.26-0.54) OS, median, mo NR 41.7 NR 37.4 NR 42.6 NR 19.2 NR 37.4 OS HR(95% CI) 0.49(0.26-0.94) 0.63(0.36-1.10) 0.59(0.39-0.90) 0.17(0.05-0.59) 0.46(0.30-0.70) pCR rate, % 54.0 9.1 53.8 7.4 53.7 8.8 81.0 7.7 54.9 8.6 C, control; EV+P, EV + pembro.