Enfortumab vedotin plus pembrolizumab (EV+P) vs chemotherapy for previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC): 3.5-year follow-up and response analyses from the phase 3 EV-302 study.

4507 Background: EV+P is the preferred standard of care for previously untreated la/mUC based on the EV-302/KEYNOTE-A39 trial (NCT04223856). We present updated data with 3.5 years of median follow-up, including exploratory subgroup analyses focusing on patients who achieved a complete response (CR) after an initial partial response (PR). Methods: Patients were randomized 1:1 to EV 1.25 mg/kg IV (days 1 and 8 of each 3-wk cycle) and P 200 mg IV (day 1) or gemcitabine + cisplatin/carboplatin, with treatment until disease progression, toxicity, or maximum number of cycles. Dual primary endpoints were progression-free survival by blinded independent central review and overall survival (OS); safety was a secondary endpoint. Results: With 42.8 months of median follow-up (data cutoff: October 6, 2025), OS benefit favoring EV+P (n=442) vs chemotherapy (chemo; n=444) was maintained (median OS, 33.6 vs 15.9 months; 42-month OS rate, 44.0% vs 24.6%; HR, 0.53 95% CI, 0.45-0.63), with no new safety signals. Of responding patients, 45.1% achieved a CR in the EV+P arm (n=295) and 32.8% in the chemo arm (n=195. Data cutoff was Aug 8, 2024. Among patients with confirmed CR in the EV+P arm, 66.2% achieved a PR initially, then converted from a PR to a CR with a median of 5 additional EV cycles (IQR, 3.0-8.0). In this subgroup, mOS was not estimable (NE), and >80% of patients were alive after 3.5 years. Longer treatment duration did not lead to new safety concerns. Overall, the most common first subsequent treatment was platinum-based chemo in the EV+P arm (n=135 30.5%) and a PD-L1 inhibitor in the chemo arm (n=265 59.7%). In the EV+P arm, investigator-assessed responses to subsequent platinum chemo occurred in 28 of 135 evaluable patients (20.7%). Conclusions: EV-302 represents the longest follow-up available for EV+P in a phase 3 trial. After 3.5 years of median follow-up, EV+P continues to demonstrate superior efficacy vs chemo, with no new safety signals. Two-thirds of patients achieving CR converted from an initial PR, suggesting that treatment duration is relevant in maximizing outcomes. Clinical trial information: EV-302 NCT04223856 . EV+PAll CR (n=133) EV+PCR after PR (n=88) Median OS (95% CI), months NE (NE-NE) NE (NE-NE) 42-month OS rate (95% CI), % 83.6 (75.6-89.1) 82.4 (71.8-89.43) Median time to CR (IQR), monthsTime to PRTime from PR to CR 4.3 (2.2-8.4)–– 6.6 (4.3-12.1)2.1 (1.9-2.2)4.5 (2.2-10.1) Median EV cycles prior to CR (IQR), nEV cycles prior to PREV cycles from PR to CR 6.0 (3.0-9.0)–– 8.0 (6.0-11.5)3.0 (3.0-3.0)5.0 (3.0-8.0) Median P cycles prior to CR (IQR), nP cycles prior to PRP cycles from PR to CR 6.0 (3.0-10.0)–– 9.0 (6.0-12.0)3.0 (3.0-3.0)6.0 (3.0-9.0) Median total EV cycles (IQR), n 13.0 (8.0-28.0) 15.0 (9.0-30.0) Median total P cycles (IQR), n 28.0 (10.0-35.0) 31.0 (12.5-35.0)