KEYNOTE-905/EV-303: A phase 3 study to evaluate the efficacy and safety of perioperative pembrolizumab or pembrolizumab plus enfortumab vedotin (EV) for muscle-invasive bladder cancer (MIBC).

TPS4601 Background: Standard of care for MIBC is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy + pelvic lymph node dissection (RC + PLND), but many patients with MIBC are ineligible for cisplatin-based chemotherapy. In the phase 1b/2 KEYNOTE-869/EV-103 study, combination therapy with the PD-1 inhibitor pembrolizumab and the Nectin-4–directed antibody-drug conjugate EV showed promising antitumor activity in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma. KEYNOTE-905/EV-303 (NCT03924895) is a multicenter, randomized, open-label, phase 3 study to evaluate efficacy and safety of perioperative pembrolizumab alone or combined with EV versus RC + PLND alone in patients with MIBC who are ineligible for or decline cisplatin-based treatment. Methods: Patients with treatment-naive MIBC (T2-T4aN0M0 or T1-T4aN1M0) and predominantly (≥50%) urothelial histology who are cisplatin ineligible or decline cisplatin-based treatment and have an ECOG PS score of 0-2 are eligible. Cisplatin ineligibility will be defined as meeting ≥1 of the following criteria: impaired renal function with calculated creatinine clearance 30-59 mL/min; ECOG PS 2; grade ≥2 audiometric hearing loss per CTCAE v4.0; or NYHA class III heart failure. Patients will receive neoadjuvant pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for ≤3 cycles followed by RC + PLND and adjuvant pembrolizumab 200 mg IV Q3W for ≤14 cycles (arm A); RC + PLND followed by observation (adjuvant nivolumab permitted based on clinical indication and regulatory approval [arm B]); or neoadjuvant EV 1.25 mg/kg + pembrolizumab 200 mg IV Q3W for ≤3 cycles followed by RC + PLND and adjuvant EV + pembrolizumab for ≤6 cycles and adjuvant pembrolizumab 200 mg IV Q3W for ≤8 cycles (arm C). In the neoadjuvant and adjuvant phases of arm C, pembrolizumab will be administered on day 1 and EV will be administered on days 1 and 8 of each cycle. Enrollment is complete for arm A; patients will continue to be randomly assigned 1:1 to arm B or arm C. Stratification factors are tumor stage (T2N0 vs T3/T4aN0 vs T1-T4aN1), geographic region (United States vs Europe vs most of world), and cisplatin eligibility (cisplatin ineligible or cisplatin eligible but declines treatment). The primary end point is event-free survival between arm B and arm C. Secondary end points are event-free survival (arm A vs arm B) pathologic complete response, overall survival, disease-free survival, pathologic downstaging rates, and safety. Enrollment is planned for 308 patients, and recruitment is ongoing in Africa, Asia, Australia, Europe, North America, and South America. © 2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO-GU Annual Meeting. All rights reserved. Clinical trial information: NCT03924895 .