Enfortumab Vedotin and Pembrolizumab in Cisplatin

Enfortumab Vedotin and Pembrolizumab in Cisplatin-Eligible Bladder Cancer Published July 22, 2026 N Engl J Med 2026;395:338-348 DOI: 10.1056/NEJMoa2601486 Abstract Background Neoadjuvant cisplatin-based chemotherapy is a standard therapy for muscle-invasive bladder cancer. The efficacy and safety of neoadjuvant and adjuvant (perioperative) enfortumab vedotin–pembrolizumab as compared with neoadjuvant cisplatin-based chemotherapy in persons with this cancer are unclear. Methods We conducted a phase 3, open-label, randomized trial involving adults with muscle-invasive bladder cancer eligible for cisplatin-based chemotherapy and radical cystectomy with pelvic lymph-node dissection (cystectomy). Participants were assigned to receive neoadjuvant enfortumab vedotin–pembrolizumab (4 cycles; enfortumab vedotin [1.25 mg per kilogram of body weight on days 1 and 8] and pembrolizumab [200 mg on day 1] every 3 weeks), cystectomy, and 5 cycles of enfortumab vedotin and 13 cycles of pembrolizumab as adjuvant therapy or to receive neoadjuvant cisplatin–gemcitabine (4 cycles; cisplatin [70 mg per square meter of body-surface area on day 1] plus gemcitabine [1000 mg per square meter on days 1 and 8] every 3 weeks) and cystectomy. The primary end point was event-free survival; key secondary end points were overall survival and pathological complete response. Safety was assessed. Results A total of 405 participants were assigned to receive enfortumab vedotin–pembrolizumab and 403 to receive cisplatin–gemcitabine. The median time from randomization to the data-cutoff date was 33.6 months (range, 22.5 to 53.6). A total of 86.7% of the participants in the enfortumab vedotin–pembrolizumab group and 89.6% of those in the cisplatin–gemcitabine group underwent cystectomy. At 2 years, estimated event-free survival was 79.4% with enfortumab vedotin–pembrolizumab and 66.2% with cisplatin–gemcitabine (hazard ratio for an event or death, 0.53; 95% confidence interval [CI], 0.41 to 0.70; P<0.001); estimated overall survival was 86.9% and 81.3%, respectively (hazard ratio for death, 0.65; 95% CI, 0.48 to 0.89; two-sided P=0.006). A pathological complete response occurred in 55.8% and 32.5% of the participants (P<0.001). The incidence of grade 3 or higher adverse events of any cause was 75.7% with enfortumab vedotin–pembrolizumab and 67.2% with cisplatin–gemcitabine. Conclusions Among participants with muscle-invasive bladder cancer eligible for cisplatin-based chemotherapy, perioperative enfortumab vedotin–pembrolizumab led to significantly better event-free and overall survival outcomes and a significantly higher incidence of pathological complete response than neoadjuvant cisplatin–gemcitabine, but with more adverse events of grade 3 or higher. (Funded by Merck Sharp and Dohme and others; KEYNOTE-B15/EV-304 ClinicalTrials.gov number, NCT04700124.) Are you a member of an institution such as a university or hospital?Learn more about Institutional Access Notes A data sharing statement provided by the authors is available with the full text of this article at NEJM.org. Supported by Merck Sharp and Dohme (MSD), a subsidiary of Merck (Rahway, NJ); Astellas Pharma; and Seagen, which was acquired by Pfizer in December 2023. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank the patients and their families and caregivers for participating in this trial, all the site personnel, and the employees of MSD, Pfizer, and Astellas Pharma, including Jing Yang of MSD for statistical analysis support and oversight, Guoqing Wang of MSD for statistical analysis support, Leslie Lipka of MSD for trial oversight, M. Catherine Pietanza of MSD for research supervision and critical review, Ina Bremer of MSD for writing assistance, and Shaun Patrick Rosebeck and Jennifer Pawlowski of MSD for administrative and logistic support. Supplementary Material Information & Authors Information Published In Copyright Copyright © 2026 Massachusetts Medical Society. All rights reserved. For personal use only. Any commercial reuse of NEJM Group content requires permission. History Published online: July 22, 2026 Published in issue: July 23, 2026 Topics Authors Metrics & Citations Metrics Altmetrics Citations Export citation Select the format you want to export the citation of this publication. Cited by Loading...