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.
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.
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.
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.).
The New England journal of medicine. 2026 Jul 23 [Epub]
Matthew D Galsky, Begoña P Valderrama, Marco Maruzzo, Albert Font, Tudor Ciuleanu, Jonathan Chatzkel, Takuya Koie, Christopher J Hoimes, Javier Puente, Yousef Zakharia, Eli Rosenbaum, Katharina Boehm, Yohann Loriot, Jens Bedke, Thomas B Powles, Andrea Necchi, Pawel Wiechno, Carlos Álvarez-Fernández, Tae-Hwan Kim, Niara Oliveira, Thomas W Flaig, Heidi S Wirtz, Michael Mihm, Qinlei Huang, Aljosja Rogiers, Blanca Homet Moreno, Alfonso Gómez de Liaño, KEYNOTE-B15/EV-304 Investigators
Mount Sinai Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York., Hospital Universitario Virgen del Rocío, Seville, Spain., Istituto Oncologico Veneto (IOV)-IRCCS, Padua, Italy., Catalan Institute of Oncology Badalona, Badalona Applied Research Group in Oncology, Translational Program in Cancer Research, Institut Germans Trias i Pujol, Barcelona., Institutul Oncologic Prof. Dr. Ion Chiricuta Cluj-Napoca, Cluj-Napoca, Romania., University of Florida, Gainesville., Department of Urology, Gifu University Graduate School of Medicine, Gifu, Japan., Duke Cancer Institute, Duke University, Durham, NC., Hospital Clínico Universitario San Carlos de Madrid, Madrid., University of Iowa Hospital and Clinics, Iowa City., Rabin Medical Center, Davidoff Cancer Center, Petah Tikva, Israel., University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany., Université Paris-Saclay, Gustave Roussy, INSERM Unité Mixte de Recherche 981 - Prédicteurs Moléculaires et Nouvelles Cibles en Oncologie, Villejuif, France., Eva Mayr-Stihl Cancer Center, Klinikum Stuttgart, Stuttgart, Germany., Barts Health NHS Trust, Barts Cancer Institute, Queen Mary University of London, London., Department of Medical Oncology, IRCCS San Raffaele Hospital, Comprehensive Cancer Center, Milan., Klinika Nowotworów Układu Moczowego, Warsaw, Poland., Hospital Universitario Central de Asturias, Oviedo, Spain., Department of Urology, Kyungpook National University School of Medicine, Daegu, South Korea., Mater Hospital Brisbane, Mater Misericordiae, Brisbane, QLD, Australia., University of Colorado School of Medicine, Anschutz Medical Campus, Aurora., Pfizer, Bothell, WA., Astellas Pharma, Northbrook, IL., Merck, Rahway, NJ., Complejo Hospitalario Universitario Insular-Materno Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain.