Patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy proceed directly to radical cystectomy with pelvic lymph-node dissection. Perioperative therapy may improve outcomes in this population.
In this phase 3, open-label trial, participants with muscle-invasive bladder cancer who were ineligible for or declined cisplatin-based chemotherapy were randomly assigned to perioperative (neoadjuvant and adjuvant) enfortumab vedotin, an antibody-drug conjugate directed at nectin-4, plus pembrolizumab and surgery (9 total cycles of enfortumab vedotin [1.25 mg per kilogram of body weight on days 1 and 8] plus 17 total cycles of pembrolizumab [200 mg on day 1 every 3 weeks], with surgery after 3 cycles) or surgery alone (control). The primary end point was event-free survival. Key secondary end points were overall survival and pathological complete response (absence of viable tumor after surgical resection). Other secondary end points included safety.
A total of 344 participants underwent randomization (170 in the enfortumab vedotin-pembrolizumab group and 174 in the control group). At data cutoff, median follow-up was 25.6 months (range, 11.8 to 53.7). Surgery was performed in 87.6% of participants in the enfortumab vedotin-pembrolizumab group and in 89.7% in the control group. At 2 years, estimated event-free survival was 74.7% in the enfortumab vedotin-pembrolizumab group and 39.4% in the control group (hazard ratio for an event or death, 0.40; 95% confidence interval [CI], 0.28 to 0.57; two-sided P<0.001); estimated overall survival was 79.7% and 63.1% (hazard ratio for death, 0.50; 95% CI, 0.33 to 0.74; two-sided P<0.001). A pathological complete response had occurred in 57.1% and 8.6% of the participants (estimated difference, 48.3 percentage points; 95% CI, 39.5 to 56.5; two-sided P<0.001). Adverse events occurred in all participants in the enfortumab vedotin-pembrolizumab group (grade ≥3, 71.3%; grade ≥3 drug-related, 45.5%) and in 64.8% in the control group (grade ≥3, 45.9%).
Perioperative enfortumab vedotin plus pembrolizumab and surgery led to significantly better event-free and overall survival outcomes and a greater percentage of participants with pathological complete response than surgery alone in a predominantly cisplatin-ineligible population with muscle-invasive bladder cancer. Safety was also assessed. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-905 ClinicalTrials.gov number, NCT03924895.).
The New England journal of medicine. 2026 Feb 18 [Epub ahead of print]
Christof Vulsteke, Nabil Adra, Pongwut Danchaivijitr, Maksym Sabadash, Alejo Rodriguez-Vida, Zhentao Zhang, Vagif Atduev, Y Emre Göger, Steffen Rausch, Seok-Ho Kang, Yohann Loriot, Jens Bedke, Matthew D Galsky, Peter H O'Donnell, Gunhild von Amsberg, Nimira Alimohamed, Grzegorz Sulimka, Shilpa Gupta, Viktor Paramonov, Keita Nakane, Michael Mihm, Changting Meng, Caizhi David Huang, Chethan Ramamurthy, Blanca Homet Moreno, Anders Ullén, KEYNOTE-905/EV-303 Investigators
Integrated Cancer Center Ghent, AZ Maria Middelares, Ghent, Belgium., Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis., Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand., Lviv State Regional Oncological Center, Lviv, Ukraine., Hospital del Mar, Barcelona., Parkview Cancer Institute, Fort Wayne, IN., Volga District Medical Center, Federal Medical-Biologic Agency, Nizhny Novgorod, Russia., Necmettin Erbakan University Meram Faculty of Medicine, Konya, Turkey., University Hospital Tübingen, Tübingen, Germany., Korea University Anam Hospital, Seoul, South Korea., Université Paris-Saclay, Gustave Roussy, INSERM Prédicteurs Moléculaires et Nouvelles Cibles en Oncologie, Villejuif, France., Eva Mayr-Stihl Cancer Center, Klinikum Stuttgart, Stuttgart, Germany., Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York., University of Chicago, Chicago., University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Arthur J.E. Child Comprehensive Cancer Centre, Calgary, AB, Canada., Szpital Wojewódzki im. Św. Łukasza, Tarnow, Poland., Taussig Cancer Institute, Cleveland Clinic, Cleveland., Clinical Center of Oncology, Hematology, Transplantology and Palliative Care of the Cherkasy Oblast Council, Cherkasy, Ukraine., Department of Urology, Gifu University Graduate School of Medicine, Gifu, Japan., Astellas Pharma, Northbrook, IL., Pfizer, Bothell, WA., Merck, Rahway, NJ., Department of Oncology-Pathology, Karolinska Institutet, Stockholm.