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Enfortumab Vedotin and Pembrolizumab in Cisplatin-Eligible Bladder Cancer
Journal article   Peer reviewed

Enfortumab Vedotin and Pembrolizumab in Cisplatin-Eligible Bladder Cancer

Matthew D Galsky, Begoña P Valderrama, Marco Maruzzo, Albert Font, Tudor Ciuleanu, Jonathan Chatzkel, Takuya Koie, Christopher J Hoimes, Javier Puente, Yousef Zakharia, …
The New England journal of medicine, Vol.395(4), pp.338-348
07/23/2026
DOI: 10.1056/NEJMoa2601486
PMID: 42485627

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Abstract

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.).
 Adult Aged Aged, 80 and over Antibodies, Monoclonal - administration & dosage Antibodies, Monoclonal - adverse effects Antibodies, Monoclonal, Humanized - administration & dosage Antibodies, Monoclonal, Humanized - adverse effects Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - adverse effects Chemotherapy, Adjuvant - adverse effects Chemotherapy, Adjuvant - methods Cisplatin - administration & dosage Cisplatin - adverse effects Cystectomy Female Gemcitabine - administration & dosage Gemcitabine - adverse effects Humans Kaplan-Meier Estimate Lymph Node Excision Male Middle Aged Neoadjuvant Therapy - adverse effects Neoadjuvant Therapy - methods Neoplasm Invasiveness Pathologic Complete Response Progression-Free Survival Urinary Bladder - pathology Urinary Bladder - surgery Urinary Bladder Neoplasms - drug therapy Urinary Bladder Neoplasms - mortality Urinary Bladder Neoplasms - pathology Urinary Bladder Neoplasms - surgery

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