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.)
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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.
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Copyright © 2026 Massachusetts Medical Society. All rights reserved.
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History
Published online: July 22, 2026
Published in issue: July 23, 2026
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Facts Only
* The trial involved 405 participants receiving enfortumab vedotin–pembrolizumab and 403 receiving cisplatin–gemcitabine.
* Median time from randomization to data-cutoff was 33.6 months.
* 86.7% of the enfortumab vedotin–pembrolizumab group and 89.6% of the cisplatin–gemcitabine group underwent cystectomy.
* Estimated event-free survival at 2 years was 79.4% for the enfortumab vedotin–pembrolizumab group and 66.2% for the cisplatin–gemcitabine group.
* Estimated overall survival at 2 years was 86.9% for the enfortumab vedotin–pembrolizumab group and 81.3% for the cisplatin–gemcitabine group.
* Pathological complete response occurred in 55.8% of participants in the enfortumab vedotin–pembrolizumab group and 32.5% in the cisplatin–gemcitabine group.
* The incidence of grade 3 or higher adverse events was 75.7% for the enfortumab vedotin–pembrolizumab group and 67.2% for the cisplatin–gemcitabine group.
Executive Summary
A phase 3, open-label, randomized trial compared neoadjuvant enfortumab vedotin–pembrolizumab versus neoadjuvant cisplatin–gemcitabine in adults with muscle-invasive bladder cancer eligible for cisplatin-based chemotherapy. Participants were split into two groups: one receiving neoadjuvant enfortumab vedotin–pembrolizumab followed by cystectomy, and the other receiving neoadjuvant cisplatin–gemcitabine followed by cystectomy. The primary endpoint assessed was event-free survival, with key secondary endpoints being overall survival and pathological complete response.
The results indicated that perioperative treatment with enfortumab vedotin–pembrolizumab was associated with better outcomes compared to cisplatin–gemcitabine, although this came with a higher incidence of adverse events. At two years, the estimated event-free survival was 79.4% for the enfortumab vedotin–pembrolizumab group and 66.2% for the cisplatin–gemcitabine group. Overall survival estimates were 86.9% versus 81.3%, respectively. Furthermore, pathological complete response occurred in 55.8% of participants in the enfortumab vedotin–pembrolizumab group compared to 32.5% in the cisplatin–gemcitabine group. The adverse event profile differed, with a higher incidence of grade 3 or higher adverse events observed in the enfortumab vedotin–pembrolizumab group (75.7%) than in the control group (67.2%).
Full Take
The core finding suggests a trade-off in therapeutic benefit: the combination of enfortumab vedotin and pembrolizumab provided superior metrics for event-free survival and pathological complete response when administered perioperatively compared to standard cisplatin–gemcitabine therapy. This outcome is contingent on accepting a higher rate of severe adverse events (grade 3 or higher). This pattern highlights a crucial tension in oncology treatment design: optimizing efficacy versus tolerability. The context implies that targeting the tumor environment with immunotherapy alongside chemotherapy may yield deeper responses, but this necessitates rigorous management of toxicity.
The implication for clinical practice is that decisions regarding neoadjuvant regimens must weigh potential survival gains and response rates against the burden of toxicity. If better long-term disease control (event-free survival) is the paramount goal, or if a higher rate of pathological response justifies managing increased acute toxicities, then this line of therapy may be prioritized for eligible patients. The missing piece is quantifying the lifetime impact of these adverse events versus the extended survival observed, and understanding how these specific combined treatments interact with subsequent adjuvant therapy selection across the patient spectrum.
Bridge questions: What is the long-term recurrence rate following these initial outcomes? How do the patterns of adverse events specifically influence the choice between multimodal therapies for future patients? Does the association between higher toxicity and better response indicate a biological shift, or simply that the combination targets more aggressive disease phenotypes?
Sentinel — Human
This text exhibits the high formality and structured detail characteristic of peer-reviewed medical journal reporting, strongly suggesting human authorship.