The results from the randomized phase III KEYNOTE-B15/EV-304 study show that neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab significantly improved event-free survival, overall survival, and pathologic complete response rate in patients with muscle-invasive bladder cancer who were eligible for cisplatin-based chemotherapy. These results, presented by Matthew Galsky, MD, and colleagues during the 2026 ASCO Genitourinary Cancers Symposium, support the use of this drug combination as an effective perioperative treatment option in this setting (Abstract LBA630).

“Cisplatin-based neoadjuvant chemotherapy plus radical cystectomy has been the standard of care for treatment of muscle-invasive bladder cancer for over 20 years,” noted Dr. Galsky, who is Deputy Director of the Mount Sinai Tisch Cancer Center in New York. “This is the first study to demonstrate an improvement in outcomes with a nonplatinum regimen in direct comparison to a platinum-based chemotherapy regimen.”

Study Methodology

The researchers enrolled 808 patients with stage T2-T4aN0M0 or T1-T4aN1 M0 muscle-invasive bladder cancer who were eligible for cisplatin-based chemotherapy and radical cystectomy plus pelvic lymph node dissection. The patients were randomly assigned 1:1 to receive either neoadjuvant enfortumab vedotin plus pembrolizumab followed by radical cystectomy plus pelvic lymph node dissection and adjuvant enfortumab vedotin plus pembrolizumab (405 patients) or standard treatment with neoadjuvant gemcitabine and cisplatin followed by radical cystectomy plus pelvic lymph node dissection (403 patients).

The median time from randomization to the data cutoff date of October 27, 2025, was 33.6 months. The primary endpoint was event-free survival. Key secondary endpoints were pathologic complete response rate and overall survival. Safety was a secondary endpoint; adverse events of special interest were based on distinct prespecified lists for each drug.

Results 

Enfortumab vedotin plus pembrolizumab significantly improved median event-free survival compared with cisplatin plus gemcitabine (not reached vs 48.5 months). The 24-month estimated event-free survival rate was 79.4% vs 66.2% (hazard ratio [HR] = 0.53; 95% confidence interval [CI] = 0.41–0.70; 1-sided P < .0001). The median overall survival in both arms was not reached, and the 24-month estimated overall survival rate was 86.9% vs 81.3% (HR = 0.65; 95% CI = 0.48–0.89; 1-sided P = .0029). The pathologic complete response rate was 55.8% in patients who received enfortumab vedotin plus pembrolizumab compared with 32.5% in the cisplatin plus gemcitabine arm (95% CI = 16.7–29.8; 1-sided P < .0001).

Grade ≥ 3 treatment-emergent adverse events occurred in 75.7% of patients receiving enfortumab vedotin plus pembrolizumab and in 67.2% of patients receiving cisplatin plus gemcitabine. The most common grade ≥ 3 drug-related adverse events of special interest with enfortumab vedotin were skin reactions (14.1%); and the most common grade ≥ 3 adverse events of special interest with pembrolizumab were severe skin reactions (13.9%).

“Neoadjuvant and adjuvant enfortumab vedotin plus [pembrolizumab] significantly improved event-free survival, overall survival, and pathologic complete response rate compared with neoadjuvant gemcitabine plus cisplatin in patients with muscle-invasive bladder cancer who were eligible for cisplatin-based chemotherapy. The safety profile of enfortumab vedotin plus [pembrolizumab] was consistent with prior experience with the combination. These results support enfortumab vedotin plus [pembrolizumab] as an effective perioperative treatment option in this setting,” concluded the study authors.

ASCO Perspective

“Muscle-invasive bladder cancer can be difficult to treat, and conventional treatments often fall short of preventing metastatic recurrence,” commented Wm. Kevin Kelly, DO, an ASCO Expert in genitourinary oncology and Professor of Medical Oncology at Thomas Jefferson University, in a statement. “The KEYNOTE B-15 study marks an exciting development in establishing a potential new treatment option and standard of care for these patients. While the trial’s control arm lacked an adjuvant therapy, the findings provide a compelling rationale for more rigorously designed comparative trials.”

DISCLOSURE: The study was funded by Merck Sharp & Dohme, Astellas Pharma, and Seagen. For full disclosures of the study authors, visit coi.asco.org.