The combination of the NECTIN4-directed antibody drug conjugate enfortumab vedotin-ejfv and the immunotherapy drug pembrolizumab is the established first-line standard-of-care treatment for patients with locally advanced/metastatic urothelial carcinoma.
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 support the use of this drug combination as an effective perioperative treatment option in this setting, according to the study authors.1 The study abstract LBA630 was presented by Matthew D. Galsky, MD, FASCO, of Mount Sinai Tisch Cancer Center, during the 2026 ASCO Genitourinary Cancers Symposium held on February 26-28, in San Francisco, California, and online.
Study Methodology
The researchers enrolled 808 patients with stage T2-T4aN0M0 or T1-T4aN1M0 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 (405 patients) or neoadjuvant gemcitabine and cisplatin (403 patients).
Matthew D. Galsky, MD, FASCO
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
The researchers found that the baseline characteristics were generally balanced between the two groups. Treatment with enfortumab vedotin plus pembrolizumab significantly improved event-free survival compared with cisplatin plus gemcitabine. Median event-free survival was not reached with enfortumab vedotin plus pembrolizumab vs 48.5 months with cisplatin plus gemcitabine; the estimated 24-month event-free survival rates were 79.4% and 66.2%, respectively (HR = 0.53, 95% confidence interval [CI] = 0.41–0.70; 1-sided P < .0001). Overall survival was also improved, with estimated 24-month survival rates of 86.9% vs 81.3% (HR = 0.65, 95% CI = 0.48–0.89; 1-sided P = .0029), although median overall survival was not reached in either group. The pathologic complete response rate was also higher with enfortumab vedotin plus pembrolizumab (55.8% vs 32.5%; estimated difference = 23.4%, 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.
Most common grade ≥ 3 drug-related adverse events of special interest with enfortumab vedotin were skin reactions (14.1%); and 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
Wm. Kevin Kelly, DO, FASCO
“Muscle-invasive bladder cancer can be difficult to treat, and conventional treatments often fall short of preventing metastatic recurrence,” commented Wm. Kevin Kelly, DO, FASCO an ASCO Expert in genitourinary oncology and Professor of Medical Oncology at Thomas Jefferson University, in a statement. “The KEYNOTE-B15 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.” ν
DISCLOSURE: Funding for this study was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.; Astellas Pharma Inc.; and Seagen Inc., which was acquired by Pfizer in Dec. 2023. Dr. Galsky reported the following disclosures: Consulting or advisory role, Abbvie, Bristol-Myers Squibb (BMS), EMD Serono, Gilead Sciences, Janssen, Merck, Pfizer; Research funding, AstraZeneca (Institution), BMS (Institution), Dendreon (Institution), Genentech/Roche (Institution), Janssen Oncology (Institution), Merck (Institution), Novartis (Institution); Patents, Royalties, other Intellectual Property, methods and compositions for treating cancer and related methods. Mount Sinai School of Medicine, July 2012. Application number: 20120322792. For disclosure information for all authors, visit https://coi.asco.org/report/viewabstractcoi?id=521450.
REFERENCE
1. Galsky MD, Valderrama BP, Maruzzo M, et al: Neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab for participants with muscle-invasive bladder cancer who are eligible for cisplatin: Randomized, open-label, phase 3 KEYNOTE-B15 study. Abstract LBA630. 2026 ASCO Genitourinary Cancers Symposium. Presented February 27, 2026.
