At the 2026 ASCO Genitourinary Cancers Symposium, Matthew D. Galsky, MD, presented results from the phase 3 KEYNOTE-B15 study showing that perioperative enfortumab vedotin plus pembrolizumab improved outcomes over neoadjuvant gemcitabine plus cisplatin in cisplatin-eligible muscle-invasive bladder cancer (MIBC). The findings are notable because cisplatin-based neoadjuvant chemotherapy has remained the standard of care for eligible patients with MIBC for decades, and KEYNOTE-B15 is the first phase 3 trial to show superior outcomes with a non-platinum perioperative regimen.
KEYNOTE-B15 enrolled patients with clinically localized muscle-invasive urothelial carcinoma of the bladder who were eligible for cisplatin-based chemotherapy and radical cystectomy. Patients were randomly assigned 1:1 to 4 cycles of neoadjuvant enfortumab vedotin plus pembrolizumab followed by cystectomy and adjuvant pembrolizumab, with the first 5 adjuvant cycles given with enfortumab vedotin, or to 4 cycles of neoadjuvant gemcitabine plus cisplatin followed by cystectomy and observation. Randomization was stratified by PD-L1 status, clinical stage, and geographic region. The primary endpoint was blinded independent central review–assessed event-free survival (EFS), with overall survival (OS) and pathologic complete response (pCR) among the key secondary endpoints.
A total of 808 patients were randomized between May 2021 and December 2023. With a median follow-up of 33.6 months, EFS was significantly improved with enfortumab vedotin plus pembrolizumab. Median EFS was not reached in the experimental arm vs 48.5 months with gemcitabine plus cisplatin (hazard ratio [HR], 0.53; 95% CI, 0.41-0.70; 1-sided P<.0001). The 24-month EFS rates were 79.4% and 66.2%, respectively. OS also favored enfortumab vedotin plus pembrolizumab (HR, 0.65; 95% CI, 0.48-0.89; 1-sided P=.0029). Median OS was not reached in either arm, and the 24-month OS rates were 86.9% with enfortumab vedotin plus pembrolizumab and 81.3% with gemcitabine plus cisplatin.
Pathologic complete response rates were higher with the perioperative enfortumab vedotin/pembrolizumab approach. In the intent-to-treat population, centrally assessed pCR was 55.8% with enfortumab vedotin plus pembrolizumab vs 32.5% with gemcitabine plus cisplatin, for an estimated difference of 23.4% (95% CI, 16.7-29.8; 1-sided P<.0001). In the presentation, Galsky noted that among patients who underwent cystectomy, the pCR rate in the enfortumab vedotin plus pembrolizumab arm was 64.4%. The ability to proceed to surgery was similar between arms, at 87% with enfortumab vedotin plus pembrolizumab and 90% with gemcitabine plus cisplatin.
Safety was consistent with the known profiles of the regimens. Treatment exposure was longer in the enfortumab vedotin plus pembrolizumab arm. Grade 3 or higher treatment-emergent adverse events occurred in 75.7% of patients receiving enfortumab vedotin plus pembrolizumab and 67.2% of those receiving gemcitabine plus cisplatin. The most common grade 3 or higher drug-related adverse event of special interest with enfortumab vedotin was skin reactions.
Overall, in a cisplatin-eligible population that has long been treated with cisplatin-based perioperative therapy, KEYNOTE-B15 showed improvements in EFS, OS, and pCR with enfortumab vedotin plus pembrolizumab. Together with prior positive perioperative data in cisplatin-ineligible disease, the study supports enfortumab vedotin plus pembrolizumab as a new treatment option across a broader MIBC population.
References
- Galsky MD, Balar AV, Maruzzo M, et al. Neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab for patients with muscle-invasive bladder cancer who are eligible for cisplatin-based chemotherapy: randomized, open-label, phase 3 KEYNOTE-B15 study. Presented at: 2026 ASCO Genitourinary Cancers Symposium; February 2026; San Francisco, CA. Abstract LBA630.