Key Clinical Summary: 

• Design/Population: The phase 3 KEYNOTE-B15 randomized 808 cisplatin-eligible patients with muscle-invasive bladder cancer to perioperative enfortumab vedotin plus pembrolizumab versus neoadjuvant gemcitabine and cisplatin followed by cystectomy.
• Key Outcomes: The enfortumab vedotin plus pembrolizumab regimen significantly improved event-free survival, overall survival, and pathologic complete response rate compared with cisplatin-based chemotherapy.
• Clinical Relevance: These results, consistent with prior phase 3 data, reinforce perioperative enfortumab vedotin plus pembrolizumab as a practice-changing option for patients with muscle-invasive bladder cancer, regardless of cisplatin eligibility.

Matthew Galsky, MD, Mount Sinai Medical Center, New York, New York, discusses results from the phase 3 KEYNOTE-B15/EV-304 study evaluating perioperative enfortumab vedotin plus pembrolizumab versus cisplatin-based chemotherapy among cisplatin-eligible patients with muscle-invasive bladder cancer.

Results demonstrated that this perioperative regimen significantly improved survival and response, supporting enfortumab vedotin plus pembrolizumab as an effective treatment option in this setting.

Dr Galsky presented these results at the 2026 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium in San Francisco, California.

Transcript: 

I'm Matt Galsky, I'm a professor of medicine at the Icahn School of Medicine at Mount Sinai and the deputy director of the Mount Sinai Tisch Cancer Center. The KEYNOTE-B15 study tested the perioperative regimen of neoadjuvant enfortumab vedotin plus pembrolizumab followed by cystectomy, followed by adjuvant enfortumab vedotin plus pembrolizumab versus our longstanding standard which is cisplatin-based neoadjuvant chemotherapy followed by cystectomy in patients with muscle-invasive bladder cancer. 

Neoadjuvant chemotherapy followed by cystectomy has been standard treatment for muscle-invasive bladder cancer for almost 25 years and has really been hard to displace cisplatin-based chemotherapy, and there have really been a paucity of improvements to such treatment since cisplatin-based therapy was initially shown to be beneficial approximately 25 years ago. 

This study tested this new regimen, enfortumab vedotin plus pembrolizumab, which is now our standard of care for patients with metastatic bladder cancer and has also become a standard of care for patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy based on the KEYNOTE-905 study.

The KEYNOTE-B15 study tested this regimen against our former standard of care, cisplatin-based chemotherapy, in patients who are cisplatin-eligible. The study randomized 808 patients. Patients randomized to the enfortumab vedotin plus pembrolizumab arm received 4 cycles of neoadjuvant enfortumab vedotin plus pembrolizumab followed by cystectomy, followed by 13 cycles of adjuvant pembrolizumab, the first 5 of which were administered along with enfortumab vedotin. The standard-of-care arm, or the control arm, received gemcitabine and cisplatin neoadjuvant chemotherapy for 4 cycles followed by cystectomy, followed by observation. The primary end point of the study was event-free survival, and that was determined by blinded independent central review and key secondary end points were overall survival and pathological complete response rate. 

The study demonstrated that event-free survival was significantly improved with the enfortumab vedotin regimen versus the gemcitabine and cisplatin regimen. The hazard ratio for event-free survival was 0.53, favoring the enfortumab vedotin plus pembrolizumab arm. Overall survival was also significantly improved on the enfortumab vedotin plus pembrolizumab arm versus the gemcitabine and cisplatin arm, with a hazard ratio of 0.65. Pathological complete response rate was also significantly improved, and this went from 32.5% on the gemcitabine and cisplatin arm to 55.8% on the enfortumab vedotin plus pembrolizumab arm so the majority of patients treated with enfortumab vedotin plus pembrolizumab prior to cystectomy—greater than 50%—will achieve a pathological complete response, and that lines up quite well with what we saw in KEYNOTE-905 also. 

This regimen really has been shown now in 2 independent, phase 3 studies to improve outcomes in patients with muscle-invasive bladder cancer, and really showing similar benefit across 2 phase 3 studies really reinforces the reproducibility and generalizability of outcomes with this treatment regimen. And the 2 studies together really support this regimen as a new treatment option for patients with muscle-invasive bladder cancer now regardless of cisplatin eligibility.

Source:

Galsky MD, Valderrama BP, Maruzzo M, et al. Neoadjuvant and adjuvant enfortumab vedotin (EV) plus pembrolizumab (pembro) for participants with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin: Randomized, open-label, phase 3 KEYNOTE-B15 study. Presented at ASCO GU. February 26 - 28, 2026. San Francisco, California. LBA630.