Perioperative pembrolizumab (Keytruda) plus enfortumab vedotin-ejfv (Padcev) led to a clinically meaningful and statistically significant improvement in event-free survival (EFS), over standard neoadjuvant chemotherapy and surgery in patients with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin-based chemotherapy, meeting the primary end point of the phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124).1,2
Top-line findings from an interim analysis of the trial also showed that it met key secondary end points, including overall survival (OS) and pathologic complete response (pCR). The safety profile for enfortumab vedotin plus pembrolizumab was consistent with the known profile of the treatment regimen, and no new safety signals were identified with the combination.
“The persistent risk of recurrence in [cisplatin]-eligible patients with MIBC, despite recent advances, underscores the continued need for effective perioperative treatments,” Matthew Galsky, MD, Lillian and Howard Stratton Professor of Medicine and director of genitourinary medical oncology at Mount Sinai Tisch Cancer Center in New York, New York, and KEYNOTE-B15 principal study investigator, stated in a news release.1 “The strength of these data demonstrates that pembrolizumab plus enfortumab vedotin—given before and after surgery—has the potential to significantly improve survival outcomes.”
Merck, Astellas Pharma Inc, and Pfizer, joint collaborators on the study, plan to submit results from KEYNOTE-B15/EV-304 for presentation at an upcoming medical meeting and share them with global health authorities for potential regulatory filings.
“Despite available treatment options, nearly half of patients with MIBC progress to metastatic disease within 3 years of diagnosis,” Christopher Hoimes, DO, director of the Bladder Cancer Program and Center for Cancer Immunotherapy at Duke Cancer Institute in Durham, North Carolina, and principal investigator of EV-304, added in a news release from Astellas.2 “The EV-304 results represent a key milestone in the new era of urothelial cancer treatment.
Positive Top-Line Findings From KEYNOTE-B15/EV-304
- Top-line findings from the phase 3 KEYNOTE-B15/EV-304 trial showed that perioperative pembrolizumab plus enfortumab vedotin-ejfv improved EFS, OS, and pCR rate vs SOC neoadjuvant chemotherapy and surgery in cisplatin-eligible patients with MIBC.
- The safety profile of enfortumab vedotin plus pembrolizumab was consistent with the known profile of these individual agents, and no new safety signals were identified.
- Results from KEYNOTE-B15/EV-304 will be shared with global regulatory authorities and presented at an upcoming medical meeting.
What was the design of KEYNOTE-B15/EV-304?
KEYNOTE-B15/EV-304 is an ongoing, open-label, randomized, controlled study evaluating perioperative enfortumab vedotin in combination with pembrolizumab and radical cystectomy and pelvic lymph node dissection compared with neoadjuvant gemcitabine/cisplatin and surgery in patients with MIBC who are eligible for cisplatin-based chemotherapy.1,2
In total, 808 patients were enrolled in the trial and randomly assigned to receive either:
- Four 21-day cycles of neoadjuvant pembrolizumab through intravenous (IV) infusion plus IV enfortumab vedotin, followed by surgery, followed by 13 cycles of adjuvant IV pembrolizumab plus 5 cycles of IV enfortumab vedotin infusion
- Four 21-day cycles of standard-of-care neoadjuvant chemotherapy followed by surgery.
The study’s primary end point is EFS by blinded independent central review. Key secondary end points include OS and pCR rate.
What are the regimen’s current indications in MIBC and urothelial cancer?
Of note, perioperative enfortumab vedotin-ejfv plus pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) was approved by the FDA in November 2025 for patients with MIBC who are ineligible for cisplatin.3 This regulatory decision was based on findings from the phase 3 EV-303/KEYNOTE-905 trial (NCT03924895), which demonstrated that perioperative enfortumab vedotin plus pembrolizumab significantly improved EFS vs radical cystectomy plus pelvic lymph node dissection alone.
“Building on the recent US approval for cisplatin-ineligible patients living with MIBC, these positive EV-304 findings reinforce the potential of [enfortumab vedotin] plus pembrolizumab to improve survival outcomes for a broad population of patients living with MIBC,” Moitreyee Chatterjee-Kishore, PhD, MBA, head of oncology development at Astellas, noted in the news release.2 “Together with the EV-303 data, these results strengthen the evidence supporting this combination regimen as a treatment option for patients regardless of cisplatin eligibility. We are committed to bringing forth much-needed advancements and hope to [help] more patients."
Enfortumab vedotin plus pembrolizumab is also currently approved for the treatment of adult patients with locally advanced or metastatic urothelial cancer in the United States, the European Union, Japan, and several other countries around the world.1
“For people living with MIBC, treatment decisions often need to be made earlier, when the opportunity to change the course of the disease is greatest,” Marjorie Green, MD, senior vice president and head of oncology, global clinical development at Merck Research Laboratories, concluded in the news release.1 “These results reinforce our conviction that moving [pembrolizumab] into earlier stages of cancer care can make a meaningful difference for patients. By exploring combinations with antibody-drug conjugates in the perioperative setting, we aim to improve survival expectations for people facing MIBC.”
References
- Keytruda (pembrolizumab) plus Padcev (enfortumab vedotin-ejfv) significantly improved event-free survival, overall survival, and pathologic complete response rates for cisplatin-eligible patients with MIBC when given before and after surgery. News release. Merck. December 17, 2025. Accessed December 17, 2025. https://www.merck.com/news/keytruda-pembrolizumab-plus-padcev-enfortumab-vedotin-ejfv-significantly-improved-event-free-survival-overall-survival-and-pathologic-complete-response-rates-for-cisplatin-eligible-pa/
- Padcev plus Keytruda significantly improves survival for patients with muscle-invasive bladder cancer regardless of cisplatin eligibility. News release. Astellas Pharma Inc. December 17, 2025. Accessed December 17, 2025. https://www.prnewswire.com/news-releases/padcev-plus-keytruda-significantly-improves-survival-for-patients-with-muscle-invasive-bladder-cancer-regardless-of-cisplatin-eligibility-302644184.html
- FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle-invasive bladder cancer. FDA. November 21, 2025. Accessed December 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-enfortumab-vedotin-ejfv-muscle-invasive-bladder-cancer
