Perioperative EV plus pembrolizumab extends survival in cisplatin-eligible MIBC

Topline results from the phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124) demonstrate the efficacy of enfortumab vedotin-ejfv (EV; Padcev) plus pembrolizumab (Keytruda) in patients with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin-based chemotherapy.^1,2

Overall, data showed that the combination, given as neoadjuvant and adjuvant treatment, yielded significant improvements in event-free survival (EFS), overall survival (OS), and pathologic complete response (pCR) rates vs neoadjuvant chemotherapy and surgery in this patient population.

“The persistent risk of recurrence in cis-eligible patients with muscle-invasive bladder cancer, despite recent advances, underscores the continued need for effective perioperative treatments,” said principal investigator Matthew D. Galsky, MD, Lillian and Howard Stratton Professor of Medicine and director of genitourinary medical oncology at the Mount Sinai Tisch Cancer Center, 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.”

According to Merck, the safety profile for the EV/pembro combination was consistent with the known profiles for each individual agent. The companies plan to submit these results to regulatory authorities worldwide and present the findings at an upcoming medical meeting.

Overall, the results build on previous success with the combination in patients with locally advanced or metastatic urothelial carcinoma and in patients with MIBC who are ineligible for cisplatin-based chemotherapy. KEYNOTE-B15 specifically mirrors the KEYNOTE-905/EV-303 trial (NCT03924895), from which results were presented at ESMO 2025.³ The findings, which showed the combination extended survival in cisplatin-ineligible MIBC, led to FDA approval of EV/pembrolizumab in this population in November 2025.

With the new results from KEYNOTE-B15, the combination becomes the first and only immunotherapy plus antibody-drug conjugate (ADC) regimen used perioperatively to demonstrate improved survival in cisplatin-eligible MIBC.

"Despite available treatment options, nearly half of patients with muscle-invasive bladder cancer progress to metastatic disease within 3 years of diagnosis," added co-principal investigator Christopher Hoimes, DO, Director of the Bladder Cancer Program and Center for Cancer Immunotherapy at Duke Cancer Institute, in a news release.² "The EV-304 results represent a key milestone in the new era of urothelial cancer treatment. Together, the EV-303 and EV-304 results show that perioperative enfortumab vedotin plus pembrolizumab can positively impact the treatment journey for patients with muscle-invasive bladder cancer, offering significant survival gains across cisplatin-ineligible and cisplatin-eligible patients, signaling a shift from conventional platinum-based chemotherapy and the potential to transform the standard of care."

In total, the open-label KEYNOTE-B15 trial enrolled 808 patients with MIBC who were eligible to receive cisplatin-based chemotherapy. Patients in the trial were randomly assigned to receive 4 cycles of neoadjuvant IV pembrolizumab plus IV EV infusion, surgery, and then 13 cycles of adjuvant IV pembrolizumab plus 5 cycles of IV EV fusion; or to receive 4 cycles of standard of care neoadjuvant chemotherapy followed by surgery.

The primary end point for the study is EFS. Key secondary end points include OS and pCR rate. Final completion of the trial is expected in December 2026.⁴

REFERENCES

1. First and only immunotherapy plus ADC regimen, used perioperatively, to extend survival for cisplatin-eligible patients with MIBC. 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/

2. PADCEV™ Plus Keytruda® Significantly Improves Survival for Patients with Muscle-Invasive Bladder Cancer Regardless of Cisplatin Eligibility. News release. Astellas Pharma. 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

3. Perioperative (periop) enfortumab vedotin (EV) plus pembrolizumab (pembro) in participants (pts) with muscle-invasive bladder cancer (MIBC) who are cisplatin-ineligible: The phase III KEYNOTE-905 study. Presented at: 2025 European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA2. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA2.html.pdf

4. Perioperative Enfortumab Vedotin (EV) Plus Pembrolizumab (MK-3475) Versus Neoadjuvant Chemotherapy for Cisplatin-Eligible Muscle Invasive Bladder Cancer (MIBC) (MK-3475-B15/​ KEYNOTE-B15 /​ EV-304) (KEYNOTE-B15). ClinicalTrials.gov. Last updated August 26, 2025. Accessed December 17, 2025. https://www.clinicaltrials.gov/study/NCT04700124