SHERIDAN, WYOMING - December 19, 2025 - Merck reported positive topline Phase 3 data showing its immunotherapy KEYTRUDA (pembrolizumab) combined with the antibody-drug conjugate Padcev (enfortumab vedotin-ejfv) improved event-free survival, overall survival and pathologic complete response when used before and after surgery in cisplatin-eligible muscle-invasive bladder cancer (MIBC), setting up a potential shift in the perioperative standard of care.
What KEYNOTE-B15 changes in the perioperative playbook
MIBC remains one of the highest-stakes settings in urothelial cancer because treatment decisions are front-loaded: patients must choose a strategy before radical cystectomy, and outcomes hinge on preventing recurrence after surgery. The current standard approach-neoadjuvant cisplatin-based chemotherapy followed by surgery-has proven survival value, yet Merck notes that nearly half of patients treated with this standard regimen experience recurrence. KEYNOTE-B15 (also known as EV-304) directly targets this gap by testing a perioperative regimen designed to deepen response before surgery and sustain disease control afterward.
Survival and response signals: topline readout highlights
Merck said the KEYTRUDA-Padcev combination delivered a statistically significant and clinically meaningful improvement versus neoadjuvant chemotherapy and surgery across three endpoints: event-free survival (EFS), overall survival (OS) and pathologic complete response (pCR) rate. While the company has not yet released full numerical results in the topline announcement, it characterized the findings as meaningful for cisplatin-eligible patients-an important distinction, given that many MIBC advances in recent years have focused on patients unable to receive cisplatin.
"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 Dr. Matthew Galsky, Lillian and Howard Stratton Professor of Medicine, director of genitourinary medical oncology, Mount Sinai Tisch Cancer Center, and KEYNOTE-B15 principal study investigator. "The strength of these data demonstrates that pembrolizumab plus enfortumab vedotin-given before and after surgery-has the potential to significantly improve survival outcomes."
Trial design and regimen intensity: what buyers should note
KEYNOTE-B15 is an open-label, randomized Phase 3 study (ClinicalTrials.gov, NCT04700124) enrolling 808 patients. Participants were randomized to either: four 21-day cycles of neoadjuvant KEYTRUDA plus enfortumab vedotin, then surgery, then 13 cycles of adjuvant KEYTRUDA plus five cycles of enfortumab vedotin; or four 21-day cycles of standard neoadjuvant gemcitabine plus cisplatin followed by surgery. The primary endpoint is EFS, defined using a composite of events that include progression precluding cystectomy, failure to undergo surgery in participants with residual disease, residual disease left at surgery, recurrence, or death due to any cause; key secondary endpoints include OS and pCR.
For health systems and integrated oncology networks, this level of perioperative treatment intensity matters operationally-particularly around infusion capacity, coordination across medical oncology and surgical teams, and the post-operative adjuvant schedule. The companies said the safety profile in this study was consistent with the known profiles of each agent and that no new safety signals were identified with the combination.
Strategic implications for Merck, Pfizer and Astellas
The program is being run in collaboration with Pfizer and Astellas and builds on the prior clinical success of the combination in locally advanced or metastatic urothelial cancer and cisplatin-ineligible MIBC. If the partners convert the topline results into regulatory filings and label expansion, it could broaden adoption of an immunotherapy-plus-ADC backbone beyond late-stage disease and further entrench combination strategies in earlier treatment lines-where both patient volumes and competitive pressure are higher.
"For people living with muscle-invasive bladder cancer, treatment decisions often need to be made earlier, when the opportunity to change the course of the disease is greatest," said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. "These results reinforce our conviction that moving KEYTRUDA into earlier stages of cancer care can make a meaningful difference for patients. By exploring combinations with ADCs in the perioperative setting, we aim to improve survival expectations for people facing muscle-invasive bladder cancer."
What to watch next
Merck said it plans to share the results with regulatory authorities worldwide for potential filings and to present the data at an upcoming medical meeting. In parallel, three additional Phase 3 studies are evaluating KEYTRUDA across bladder cancer stages, including KEYNOTE-866 and KEYNOTE-992 in MIBC and KEYNOTE-676 in NMIBC-signaling a sustained push to shape treatment algorithms across the full urothelial cancer continuum.
For more on Merck's oncology research and development focus, visit https://www.merck.com/research/oncology.