FDA Approves Pembrolizumab Plus Enfortumab Vedotin for MIBC

The FDA approved the combination of pembrolizumab (Keytruda) and enfortumab vedotin-ejfv (Padcev) for neoadjuvant and adjuvant treatment of muscle-invasive bladder cancer (MIBC) in adults who are ineligible for cisplatin.¹ The decision provides a new frontline option for a patient population historically associated with poor prognosis.

The approval encompasses the use of Merck's formulation of pembrolizumab with berahyaluronidase alfa-pmph (Keytruda Qlex) in combination with Astellas Pharma's enfortumab vedotin-ejfv (Padcev). The regimen is administered both before (neoadjuvant) and after (adjuvant) radical cystectomy with pelvic lymph node dissection. The FDA review was expedited under Project Orbis and granted priority review, resulting in approval 5 months ahead of the agency’s goal date.

The approval was supported by robust efficacy data presented at the 50th European Society for Medical Oncology Congress in Berlin.^2,3 The phase 3 KEYNOTE-905/EV-303 trial (NCT03924895) demonstrated that perioperative therapy with enfortumab vedotin plus pembrolizumab (EV + P) significantly improved outcomes compared with surgery alone in cisplatin-ineligible patients.

For this challenging population—representing up to half of all MIBC cases—standard treatment without upfront chemotherapy leads to high relapse rates, often reaching 70%. EV + P therapy reduced the risk of disease progression or death by 60%.² Patients receiving the combination therapy had superior outcomes across multiple end points. Event-free survival (EFS), assessed by blinded independent central review, was significantly improved; median EFS was not reached in the EV + P arm vs 15.7 months in the surgery-only group (HR, 0.40).

KEYNOTE-905/EV-303 also reported the first overall survival (OS) benefit in this population. Median OS was not reached in the combination arm vs 41.7 months in the control group (HR, 0.50), representing a 50% reduction in the risk of death after 25 months. Pathological complete response rates were markedly higher with EV + P, at 57.1% compared with 8.6% in the control arm.

The safety profile was consistent with prior trials in advanced urothelial cancer. All patients in the EV + P arm experienced treatment-emergent adverse events (100%), with 71.3% experiencing grade 3 or higher events compared with 64.8% (grade ≥ 3, 45.9%) in the control group. Common grade 3 events included fatigue, dehydration, and maculopapular rash.³

Jeff Legos, PhD, MBA, chief oncology officer at Pfizer, emphasized that the combination’s ability to "reduce the risk of death by half" suggests its transformational efficacy in advanced bladder cancer may now extend to earlier disease stages.² EV-303 principal investigator Christof Vulsteke, MD, PhD, predicted the regimen "might become the standard of care for patients who have had grim prospects," a view echoed by Astellas, which stated that the results "may establish a new efficacy benchmark in muscle-invasive bladder cancer."

The success of KEYNOTE-905/EV-303 underscores the critical role of antibody-drug conjugates in first-line cancer treatment, demonstrating their potential to improve survival when integrated into treatment plans for early-stage disease.

References

1. FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle invasive bladder cancer. FDA. November 21, 2025. Accessed November 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-enfortumab-vedotin-ejfv-muscle-invasive-bladder-cancer

2. Caffrey M. Enfortumab vedotin plus pembro cuts risk of disease progression, death 60% for patients with MIBC who can’t have chemo with bladder removal. AJMC®. October 18, 2025. Accessed November 21, 2025. https://www.ajmc.com/view/enfortumab-vedotin-plus-pembro-cuts-risk-of-disease-progression-death-60-for-patients-with-mibc-who-can-t-have-chemo-with-bladder-removal

3. Caffrey M. At ESMO, 39% response rate seen for EV plus pembro in recurrent head and neck squamous cell carcinoma. AJMC. Published October 23, 2025. Accessed November 21, 2025. https://www.ajmc.com/view/at-esmo-39-response-rate-seen-for-ev-plus-pembro-in-recurrent-head-and-neck-squamous-cell-carcinoma