FDA Prioritizes sBLA Review for Enfortumab Vedotin/Pembro in MIBC

The FDA has granted priority review to the supplemental biologics license application (sBLA) of enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab (Keytruda), radical cystectomy (RC), and standard pelvic lymph node dissection (PLND) as perioperative treatment for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for or decline cisplatin-containing chemotherapy.¹

A Prescription Drug User Fee Act (PDUFA) target action date has been set for April 7, 2026. Approval of the sBLA would establish this combination as a new therapeutic option for a patient population with high recurrence rates, historically limited treatment options, and poor prognosis²; the priority review signifies the FDA’s recognition of this critical unmet need.

What data support the sBLA submission?

This combination was investigated in the pivotal phase 3 EV-303/KEYNOTE-905 study (NCT03924895),³ the updated results of which were recently presented at a late-breaking session at the 2025 European Society for Medical Oncology (ESMO) Congress in Berlin, Germany. Here, data revealed a striking 60% reduction in the risk of tumor recurrence, progression, or death of patients treated with the combination compared with surgery alone (HR, 0.40; 95% CI, 0.28–0.57; P <.0001), meeting its primary end point of event-free survival (EFS).⁴

“The topline results of the study for [EFS] were a strong hit as a primary end point. There was an early and sustained separation of the [Kaplan-Meier] curves in favor of pembrolizumab, and this was translated in a significant hazard ratio of 0.4,” said Christof Vulsteke, MD, PhD, head of Integrated Cancer Center Ghent at AZ Maria Middelares, professor at the Center for Oncological Research at Antwerp University, and study principal investigator, in an interview with Targeted Oncology.

The study’s secondary end point of overall survival (OS) also yielded promising results with a 50% reduction in the risk of death with the combination compared with surgery alone (HR, 0.50; 95% CI, 0.33–0.74; P <.0002),⁴ which Vulsteke remarked as the first demonstrated OS benefit in this population during his interview. Further, a significant difference (48.3%; 95% CI, 39.5%–56.5%; P <.000001) in pathologic complete response (pCR) rate was observed between patients who received the combination (57.1%) and patients who received surgery only (8.6%).⁴

Regarding safety, the safety profile was manageable and consistent with that previously reported in this combination, with no new safety signals identified.¹ The most common adverse events (AEs) observed with the combination include pruritus, alopecia, diarrhea, fatigue, and anemia.⁴ The incidence of any-cause grade ≥3 AEs were 71.3% and 45.9% among those who received the combination and those who received surgery only, respectively.

The ongoing multicenter, open-label, randomized EV-303 study enrolled 595 adult patients with MIBC and randomized them to receive 1 of 3 treatments: neoadjuvant and adjuvant pembrolizumab (arm A), surgery alone (arm B), or neoadjuvant and adjuvant enfortumab vedotin in combination with pembrolizumab (arm C). Arm C was added following promising efficacy results in the metastatic setting, according to Vulsteke in his interview.

The primary end point of the study was EFS between arms C and B; secondary end points included EFS between arms A and B, OS, pCR, disease-free survival, pathologic downstaging rate, and measures of safety.

REFERENCES:

1. PADCEV™ (enfortumab vedotin-ejfv) Plus KEYTRUDA® (pembrolizumab) sBLA Granted FDA Priority Review for Treatment of Certain Patients with Muscle-Invasive Bladder Cancer. News release. PR Newswire. October 21, 2025. Accessed October 22, 2025. https://tinyurl.com/43ujkkj2

2. Galsky MD, Hoimes CJ, Necchi A, et al. Perioperative pembrolizumab therapy in muscle-invasive bladder cancer: Phase III KEYNOTE-866 and KEYNOTE-905/EV-303. Future Oncol. 2021 Aug;17(24):3137-3150. doi: 10.2217/fon-2021-0273. Epub 2021 May 19. PMID: 34008425.

3. Perioperative Pembrolizumab (MK-3475) Plus Cystectomy or Perioperative Pembrolizumab Plus Enfortumab Vedotin Plus Cystectomy Versus Cystectomy Alone in Participants Who Are Cisplatin-ineligible or Decline Cisplatin With Muscle-invasive Bladder Cancer (MK-3475-905/​KEYNOTE-905/​EV-303). ClinicalTrials.gov. Updated August 28, 2025. Accessed October 22, 2025. https://clinicaltrials.gov/study/NCT03924895

4. PADCEV Plus KEYTRUDA, Given Before and After Surgery, Cuts the Risk of Recurrence, Progression or Death by 60% and the Risk of Death by 50% for Certain Patients with Bladder Cancer. News Release. Astellas Pharma Inc. October 18, 2025. Accessed October 22, 2025. https://tinyurl.com/5e3yjh9s