Perioperative Enfortumab Vedotin Combo Earns Priority Review For MIBC

The FDA has granted priority review to a supplemental biologics license application for enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) for the treatment of patients with muscle-invasive bladder cancer (MIBC) regardless of cisplatin eligibility, according to a news release from the developer, Astellas Pharma.¹

The FDA has set a target action date of August 17, 2026, under the Prescription Drug User Fee Act.

Supporting the regulatory decision for the enfortumab vedotin-based combination are findings from the phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124), which evaluated the regimen against cisplatin and gemcitabine in patients eligible for cisplatin-based therapy and radical cystectomy.² Efficacy data revealed a median event-free survival (EFS) that was not reached (NR; 95% CI, NR-NR) with the investigational regimen vs 48.5 months (95% CI, 43.3-NR) with chemotherapy. Additionally, the 24-month EFS rates were 79.4% vs 66.2% in each respective arm (HR, 0.53; 95% CI, 0.41-0.70; P <.0001).

Moreover, the investigational regimen conferred a longer overall survival (OS), with a median value not reached in either arm and 24-month rates of 86.9% vs 81.3%, respectively (HR, 0.65; 95% CI, 0.48-0.89; P = .0029). Moreover, the pathologic complete response (pCR) rates also favored the investigational regimen, with a rate of 55.8% (95% CI, 50.8%-60.7%) vs 32.5% (95% CI, 28.0%-37.3%) with chemotherapy. The estimated difference was 23.4% (95% CI, 16.7%-29.8%; P <.001).

"The data from the EV-304 trial take us another step closer to bringing perioperative enfortumab vedotin plus pembrolizumab to patients with [MIBC] regardless of cisplatin eligibility, who still [have] a recurrence rate of more than [50%] despite curative-intent surgery, highlighting the ongoing need for improved treatment strategies,” Moitreyee Chatterjee-Kishore, PhD, MBA, head of Oncology Development at Astellas, stated in the news release.¹

Investigators in the phase 3 study enrolled patients with localized, muscle-invasive urothelial cancer of the bladder, 808 of whom were randomly assigned 1:1 to the investigational (n = 405) and chemotherapy arms (n = 403). In the chemotherapy arm, patients received 70 mg/m² of cisplatin and 1000 mg/m² of gemcitabine, with both arms receiving 4 cycles in each arm followed by radical cystectomy. Those in the enfortumab vedotin arm received the agent at 1.25 mg/kg plus pembrolizumab at 200 mg intravenously every 3 weeks and continued to receive enfortumab vedotin for 5 additional cycles as well as pembrolizumab for 13 cycles following surgery.

The primary end point of the trial was EFS per blinded independent central review (BICR). Key secondary end points included pCR per blinded central pathology review and OS.

“For people with [MIBC], surgery is often just the beginning of a long and uncertain journey, with far too many patients seeing their cancer return. If approved, perioperative [enfortumab vedotin] plus pembrolizumab could meaningfully change that experience, potentially helping patients reduce the risk of recurrence and live longer, regardless of whether they are eligible for cisplatin,” said Jeff Legos, PhD, MBA, chief oncology officer of Pfizer, in the news release.¹

The safety profiles in each arm were consistent with prior observations. Treatment-emergent adverse effects (TEAEs) during the surgical phase of the trial were comparable in each study arm. Grade 3 or higher TEAEs were reported in 75.7% of the enfortumab vedotin arm vs 67.2% of the chemotherapy arm, with TEAEs leading to death in 2 patients and 1 patient in each respective arm.

AEs of special interest included skin reactions (63.5%), peripheral neuropathy (36.0%), and ocular disorders (23.3%) with enfortumab vedotin and severe skin reactions (17.1%), hypothyroidism (12.2%), and pneumonitis (6.9%) with pembrolizumab.

The FDA previously approved the enfortumab vedotin/pembrolizumab combination in the cisplatin-ineligible MIBC population in November 2025.³

References

1. U.S. FDA grants priority review to sBLA for PADCEV™ + Keytruda® as perioperative treatment for muscle-invasive bladder cancer regardless of cisplatin eligibility. News release. Astellas Pharma. April 20, 2026. Accessed April 20, 2026. https://tinyurl.com/3f86zsec
2. Galsky MD, Valderrama BP, Maruzzo M, et al. Neoadjuvant and adjuvant enfortumab vedotin (EV) plus pembrolizumab (pembro) for participants with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin: randomized, open-label, phase 3 KEYNOTE-B15 study. J Clin Oncol. 2026;44(suppl 7):LBA630. doi:10.1200/JCO.2026.44.7_suppl.LBA630
3. FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle invasive bladder cancer. News release. FDA. November 21, 2025. Accessed April 20, 2026. https://tinyurl.com/bdfhmhnk