EU Approves Enfortumab Vedotin/Pembrolizumab in Cisplatin-Ineligible MIBC

The European Commission has approved enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab (Keytruda) for the treatment of adult patients with cisplatin-ineligible, resectable muscle invasive bladder cancer (MIBC), according to a news release from the developer, Astellas Pharma.¹

Supporting the regulatory decision were data from the phase 3 KEYNOTE-905/EV-303 trial (NCT03924895), which evaluated the enfortumab-containing regimen against surgery alone among this MIBC population.² Previously presented at the European Society of Medical Oncology (ESMO) Congress 2025 and published in The New England Journal of Medicine, the investigational regimen conferred a 60% reduction in the risk of an event-free survival (EFS) event compared with surgery alone (HR, 0.40; 95% CI, 0.28-0.57; P <.0001).³ Moreover, the median EFS was not reached (NR; 95% CI, 37.3 months-NR) in the pembrolizumab-containing arm compared with 15.7 months (95% CI, 10.3-20.5) in the surgery alone arm.

Compared with surgery alone, the combination therapy conferred a 50% reduction in the risk of death (HR, 0.50; 95% CI, 0.33-0.74; P = .0002). The median overall survival (OS) was NR (95% CI, NR-NR) and 41.7 months (95% CI, 31.8-NR) in the respective arms. Additionally, the pathologic complete response (pCR) rate was 57.1% (95% CI, 49.3%-64.6%) vs 8.6% (95% CI, 4.9%-13.8%) in each cohort (P <.0001).

“Despite surgery with curative intent, many patients with [MIBC] experience disease recurrence,” Christof Vulsteke, MD, PhD, head of Integrated Cancer Center Ghent at IKG, Belgium, and Clinical Trial Unit Oncology Ghent, and EV-303 principal investigator, stated in the news release.¹ “The EV-303 results demonstrated clinically meaningful improvements in both [EFS and OS], supporting perioperative enfortumab vedotin plus pembrolizumab as an important new treatment option for [patients who are] cisplatin-ineligible in Europe.”

The phase 3 trial enrolled adults with cisplatin-ineligible MIBC who had an ECOG performance status of 0 to 2, clinical stage T2 to T4aN0M0 or T1 to T4aN1M0 disease by central assessment, and a urothelial histology of 50% at a minimum.

Those enrolled in the investigational regimen received 200 mg of pembrolizumab every 3 weeks plus 1.25 mg/kg of enfortumab vedotin on days 1 and 8 every 3 weeks for 3 cycles, followed by radical cystectomy and standard pelvic lymph node dissection. Thereafter, patients received the same therapeutic regimen as adjuvant therapy for a maximum of 14 cycles.

Patients assigned to the control arm received radical cystectomy and standard pelvic lymph node dissection followed by observation.

In the investigational and control arms, the median age was 74.0 years (range, 47-87) and 72.5 years (range, 46-87). Most patients in each arm were male (80.6% vs 75.3%), had an ECOG performance status of 0 (60.0% vs 54.6%), and were from the European Union (45.9% vs 44.3%). A total of 16.5% vs 20.1% of the respective arms were eligible for but refused cisplatin-based treatment.

The primary end point was EFS assessed by blinded independent central review. Key secondary end points included OS and pCR by central pathologist review; EFS was also evaluated per pCR status.

Treatment-emergent adverse effects (TEAEs) occurred in 100% of the enfortumab vedotin-containing arm vs 64.8% in the surgery-only arm. The rates of grade 3 or higher TEAEs was 71.3% vs 45.9%, with serious TEAEs occurring in 58.1% vs 40.9% of the respective arms.

AEs leading to surgery delay occurred in 4.0% vs 0.6% of the respective arms. Toxicities led to dose reduction or discontinuation of enfortumab vedotin for 16.8% and 41.3% of the investigational arm, respectively; they led to discontinuation of pembrolizumab for 34.1% of patients. Fatal AEs were observed in 7.8% vs 5.7% of the investigational and control arms, respectively.

The enfortumab vedotin combination regimen was previously granted FDA approval for adult patients with MIBC ineligible for cisplatin in November 2025.⁴ Moreover, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) gave a positive opinion to the regimen for patients with cisplatin-ineligible, resectable MIBC in May 2026.⁵

References

1. European Commission approves PADCEV™ (enfortumab vedotin) in combination with Keytruda® (pembrolizumab) as the first and only approved perioperative treatment option for cisplatin-ineligible patients with resectable muscle-invasive bladder cancer. News release. Astellas Pharma, Inc. June 24, 2026. Accessed June 24, 2026. https://tinyurl.com/3z57n9na
2. Vulsteke C, Kaimakliotis HZ, Danchaivijitr P, et al. Perioperative enfortumab vedotin plus pembrolizumab in participants with muscle-invasive bladder cancer who are cisplatin-ineligible: phase 3 KEYNOTE-905 study. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA2.
3. Vulsteke C, Adra N, Danchaivijitr P, et al. Perioperative enfortumab vedotin and pembrolizumab in bladder cancer. N Engl J Med. 2026;394(13):1257-1269. doi:10.1056/NEJMoa2511674
4. FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle invasive bladder cancer. News release. FDA. November 21, 2025. Accessed June 24, 2026. https://tinyurl.com/bdfhmhnk
5. Merck receives positive EU CHMP opinion for KEYTRUDA® (pembrolizumab) plus Padcev® (enfortumab vedotin-ejfv) as perioperative treatment for adults with cisplatin-ineligible resectable muscle-invasive bladder cancer. News release. Merck. May 22, 2026. Accessed June 24, 2026. https://tinyurl.com/yhzjrj5u