European Commission approves perioperative EV/pembrolizumab for cisplatin-ineligible MIBC

The European Commission has approved the combination of enfortumab vedotin-ejfv (EV; Padcev) plus pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) as a perioperative regimen for adult patients with muscle-invasive bladder cancer (MIBC) who decline or are ineligible for cisplatin-based chemotherapy.^1,2

The approval is valid across all 27 European Union (EU) member states, as well as Iceland, Liechtenstein, and Norway. This decision marks the first approval of a PD-1 inhibitor plus antibody-drug conjugate regimen in the EU.

The regimen was previously approved in the US in November 2025.

“Patients with resectable muscle-invasive bladder cancer who are ineligible for cisplatin‑containing chemotherapy face an aggressive disease and few effective therapies, with surgery alone as the longstanding standard of care,” said Christof Vulsteke, MD, PhD, head of Integrated Cancer Center Ghent and Clinical Trial Unit Oncology Ghent, in a news release on the approval.¹ “Based on robust data from the KEYNOTE-905 trial, this approval marks a turning point in bladder cancer care. It introduces a potentially practice-changing perioperative treatment option that may significantly improve outcomes and extend survival for this underserved patient population across the European Union.”

Data on perioperative EV plus pembrolizumab

The approval is supported by results from the phase 3 KEYNOTE-905/EV-303 trial (NCT03924895), which were published in the New England Journal of Medicine.³ Data showed that the treatment regimen—consisting of neoadjuvant EV plus pembrolizumab, radical cystectomy plus pelvic lymph node dissection, and adjuvant EV plus pembrolizumab—yielded significant improvements in event-free survival (EFS), overall survival (OS), and pathological complete response (pCR) rate compared with surgery alone.

The open-label trial included 344 patients who were randomly assigned to either enfortumab vedotin plus pembrolizumab (EV + P; n = 170) or the control arm of surgery alone (n = 174). The primary end point was EFS, and key secondary end points included OS, pCR, and safety. The median follow-up at data report was 25.6 months (range, 11.8 to 53.7).

Overall, the study met its primary end point, showing that perioperative EV + P reduced the risk of recurrence, progression, or death by 60% compared with surgery alone (HR for an event or death, 0.40; 95% CI, 0.28-0.57; two-sided P < .001). The estimated 2-year EFS was 74.7% in the EV + P arm vs 39.4% in the control arm. The median duration of EFS was not reached (NR; 95% CI, 37.3-NR) in the EV + P arm and was 15.7 months (95% CI, 10.3-20.5) in the control arm.

The perioperative regimen also reduced the risk of death by 50% compared with surgery alone (HR, 0.50; 95% CI, 0.33 to 0.74; two-sided P < .001). At 2 years, the estimated OS was 79.7% in the EV + P arm vs 63.1% in the control arm. The median OS was NR (95% CI, NR-NR) in the treatment arm and 41.7 months (95% CI, 31.8-NR) in the control arm. As with EFS, OS gains were observed across key patient subgroups.

The investigators also reported that 97 patients in the EV plus pembrolizumab group achieved pCR compared with 15 patients in the control group. This translated to a pCR rate of 57.1% (95% CI, 49.3%-64.6%) in the EV plus pembrolizumab arm vs 8.6% (95% CI, 4.9%-13.8%) in the control arm (estimated difference, 48.3 percentage points; 95% CI, 39.5-56.5; two-sided P < .001).

Regarding safety, any-grade treatment-emergent adverse events (TEAEs) were reported in 167 (100%) patients in the EV plus pembrolizumab arm vs 103 (64.8%) patients in the control arm. Grade 3 or higher TEAEs were seen in 119 (71.3%) patients in the EV plus pembrolizumab group vs 73 (45.9%) patients in the control group.

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