EU CHMP Issues Positive Opinion for Perioperative Pembrolizumab/Enfortumab Vedotin in Cisplatin-Ineligible MIBC

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) granted a positive opinion to pembrolizumab (Keytruda) plus enfortumab vedotin-ejfv (Padcev) as neoadjuvant treatment followed by adjuvant treatment after radical cystectomy in adult patients with resectable muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-containing chemotherapy.¹ The recommendation also includes pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) and will be reviewed by the European Commission European Commission for marketing authorization in the European Union, Iceland, Liechtenstein and Norway; a final decision expected in the third quarter of 2026.

The regulatory decision was supported by data from the phase 3 KEYNOTE-905/EV-303 trial (NCT03924895). At a median follow-up of 25.6 months (range, 11.8-53.7), findings from KEYNOTE-905 published in The New England Journal of Medicine demonstrated that perioperative pembrolizumab plus enfortumab vedotin reduced the risk of event-free survival (EFS) events by 60% vs surgery alone (HR, 0.40; 95% CI, 0.28-0.57; 2-sided P < .0001). The median EFS was not reached (NR; 95% CI, 37.3-NR) with the combination (n = 170) vs 15.7 months (95% CI, 10.3-20.5) with surgery alone (n = 174).^1,2

“Patients in Europe with resectable MIBC who are ineligible for cisplatin-containing chemotherapy have limited treatment options and are at high risk for disease recurrence,” Marjorie Green, MD, senior vice president and head of oncology, global clinical development, at Merck Research Laboratories, stated in a news release.¹ “This positive CHMP recommendation brings us closer to a new chapter of patient care – one that could address this significant unmet need by offering a [pembrolizumab]-based regimen both before and after surgery, based on the compelling results from KEYNOTE-905.”

In November 2025, the FDA approved enfortumab vedotin in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa as neoadjuvant treatment followed by adjuvant treatment after cystectomy for patients with MIBC who are ineligible for cisplatin.³ The approval was supported by prior data from KEYNOTE-905.

How was the KEYNOTE-905 designed?

KEYNOTE-905 was an open-label, multicenter, randomized trial that evaluated pembrolizumab plus enfortumab vedotin as perioperative treatment compared with surgery alone in adult patients with MIBC who were not eligible for, or declined, cisplatin-based chemotherapy.² Patients needed to have included having stage T2 to T4a with N0M0 or T1 to T4a with N1M0 disease with predominantly urothelial histologic features, an ECOG performance status of 2 or less, and the ability to undergo surgery.

In the investigational arm, patients received neoadjuvant and adjuvant enfortumab vedotin at 1.25 mg/kg on days 1 and 8 for 9 total cycles plus pembrolizumab at 200 mg on day 1 every 3 weeks for a total of 17 cycles, with surgery after 3 cycles. Patients in the control arm underwent surgery only.

The primary end point was EFS. Overall survival (OS) and pathological complete response (pCR) represented key secondary end points. Additional secondary end points included disease-free survival as assessed by central review, pathological downstaging, and safety.

What additional efficacy data were reported?

OS also favored perioperative pembrolizumab plus enfortumab vedotin, with a 50% reduction in the risk of death vs surgery alone (HR, 0.50; 95% CI, 0.33-0.74; 2-sided P < .001). The median OS was NR (95% CI, NR-NR) in the combination arm vs 41.7 months (95% CI, 31.8-NR) in the surgery-alone arm. The pCR rate was 57.1% (95% CI, 49.3%-64.6%) with pembrolizumab plus enfortumab vedotin vs 8.6% (95% CI, 4.9%-13.8%) with surgery alone, representing a 48.3% estimated difference (95% CI, 39.5%-56.5%; 2-sided P < .0001).

What was the safety profile in KEYNOTE-905?

Among cisplatin-ineligible patients with MIBC treated with pembrolizumab plus enfortumab vedotin in KEYNOTE-905 (n = 167), any-grade adverse effects (AEs) occurred in all patients; 71.3% of patients experienced a grade 3 or higher AE. AEs leading to dose reduction of enfortumab vedotin (16.8%), leading to discontinuation of any trial drug (48.5%), or death (7.8%) also occurred in the combination arm; serious AEs occurred at a rate of 58.1%.

In the control arm, any-grade AEs were reported at a rate of 64.8% and 45.9% experienced a grade 3 or higher AE. AEs that led to death and serious AEs occurred at respective rates of 5.7% and 40.9%.

References

1. 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 May 22, 2026. https://www.merck.com/news/merck-receives-positive-eu-chmp-opinion-for-keytruda-pembrolizumab-plus-padcev-enfortumab-vedotin-ejfv-as-perioperative-treatment-for-adults-with-cisplatin-ineligible-resectable-muscle/
2. 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
3. FDA Approves Keytruda (pembrolizumab) and Keytruda Qlex (pembrolizumab and berahyaluronidase alfa-pmph), each with Padcev (enfortumab vedotin-ejfv), as perioperative treatment for adults with cisplatin-ineligible muscle-invasive bladder cancer. News release. Merck. November 21, 2025. Accessed May 22, 2026. https://www.merck.com/news/fda-approves-keytruda-pembrolizumab-and-keytruda-qlex-pembrolizumab-and-berahyaluronidase-alfa-pmph-each-with-padcev-enfortumab-vedotin-ejfv-as-perioperative-treatment-for/