CHMP Backs Perioperative Pembrolizumab Plus Enfortumab Vedotin for Resectable MIBC

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending the approval of pembrolizumab (Keytruda) plus enfortumab vedotin (Padcev) as neoadjuvant therapy followed by continued treatment after radical cystectomy as adjuvant therapy for adult patients with resectable muscle-invasive bladder cancer (MIBC); the recommendation also applies to the subcutaneous formulation of pembrolizumab.¹

The opinion was supported by findings from the phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124). Data showed that among patients eligible for cisplatin-based chemotherapy, perioperative pembrolizumab plus enfortumab vedotin (n = 405) reduced the risk of disease progression, recurrence, or death by 47% compared with neoadjuvant chemotherapy and surgery (n = 403; HR, 0.53; 95% CI, 0.41-0.70; P < .0001). Event-free survival (EFS) events occurred in 21% of patients in the investigational arm vs 36% of those in the control arm.

The combination also reduced the risk of death by 35% (HR, 0.65; 95% CI, 0.48-0.89; P = .0029). Deaths were reported in 17% and 25% of patients in the experimental and control arms, respectively. Moreover, the pathologic complete response (pCR) rate was 55.8% (95% CI, 50.8%-60.7%) with pembrolizumab plus enfortumab vedotin vs 32.5% (95% CI, 28.0%-37.3%) with chemotherapy (P < .0001).

“Despite advances in the treatment of MIBC, recurrence remains a significant concern for many patients regardless of cisplatin eligibility, and up to half may be unable to receive cisplatin-based chemotherapy,” Marjorie Greene, MD, senior vice president,oncology, global clinical development, Merck Research Laboratories. “If approved, [pembrolizumab] plus [enfortumab vedotin] would become the first and only PD-1 inhibitor plus antibody-drug conjugate regimen in the European Union for people with MIBC regardless of cisplatin eligibility, expanding on the previously approved indication.”

In July 2026, the FDA approved pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex), each in combination with enfortumab vedotin-ejfv, as neoadjuvant treatment followed by adjuvant treatment following cystectomy in adult patients with MIBC; this decision was also backed by data from KEYNOTE-B15/EV-304.³

How was KEYNOTE-B15/EV-304 Designed?

The open-label, randomized KEYNOTE-B15/EV-304 trial enrolled 808 adult patients with MIBC who were eligible for cisplatin-based chemotherapy and radical cystectomy with pelvic lymph-node dissection.^1,2,4 

Patients were randomly assigned to receive 4 neoadjuvant 3-week cycles of enfortumab vedotin at 1.25 mg/kg on days 1 and 8 plus pembrolizumab at 200 mg on day 1, followed by cystectomy, then adjuvant therapy with 5 cycles of enfortumab vedotin and 13 cycles of pembrolizumab; or 4 neoadjuvant 3-week cycles of cisplatin at 70 mg/m on day 1 plus gemcitabine at 1000 mg/m on days 1 and 8, followed by cystectomy.^1,2

The primary end point was EFS; key secondary end points included overall survival (OS) and pCR rate.

What was the safety profile of pembrolizumab plus enfortumab vedotin in KEYNOTE-B15?

Any-grade treatment-emergent adverse effects (TEAEs) from any cause occurred in 98.0% of patients treated with pembrolizumab plus enfortumab vedotin (n = 403) and 98.2% of those given gemcitabine/cisplatin (n = 396); the respective rates of grade 3 or higher TEAEs were 75.7% and 67.2%.² Serious TEAEs occurred at rates of 63.3% and 48.0%, respectively. TEAEs led to death in 4.2% of patients in the experimental arm vs 2.8% of patients in the control arm; treatment-related TEAEs leading to deaths occurred at respective rates of 0.5% and 0.3%. In the experimental arm, TEAEs led to treatment discontinuation in 25.1% of patients during the neoadjuvant phase and 28.6% of patients in the adjuvant phase; 15.4% of patients in the control arm discontinued treatment during the neoadjuvant phase.

References

1. Merck receives positive EU CHMP opinion for Keytruda (pembrolizumab) plus Padcev (enfortumab vedotin-ejfv) as perioperative treatment for adults with resectable muscle-invasive bladder cancer (MIBC). News release. Merck. September 18, 2026. Accessed September 18, 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-resectable-muscle-invasive-bladder-can/
2. Galsky MD, Valderrama RP, 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 or pembrolizumab and berahyaluronidase alfa-pmph each with enfortumab vedotin-ejfv for muscle invasive bladder cancer. FDA. July 10, 2026. Accessed September 18, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-or-pembrolizumab-and-berahyaluronidase-alfa-pmph-each-enfortumab-vedotin
4. Perioperative enfortumab vedotin (EV) plus pembrolizumab (MK-3475) versus neoadjuvant chemotherapy for cisplatin-eligible muscle invasive bladder cancer (MIBC) (MK-3475-B15/​ KEYNOTE-B15 /​ EV-304) (KEYNOTE-B15). ClinicalTrials.gov. Updated July 16, 2026. Accessed September 18, 2026. https://clinicaltrials.gov/study/NCT04700124