Pembrolizumab/Enfortumab Vedotin Earns Positive CHMP Opinion in MIBC

The European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending approval of pembrolizumab (Keytruda) in combination with enfortumab vedotin-ejfv (Padcev) as perioperative treatment, administered as neoadjuvant therapy before radical cystectomy and then continued as adjuvant treatment, for adults with resectable muscle-invasive bladder cancer (MIBC), according to a news release from the developer, Merck.¹

The recommendation also includes the subcutaneous formulation, pembrolizumab SC (Keytruda SC; known as Keytruda QLEX in the US). The opinion will now be reviewed by the European Commission (EC) for marketing authorization in the EU, Iceland, Liechtenstein, and Norway, with a final decision expected in the fourth quarter of 2026.

What did the KEYNOTE-B15 trial demonstrate to support the CHMP positive opinion?

The recommendation is based on results from the phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124). Trial data was previously published in the New England Journal of Medicine.²

In the study, 808 patients with cisplatin-eligible, resectable MIBC were randomly assigned 1:1 to perioperative pembrolizumab plus enfortumab vedotin (n = 405) or neoadjuvant gemcitabine plus cisplatin followed by radical cystectomy and observation (n = 403). Patients in the pembrolizumab/enfortumab vedotin arm received 4 neoadjuvant cycles followed by surgery, then up to 5 adjuvant cycles of enfortumab vedotin and 13 cycles of pembrolizumab.

Perioperative pembrolizumab plus enfortumab vedotin significantly improved event-free survival (EFS), the primary end point, reducing the risk of disease progression, recurrence, or death by 47% compared with neoadjuvant gemcitabine plus cisplatin (hazard ratio [HR], 0.53; 95% CI, 0.41-0.70; P <.001). The median EFS was not reached (NR; 95% CI, NR-NR) in the pembrolizumab/enfortumab vedotin arm vs 48.5 months (95% CI, 43.3-NR) in the gemcitabine plus cisplatin arm; the 24-month EFS rates were 79.4% (95% CI, 74.9%-83.1%) and 66.2% (95% CI, 61.2%-70.8%), respectively. The EFS benefit was consistent across subgroups, including by PD-L1 status, clinical stage, and geographic region.

The combination also significantly improved overall survival (OS), reducing the risk of death by 35% (HR, 0.65; 95% CI, 0.48-0.89; P = .006). The median OS was not reached in either arm; the 24-month OS rates were 86.9% (95% CI, 83.2%-89.8%) with pembrolizumab/enfortumab vedotin vs 81.3% (95% CI, 77.1%-84.8%) with gemcitabine plus cisplatin.

Pathologic complete response (pCR) favored the experimental arm at 55.8% (95% CI, 50.8%-60.7%) vs 32.5% (95% CI, 28.0%-37.3%) for gemcitabine plus cisplatin (estimated difference, 23.4%; 95% CI, 16.7-29.8; P <.001).

“This is a pivotal moment. For the first time in almost 25 years, since we first saw that cisplatin-based neoadjuvant therapy could improve outcomes in [MIBC], a non-platinum regimen has now surpassed it,” said Matthew Galsky, MD, professor of medicine and deputy director of the Mount Sinai Tisch Cancer Center in New York, New York, in a presentation of the data at the 2026 ASCO Genitourinary Cancers Symposium.³

What is the prior regulatory history for pembrolizumab plus enfortumab vedotin in MIBC?

The current CHMP recommendation extends a prior EC approval from June 2026, in which the combination received EU marketing authorization specifically for cisplatin-ineligible patients with resectable MIBC based on results from the phase 3 KEYNOTE-905/EV-303 trial (NCT03924895). ⁴ If the EC grants the new approval, pembrolizumab/enfortumab vedotin would become the first PD-1 inhibitor plus antibody-drug conjugate (ADC) regimen available in the EU for patients with MIBC regardless of cisplatin eligibility.

The FDA approved pembrolizumab plus enfortumab vedotin as perioperative treatment for adult patients with MIBC in July 2026 based on the KEYNOTE-B15 trial, also representing the first and only PD-1 inhibitor plus ADC regimen approved in the US for MIBC regardless of cisplatin eligibility.⁵

What is the safety profile of perioperative pembrolizumab plus enfortumab vedotin?

In KEYNOTE-B15, grade 3 or higher treatment-related adverse effects (AEs) occurred in 75.7% of patients receiving pembrolizumab plus enfortumab vedotin vs 67.2% with gemcitabine plus cisplatin. Patients in the experimental arm more commonly experienced pruritus, diarrhea, alopecia, and rash. AEs of special interest with enfortumab vedotin included skin reactions, peripheral neuropathy, and ocular disorders; those attributed to pembrolizumab included skin reactions, hypothyroidism, and pneumonitis.

In contrast, patients receiving gemcitabine plus cisplatin more commonly experienced neutropenia, thrombocytopenia, anemia, and nausea. Treatment-related AEs leading to death were reported in 2 patients in the pembrolizumab plus enfortumab vedotin arm and 1 patient in the gemcitabine plus cisplatin arm.

What unmet need does this opinion address in resectable MIBC?

“If approved, [pembrolizumab] plus [enfortumab vedotin] would become the first and only PD-1 inhibitor plus [ADC] regimen in the EU for people with [MIBC] regardless of cisplatin eligibility, expanding on the previously approved indication,” stated Marjorie Green, MD, senior vice president of oncology and global clinical development of Merck Research Laboratories, in the press release.¹

References

1. Merck & Co., Inc. 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 & Co., Inc. September 18, 2026. Accessed September 18, 2026. https://tinyurl.com/55yyshcn
2. Galsky MD, Valderrama BP, Maruzzo M, et al. Neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab for participants with muscle-invasive bladder cancer who are eligible for cisplatin: randomized, open-label, phase 3 KEYNOTE-B15 study. N Engl J Med. 2026;395(4):338-348. doi:10.1056/NEJMoa2601486
3. 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
4. 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 September 18, 2026. https://tinyurl.com/3z57n9na
5. FDA approves pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph each with enfortumab vedotin-ejfv for muscle invasive bladder cancer. News release. FDA. July 10, 2026. Accessed September 18, 2026. https://tinyurl.com/ywwuhr5k