EC Expands Enfortumab Vedotin/Pembrolizumab Approval for Resectable MIBC

The European Commission (EC) has approved pembrolizumab (Keytruda) plus enfortumab vedotin-ejfv (Padcev) as neoadjuvant treatment, continued as adjuvant treatment after radical cystectomy, for adults with resectable muscle-invasive bladder cancer (MIBC), according to a news release from the developer, Merck.¹ The approval covers both intravenous pembrolizumab and subcutaneous pembrolizumab (Keytruda SC; marketed as Keytruda Qlex in the US).

Forming the basis for the EC decision were data the phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124)and extends use of the regimen to patients regardless of cisplatin eligibility. The approval applies across all 27 EU member states as well as Iceland, Liechtenstein, and Norway.

What were the results of the KEYNOTE-B15 trial?

In the trial, 808 patients with cisplatin-eligible MIBC were randomly assigned to receive perioperative pembrolizumab plus enfortumab vedotin (n = 405) or neoadjuvant gemcitabine and cisplatin followed by surgery (n = 403). Event-free survival (EFS) events occurred in 21% of patients in the pembrolizumab/enfortumab vedotin arm vs 36% in the chemotherapy arm (HR, 0.53; 95% CI, 0.41-0.70; P < .0001), representing a 47% reduction in the risk of an EFS event. The median EFS was not reached (95% CI, NR-NR) with the combination vs 48.5 months (95% CI, 43.3-NR) with chemotherapy, and the 24-month EFS rates were 79.4% (95% CI, 74.9%-83.1%) vs 66.2% (95% CI, 61.2%-70.8%), respectively.²

The combination also reduced the risk of death by 35% vs chemotherapy (HR, 0.65; 95% CI, 0.48-0.89; P = .0029). The median overall survival (OS) was not reached in either arm, and the 24-month OS rates were 86.9% (95% CI, 83.2%-89.8%) vs 81.3% (95% CI, 77.1%-84.8%). The pathologic complete response (pCR) rate was 55.8% (95% CI, 50.8%-60.7%) with pembrolizumab/enfortumab vedotin vs 32.5% (95% CI, 28.0%-37.3%) with chemotherapy (P < .0001).

Grade 3 or higher treatment-related adverse events (AEs) occurred in 75.7% of patients in the combination arm and 67.2% of those in the chemotherapy arm. The most common AEs with the combination included rash (63%), fatigue (48%), pruritus (46%), and peripheral neuropathy (43%). During the neoadjuvant phase, 13 patients (3.2%) did not undergo surgery because of AEs.

“Although cisplatin-based chemotherapy has been a standard treatment approach for many patients with [MIBC], recurrence remains a significant challenge,” said Alfonso Gómez de Liaño, MD, lead of the Genitourinary Oncology Unit at Hospital Universitario Insular de Gran Canaria and KEYNOTE-B15 primary investigator, in the press release.¹ “Based on results from the KEYNOTE-B15 trial, today’s approval is a meaningful advance for patients with [MIBC] in the EU, extending this chemotherapy-free perioperative treatment option to patients regardless of cisplatin eligibility.”

How was the KEYNOTE-B15 trial designed?

KEYNOTE-B15 is an open-label, randomized, multicenter, active-controlled phase 3 trial that enrolled previously untreated patients with MIBC who were eligible for cisplatin-based chemotherapy and radical cystectomy. In the investigational arm, patients received 4 neoadjuvant cycles of pembrolizumab at 200 mg intravenously on day 1 plus enfortumab vedotin at 1.25 mg/kg on days 1 and 8 of each 21-day cycle, followed by radical cystectomy with pelvic lymph node dissection. After surgery, patients received up to 13 cycles of adjuvant pembrolizumab and 5 cycles of enfortumab vedotin. Patients in the control arm received 4 cycles of neoadjuvant gemcitabine at 1000 mg/m² plus cisplatin at 70 mg/m², followed by surgery and observation.

The primary end point was EFS by blinded independent central review. Secondary end points included OS and pCR by blinded independent pathology review.

What is the regulatory history of this regimen in MIBC?

In June 2026, the EC approved pembrolizumab plus enfortumab vedotin for patients with resectable MIBC who are ineligible for cisplatin, based on findings from the phase 3 KEYNOTE-905/EV-303 trial.³ Additionally the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion in September 2026 for the expanded indication.⁴ In the US, the FDA approved the regimen for patients with MIBC regardless of cisplatin eligibility in July 2026, also based on KEYNOTE-B15 data.⁵

“Building on the previous approval of [pembrolizumab plus enfortumab vedotin] in the EU less than 6 months ago, we’re pleased to bring this important treatment option to a broader patient population as the first PD-1 inhibitor plus antibody-drug conjugate regimen approved for [patients with MIBC] regardless of cisplatin eligibility,” said Marjorie Green, MD, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, in the press release.¹

References

1. European Commission approves KEYTRUDA (pembrolizumab) plus Padcev (enfortumab vedotin-ejfv) as perioperative treatment for adults with resectable muscle-invasive bladder cancer (MIBC). News release. Merck. October 21, 2026. Accessed October 21, 2026. https://tinyurl.com/5n82haer
2. Galsky MD, Valderrama BP, Maruzzo M, et al. Enfortumab vedotin and pembrolizumab in cisplatin-eligible bladder cancer. N Engl J Med. 2026;395(4):338-348. doi:10.1056/NEJMoa2601486
3. European Commission approves Padcev plus Keytruda for cisplatin-ineligible resectable MIBC. News release. Astellas Pharma Inc. June 24, 2026. Accessed October 21, 2026. https://tinyurl.com/3z57n9na
4. Keytruda plus Padcev receives positive EU CHMP opinion for resectable MIBC. News release. Merck. September 18, 2026. Accessed October 21, 2026. https://tinyurl.com/55yyshcn
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 October 21, 2026. https://tinyurl.com/ywwuhr5k