On June 24, 2026, Merck announced that the European Commission approved KEYTRUDA® (pembrolizumab) in combination with Padcev® (enfortumab vedotin-ejfv) for adults with resectable muscle-invasive bladder cancer who are ineligible for cisplatin-containing chemotherapy.
The regimen is approved as neoadjuvant treatment and then continued after radical cystectomy as adjuvant treatment. According to Merck, this makes pembrolizumab plus enfortumab vedotin the first and only PD-1 inhibitor plus antibody-drug conjugate regimen available in the European Union for this patient population. The approval also covers KEYTRUDA SC®.
The approval follows a positive recommendation from the European Medicines Agency’s Committee for Medicinal Products for Human Use, received in May 2026.
Read more about the CHMP recommendation for EV-303/KEYNOTE-905 on OncoDaily.
Approval Based on KEYNOTE-905/EV-303
The approval was based on results from KEYNOTE-905, also known as EV-303, an open-label, randomized, multi-arm, controlled phase 3 trial. The study enrolled 595 patients with muscle-invasive bladder cancer who were not eligible for or declined cisplatin-based chemotherapy.
Patients were randomized to receive:
- Arm A: neoadjuvant pembrolizumab followed by radical cystectomy and adjuvant pembrolizumab.
- Arm B: surgery alone.
- Arm C: neoadjuvant pembrolizumab plus enfortumab vedotin followed by radical cystectomy, then adjuvant pembrolizumab plus enfortumab vedotin, followed by pembrolizumab alone.
The European approval was supported by the comparison of Arm C with surgery alone.
Read more about the KEYNOTE-905/EV-303 Trial on OncoDaily.
Understanding Pembrolizumab Plus Enfortumab Vedotin
Pembrolizumab plus enfortumab vedotin combines immunotherapy with an antibody-drug conjugate, using two different mechanisms against urothelial cancer.
Enfortumab vedotin is an antibody-drug conjugate designed to target Nectin-4, a protein expressed on urothelial cancer cells. After binding to Nectin-4 on the tumor cell surface, the drug is internalized and releases its cytotoxic payload, monomethyl auristatin E. This payload disrupts microtubules, interferes with cell division, and can lead to cancer cell death.
This targeted delivery distinguishes enfortumab vedotin from traditional chemotherapy. By directing its cytotoxic payload toward Nectin-4–expressing cells, enfortumab vedotin is designed to deliver treatment more selectively than conventional cytotoxic chemotherapy.
Pembrolizumab works through a different mechanism. As a PD-1 immune checkpoint inhibitor, it blocks the PD-1 pathway and helps restore T-cell activity, allowing the immune system to better recognize and attack cancer cells.
Together, pembrolizumab plus enfortumab vedotin provides a dual approach in urothelial cancer: direct tumor cell killing through antibody-drug conjugate delivery and immune activation through checkpoint inhibition.
Read more about Padcev® (enfortumab vedotin-ejfv) on OncoDaily.
Efficacy Results
Perioperative pembrolizumab plus enfortumab vedotin showed statistically significant and clinically meaningful improvements in event-free survival, overall survival, and pathologic complete response rate compared with surgery alone.
Pembrolizumab plus enfortumab vedotin reduced the risk of event-free survival events by 60% compared with surgery alone (HR=0.40; 95% CI, 0.28–0.57; p<0.0001). Median event-free survival was not reached with pembrolizumab plus enfortumab vedotin, compared with 15.7 months with surgery alone.
The regimen also reduced the risk of death by 50% compared with surgery alone (HR=0.50; 95% CI, 0.33–0.74; p=0.0002). Median overall survival was not reached with pembrolizumab plus enfortumab vedotin, compared with 41.7 months with surgery alone. The pathologic complete response rate was 57.1% with pembrolizumab plus enfortumab vedotin, compared with 8.6% with surgery alone.
Safety
In KEYNOTE-905, the most common adverse reactions reported in at least 20% of cisplatin-ineligible patients treated with pembrolizumab plus enfortumab vedotin were rash, pruritus, fatigue, peripheral neuropathy, alopecia, dysgeusia, diarrhea, constipation, decreased appetite, nausea, urinary tract infection, dry eye, and weight loss.
During the neoadjuvant phase, serious adverse reactions occurred in 27% of patients treated with pembrolizumab plus enfortumab vedotin. During the adjuvant phase, serious adverse reactions occurred in 43% of patients who received adjuvant treatment.
Among patients who received neoadjuvant treatment with pembrolizumab plus enfortumab vedotin, 4.2% did not undergo surgery because of adverse reactions. Among those who received neoadjuvant therapy and underwent radical cystectomy, 4.1% had surgery delayed because of adverse reactions.
Clinical Context
Muscle-invasive bladder cancer has historically been treated with neoadjuvant cisplatin-based chemotherapy followed by surgery. However, many patients are not eligible for cisplatin and have had limited treatment options, often proceeding directly to surgery.
With this approval, pembrolizumab plus enfortumab vedotin becomes a new perioperative option in the European Union for adults with resectable MIBC who are ineligible for cisplatin-containing chemotherapy.
The approval applies across all 27 EU member states, as well as Iceland, Liechtenstein, and Norway. Commercial availability in individual countries will depend on national reimbursement processes.
Expert Highlights
Professor Christof Vulsteke, head of Integrated Cancer Center Ghent (IKG) and Clinical Trial Unit Oncology Ghent and KEYNOTE-905 principal investigator, said:
“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. 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.”
Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, said:
“For patients with resectable muscle-invasive bladder cancer in Europe, this approval represents a meaningful advance after years of limited progress in the field. As the first PD-1 inhibitor plus antibody-drug conjugate regimen approved in this setting, this treatment is poised to address a crucial unmet need, reflecting our continued commitment to delivering innovative KEYTRUDA-based therapies to patients with bladder cancer worldwide.”
Takeaway
The European Commission approval of pembrolizumab plus enfortumab vedotin introduces the first PD-1 inhibitor plus antibody-drug conjugate perioperative regimen for cisplatin-ineligible adults with resectable muscle-invasive bladder cancer in the European Union, supported by significant improvements in event-free survival, overall survival, and pathologic complete response in KEYNOTE-905/EV-303.
Full information is available on the official Merck website.