EMA has validated Astellas’ Type II variation application for enfortumab vedotin (PADCEV) plus pembrolizumab as neoadjuvant and adjuvant treatment for cisplatin-eligible muscle-invasive bladder cancer
Written By: Pharmacally Editorial Team
Astellas Pharma Inc. announced that the European Medicines Agency has validated a Type II variation application for PADCEV (enfortumab vedotin) in combination with Keytruda (pembrolizumab) as perioperative treatment for adults with Muscle-Invasive Bladder Cancer (MIBC) who are eligible for cisplatin-containing chemotherapy. The regimen is proposed as neoadjuvant therapy before surgery followed by continued adjuvant treatment after radical cystectomy.
The regulatory submission is supported by results from the Phase 3 EV-304 trial (KEYNOTE-B15) (NCT04700124), which evaluated enfortumab vedotin plus pembrolizumab against standard neoadjuvant gemcitabine and cisplatin chemotherapy. The study showed the combination reduced the risk of tumor recurrence, progression, or death by 47% and lowered the risk of death by 35% compared with the current standard of care.
At the time of surgery, the combination therapy demonstrated a markedly higher pathological complete response rate. A total of 55.8% of patients receiving enfortumab vedotin plus pembrolizumab achieved pCR, compared with 32.5% of patients treated with neoadjuvant chemotherapy. Clinical benefits were broadly consistent across predefined patient subgroups, including age, gender, PD-L1 status, disease stage, and geographic region. The safety profile was in line with previous studies of the regimen, with no new safety signals identified.
MIBC represents a significant clinical burden in Europe, where more than 224,000 people are diagnosed with bladder cancer each year and roughly 30% present with muscle-invasive disease. Despite curative surgery, approximately half of patients eventually experience disease recurrence, highlighting the need for more effective perioperative therapies.
The EV-304 study is an ongoing open-label, randomized Phase 3 trial comparing perioperative enfortumab vedotin plus pembrolizumab with standard neoadjuvant gemcitabine and cisplatin chemotherapy. Patients receive the investigational combination both before and after cystectomy, with event-free survival as the primary endpoint and overall survival and pathological complete response among the key secondary endpoints.
In December 2025, the EMA also validated a separate Type II variation application evaluating the same regimen in cisplatin-ineligible patients with MIBC. Regulatory reviews for both patient populations are currently ongoing.
Enfortumab vedotin is a first-in-class antibody-drug conjugate targeting Nectin-4, a protein highly expressed on bladder cancer cells. After binding to Nectin-4, the therapy is internalized by tumor cells and releases the cytotoxic agent monomethyl auristatin E (MMAE), which disrupts cell division and induces apoptosis.
If approved, the perioperative combination of enfortumab vedotin and pembrolizumab could offer a new treatment approach aimed at reducing recurrence risk and improving survival outcomes in patients undergoing surgery for muscle-invasive bladder cancer.
References
EMA Validates Type II Variation Application for PADCEV™ (enfortumab vedotin) plus Keytruda® (pembrolizumab) in Cisplatin-Eligible Patients with Muscle-Invasive Bladder Cancer, 23 March 2026, EMA Validates Type II Variation Application for PADCEV™ (enfortumab vedotin) plus Keytruda<sup>®</sup> (pembrolizumab) in Cisplatin-Eligible Patients with Muscle-Invasive Bladder Cancer
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 ID NCT04700124, https://clinicaltrials.gov/study/NCT04700124