The European Commission has approved Astellas Pharma's PADCEV™ (enfortumab vedotin), an antibody-drug conjugate (ADC), in combination with Merck's KEYTRUDA® (pembrolizumab), a PD-1 inhibitor, for the first-line treatment of adult patients with unresectable or metastatic urothelial cancer (la/mUC) who are eligible for platinum-containing chemotherapy. This decision marks a significant advancement in the treatment landscape for this aggressive cancer, offering a potential alternative to the standard platinum-based chemotherapy, which has been the mainstay for nearly 40 years.
The approval is based on the Phase 3 EV-302 clinical trial (also known as KEYNOTE-A39), a global study that demonstrated a near doubling of median overall survival (OS) with the enfortumab vedotin and pembrolizumab combination compared to platinum-containing chemotherapy. The trial enrolled 886 patients with previously untreated la/mUC who were eligible for cisplatin- or carboplatin-containing chemotherapy, regardless of PD-L1 status. Patients were randomized to receive either the combination therapy or platinum-containing chemotherapy.
Significant Survival Benefits
The EV-302 trial results, presented at the 2023 European Society for Medical Oncology (ESMO) Congress and published in the New England Journal of Medicine, showed a median OS of 31.5 months (95% CI: 25.4-NR) with the combination therapy compared to 16.1 months (95% CI: 13.9-18.3) with chemotherapy (HR=0.47; 95% CI: 0.38-0.58; P<0.00001). The median progression-free survival (PFS) was 12.5 months (95% CI: 10.4-16.6) with the combination versus 6.3 months (95% CI: 6.2-6.5) with chemotherapy (HR=0.45; 95% CI: 0.38-0.54; P<0.00001).
Dr. Thomas Powles from Barts Cancer Institute Biomedical Research Centre, UK, emphasized the importance of this approval, stating, "Having an effective new first-line treatment for advanced urothelial cancer is opening a long-awaited new chapter in the management of this usually fatal disease. The impressive effects of the treatment combination were clearly seen during the Phase 3 clinical trial program, with enfortumab vedotin in combination with pembrolizumab significantly extending overall survival and progression-free survival compared to platinum-containing chemotherapy."
Impact on Clinical Practice
The European Marketing Authorization is valid across all 27 EU member states, as well as Iceland, Liechtenstein, and Norway. This approval aligns with recent updates to clinical guidelines from the European Society for Medical Oncology and the European Association of Urology, which now recommend enfortumab vedotin in combination with pembrolizumab as a first-line treatment option for la/mUC.
Ahsan Arozullah, MD, MPH, Senior Vice President and Head of Oncology Development at Astellas, noted, "In line with the recent updates to European clinical guidelines, we are delighted that the European Commission has approved enfortumab vedotin in combination with pembrolizumab as first-line treatment for patients with unresectable or metastatic urothelial cancer. We look forward to patients across the European Union gaining benefit from this combination early in their treatment journey."
Disease Burden and Unmet Needs
Bladder cancer is the fifth most commonly diagnosed cancer in Europe, with over 165,000 new cases and 50,000 deaths annually within the EU. Approximately 12% of cases are diagnosed at the locally advanced or metastatic stage, where survival outcomes are particularly poor. This approval addresses a critical unmet need by providing a superior treatment option compared to the long-standing standard of care.
Safety Profile
The most common (≥3%) Grade 3 or higher adverse events related to the combination therapy in the EV-302 trial were maculo-papular rash, hyperglycemia, neutropenia, peripheral sensory neuropathy, diarrhea, and anemia. The safety profile was consistent with previous reports of the combination in cisplatin-ineligible patients with la/mUC, with no new safety concerns identified.
Ongoing Research
Enfortumab vedotin in combination with pembrolizumab is being investigated in an extensive clinical program across multiple stages of urothelial cancer, including Phase 3 trials in muscle-invasive bladder cancer (MIBC).
