Astellas Pharma Ltd. today announced that the Medicines and Healthcare products Regulatory Agency (MHRA) has granted authorization for PADCEV™ (enfortumab vedotin, an antibody-drug conjugate [ADC]) in combination with KEYTRUDA® (pembrolizumab, a PD-1 inhibitor) for the first-line treatment of adult patients with unresectable or metastatic urothelial cancer, who are eligible for platinum-containing chemotherapy.
The indication is based on results of the Phase 3 EV-302 clinical trial (also known as KEYNOTE-A39). The Phase 3 clinical trial showed that enfortumab vedotin in combination with pembrolizumab nearly doubled median overall survival (OS) and signficantly extended progression-free survival (PFS) compared to platinum-containing chemotherapy.
“The foundations of advanced bladder cancer treatment haven’t changed since the 1980s,” said Professor. Thomas Powles, Director of Barts Cancer Institute Biomedical Research Centre (QMUL), UK and primary investigator on the EV-302 trial, “to see EV-302 move from clinical trial to licensed indication within a year shows the strength of those results and the potential benefit to people with advanced bladder cancer.”
Advanced bladder cancer has a poor prognosis compared to other forms of cancer. Diagnosis often comes late, with many patients presenting with advanced or metastatic disease where survival outcomes are particularly poor. Only 10 % of patients with stage 4 bladder cancer survive for more than 5 years after diagnosis.
Behind the news today is a tremendous amount of hard work and collaboration between the medical community and pharma. It’s testament to what we can achieve together and I look forward to doctors across the UK being able to access this combination of medicines for their patients.”
Dr Timir Patel, Medical Director, Astellas, UK
The Phase 3 EV-302 clinical trial explored the efficacy and safety of enfortumab vedotin in combination with pembrolizumab in patients with previously untreated unresectable locally advanced or metastatic urothelial cancer (la/mUC). Results showed that the treatment combination resulted in a median OS of 31.5 months (95 % CI: 25.4-NR) compared to 16.1 months (95 % CI: 13.9-18.3) with platinum-containing chemotherapy, representing a 53 % reduction in risk of death (Hazard Ratio [HR]=0.47; 95 % Confidence Interval [CI]: 0.38-0.58; P<0.00001). The median PFS of 12.5 months (95 % CI: 10.4-16.6) with the combination compared to 6.3 months (95 % CI: 6.2-6.5) with chemotherapy represents a 55 % reduction in the risk of cancer progression or death (HR=0.45; 95 % CI: (0.38-0.54); P<0.00001). During the EV-302 trial, approximately 30 % of patients completed treatment with chemotherapy and then went on to receive maintenance therapy with avelumab, a PD-L1 inhibitor, which is reflective of current real world clinical practice. Results were presented at the 2023 European Society for Medical Oncology (ESMO) Congress and published in the New England Journal of Medicine.
The approval follows the December 2023 and August 2024 approval of enfortumab vedotin in combination with pembrolizumab for the treatment of adult patients with la/mUC by the U.S. Food and Drug Administration (FDA) and European Commission respectively. The indication for Great Britain was issued via the European Commission Reliance Procedure Process following European Commission authorization of enfortumab vedotin.
Astellas has already reflected the impact from this result in its financial forecast for the current fiscal year ending March 31, 2025.
About EV-302
EV-302 is an ongoing, open-label, randomized, controlled Phase 3 trial, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated la/mUC. 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 enfortumab vedotin in combination with pembrolizumab or platinum-containing chemotherapy. The dual primary endpoints of this trial are OS and PFS per RECIST v1.1 by blinded independent central review (BICR). Select secondary endpoints include ORR per RECIST v1.1 by BICR, DOR per RECIST v1.1 by BICR, and safety.
The most common (≥3 %) Grade 3 or higher adverse events related to treatment with enfortumab vedotin and pembrolizumab were maculo-papular rash, hyperglycemia, neutropenia, peripheral sensory neuropathy, diarrhea, and anemia. The safety results in EV-302 are consistent with those previously reported with this combination in EV-103 in cisplatin-ineligible patients with la/mUC. No new safety issues were identified.
The EV-302 trial is part of an extensive clinical program evaluating this combination in multiple stages of urothelial cancer and other solid tumors. Findings from EV-302 were presented at the 2023 European Society for Medical Oncology (ESMO) Congress and were published in the New England Journal of Medicine.
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