TOKYO, Japan — Astellas Pharma Inc. today announced that Japan’s Ministry of Health, Labour and Welfare (MHLW) has granted priority review for the company’s Supplemental New Drug Application (sNDA) for PADCEV™ (enfortumab vedotin (genetical recombination)) with KEYTRUDA® (pembrolizumab (genetical recombination)) as a combination therapy for the first-line treatment of adult patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC). The sNDA was submitted in January 2024. If approved, PADCEV with KEYTRUDA has the potential to change the treatment paradigm, becoming the first combination treatment to offer an alternative to platinum-containing chemotherapy, the current standard of care in first-line la/mUC.
Priority reviews are granted by MHLW for applications based on their clinical usefulness and the seriousness of the diseases for which they are indicated. The sNDA for the first-line use of this combination is based on results from the Phase 3 EV-302 clinical trial (also known as KEYNOTE-A39). The study found the combination improved overall survival (OS) and progression-free survival (PFS) with statistically significant and clinically meaningful results in patients with previously untreated la/mUC compared to platinum-containing chemotherapy. The safety results were consistent with those previously reported with this combination, and no new safety issues were identified.
Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas
“The MHLW’s priority review for our application for PADCEV in combination with pembrolizumab reflects the significance of the EV-302 trial findings and the urgent need for innovative new treatment options. We are pleased by this review designation and hope to quickly bring this treatment option to those who need it most.”
The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency is also reviewing the combination therapy. The U.S. Food and Drug Administration approved the combination therapy in December 2023.
Globally, approximately 614,000 new cases of bladder cancer and approximately 220,000 deaths are reported annually. It is estimated that approximately 25,000 people in Japan are diagnosed with bladder cancer each year and approximately 10,000 deaths were reported in 2022.
About EV-302
The EV-302 trial is an open-label, randomized, controlled Phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated la/mUC. The study 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 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 European Society for Medical Oncology (ESMO) Congress 2023 in October 2023.
About Bladder and Urothelial Cancer
- Urothelial cancer, or bladder cancer, begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis, and some other organs.
- If bladder cancer has spread to surrounding organs or muscles, it is called locally advanced disease. If the cancer has spread to other parts of the body, it is called metastatic disease.
- Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra.
- Approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.
Ongoing Investigational Trials
The EV-302 trial (NCT04223856) is an open-label, randomized, controlled Phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC) who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status.
The EV-103 trial (NCT03288545) is an ongoing, multi-cohort, open-label, multicenter Phase 1b/2 study investigating enfortumab vedotin alone or in combination with pembrolizumab and/or chemotherapy in first- or second-line settings in patients with la/mUC and patients with muscle-invasive bladder cancer (MIBC).
Enfortumab vedotin in combination with pembrolizumab is being investigated in an extensive program in multiple stages of urothelial cancer, including two Phase 3 clinical trials in MIBC in EV-304 (NCT04700124, also known as KEYNOTE-B15) and EV-303 (NCT03924895, also known as KEYNOTE-905). The use of enfortumab vedotin in combination with pembrolizumab in second-line urothelial cancer and MIBC has not been proven safe or effective.
The EV-202 trial (NCT04225117) is an ongoing, multi-cohort, open-label, multicenter Phase 2 study investigating enfortumab vedotin alone in patients with previously treated advanced solid tumors. This study also has a cohort that is investigating enfortumab vedotin in combination with pembrolizumab in patients with previously untreated recurrent/ metastatic head and neck squamous cell carcinoma.
About PADCEV™ (enfortumab vedotin (genetical recombination))
PADCEV (enfortumab vedotin (genetical recombination)) is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.vi Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4-expressing cells, followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which results in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).
About Astellas
Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+® healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into VALUE for patients.
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