- Positive opinion is based on Phase 3 EV-302 clinical trial results which showed enfortumab vedotin in combination with pembrolizumab nearly doubled median overall survival compared to platinum-containing chemotherapy1 Ahsan Arozullah, MD, MPH, Senior Vice President and Head of Oncology Development, Astellas The positive CHMP opinion is based on data from the Phase 3 EV-302 clinical trial (also known as KEYNOTE-A39) which showed enfortumab vedotin in combination with pembrolizumab significantly extends overall survival (OS) and progression-free survival (PFS) compared to platinum-containing chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC). Treatment with the 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 chemotherapy, representing a 53% reduction in risk of death (Hazard Ratio [HR]=0.47; 95% Confidence Interval [CI]: 0.38-0.58; P1 Results were presented at the 2023 European Society for Medical Oncology (ESMO) Congress and published in the New England Journal of Medicine. Europe has the highest rate of new bladder cancer cases in the world.3 Every year, more than 165,000 people are diagnosed with the disease in the European Union (EU), and it claims the lives of over 50,000 people.3 Not only does bladder cancer affect a person's physical functioning throughout the disease journey, patients and caregivers also report significant impacts on quality of life and mental well-being which are often exacerbated by late detection and challenging pathways to diagnosis.4 The positive opinion will now be reviewed by the European Commission (EC), which has the authority to approve medicines in all 27 EU member states as well as Iceland, Liechtenstein and Norway.5
Astellas has already reflected the impact from this result in its financial forecast for the current fiscal year ending March 31, 2025. 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.1 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. For more information on the EV-302 trial (NCT04223856) go to https://clinicaltrials.gov. Urothelial cancer, or bladder cancer, begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis, and some other organs.8 Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra.9,10 If cancer is not able to be treated with surgery, it is called unresectable.11 If cancer has spread to surrounding organs or muscles, it is called locally advanced disease.12 If cancer has spread to other parts of the body, it is called metastatic disease.13 Approximately 12% of cases are unresectable locally advanced or metastatic urothelial cancer at diagnosis.14 Bladder cancer is diagnosed in approximately 614,000 people and causes 220,000 deaths worldwide each year.15 In Europe, bladder cancer is the fifth most common cancer;16 more than 165,000 people are diagnosed with the disease in the EU each year.3 Continuous treatment and surveillance makes bladder cancer one of the most expensive cancer types over the lifetime of a patient and, in fact, have been shown to be the costliest cancer when compared to other malignancies.17 PADCEV (enfortumab vedotin) 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.7,18 Nonclinical data suggest the anticancer activity of enfortumab vedotin 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 result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).7 Ongoing Investigational Trials
EV-203 (NCT04995419) is a Phase 2, multicenter, single-arm bridging trial in China designed to evaluate the efficacy, safety, and pharmacokinetic performance of enfortumab vedotin as treatment for patients in China. A total of 40 patients were enrolled in the trial. Important Safety Information
For Important Safety Information for enfortumab vedotin please see the full Summary of Product Characteristics at: https://www.ema.europa.eu/en/documents/product-information/padcev-epar-product-information_en.pdf 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. For more information, please visit our website at https://www.astellas.com/en. Astellas Cautionary Notes
In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties. Information about pharmaceutical products (including products currently in development) which is included in this press release is not intended to constitute an advertisement or medical advice.
2 European Medicines Agency. PADCEV - opinion on variation to marketing authorisation. Available at: www.ema.europa.eu/en/medicines/human/variation/padcev. Last accessed: July 2024.
3 International Agency for Research on Cancer. Global Cancer Observatory. Cancer Today: 2022. Available at: https://gco.iarc.who.int. Last accessed: July 2024. 5 European Medicines Agency. Authorisation of medicines. Available at: https://www.ema.europa.eu/en/about-us/what-we-do/authorisation-medicines. Last accessed: July 2024.
7 European Medicines Agency. PADCEV EMA SmPC. Available at: https://www.ema.europa.eu/en/documents/product-information/padcev-epar-product-information_en.pdf. Last accessed: July 2024.
8 National Cancer Institute. What is bladder cancer? (February 2023) Available at: https://www.cancer.gov/types/bladder. Last accessed: July 2024. 11 National Cancer Institute. NCI dictionary of cancer terms: Unresectable. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/unresectable. Last accessed: July 2024. 12 National Cancer Institute. NCI dictionary of cancer terms: Locally advanced cancer. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/locally-advanced-cancer. Last accessed: July 2024. 13 American Cancer Society. If you have bladder cancer. (March 2024). Available at: https://www.cancer.org/cancer/types/bladder-cancer/if-you-have-bladder-cancer.html. Last accessed: July 2024. 14 National Cancer Institute. Cancer stat facts: bladder cancer. Available at: https://seer.cancer.gov/statfacts/html/urinb.html. Last accessed: July 2024. 15 International Agency for Research on Cancer. Global Cancer Observatory. Bladder Factsheet. Available at: https://gco.iarc.fr/today/data/factsheets/cancers/30-Bladder-fact-sheet.pdf. Last accessed: July 2024. 16 International Agency for Research on Cancer. Global Cancer Observatory. WHO Europe Region (EURO) Factsheet. Available at: https://gco.iarc.who.int/media/globocan/factsheets/populations/994-who-europe-euro-fact-sheet.pdf. Last accessed: July 2024. 17 Aly A, et al. The Real-World Lifetime Economic Burden of Urothelial Carcinoma by Stage at Diagnosis. J Clin Pathw. 2020;6(4):51-60.
18 Challita-Eid PM, et al. Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res. 2016;76(10):3003-13.