– Pivotal trial found the enfortumab vedotin plus pembrolizumab combination significantly extended overall and progression-free survival –
– If approved, PADCEV with KEYTRUDA would be the first combination in the EU to offer an alternative to platinum-containing chemotherapy, the current standard of care in first-line locally advanced or metastatic urothelial cancer –
NEW YORK, NY, USA & TOKYO, Japan I January 26, 2024 I Pfizer Inc. (NYSE: PFE) and Astellas Pharma Inc. (TSE:4503, President and CEO: Naoki Okamura, “Astellas”) today announced that on January 26 the European Medicines Agency (EMA) validated for review a Type II variation application for PADCEV® (enfortumab vedotin) with KEYTRUDA® (pembrolizumab) as a combination therapy for the first-line treatment of adult patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC). 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.
Globally, approximately 573,000 new cases of bladder cancer and 212,000 deaths are reported annually.1 It is estimated that approximately 200,000 people in Europe are diagnosed with bladder cancer each year.2
Roger Dansey, M.D., Chief Development Officer, Oncology, Pfizer
“The EV-302 pivotal trial demonstrated the benefits of combining PADCEV with pembrolizumab for advanced bladder cancer. Patients with bladder cancer in Europe face poor outcomes at the advanced stage, and innovative therapies that extend survival are needed. This acceptance brings us closer to our mission: delivering breakthroughs that help address the unmet needs of patients and reshape the advanced urothelial cancer treatment landscape.”
Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas
“Patients in Europe need better treatment options for advanced stage urothelial cancer, and we look forward to working with the EMA on their review of the combination of enfortumab vedotin and pembrolizumab. If approved, the combination would be the first alternative to a chemotherapy-based treatment for this patient population. This milestone is another opportunity to affirm our commitment to helping patients with advanced urothelial cancer live longer.”
The Type II variation application for first-line use of the 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.
The EMA’s Committee for Medicinal Products for Human Use (CHMP) and subsequently the European Commission (EC) are expected to share their opinions and decisions on the Type II variation application in calendar year 2024. The U.S. Food and Drug Administration approved the combination therapy in December 2023.
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.3
- 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.4
- Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra.3
- Approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.5
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 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 in 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 in 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)
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.6 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 result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).7
PADCEV (enfortumab vedotin-ejfv) U.S. Indication & Important Safety Information
BOXED WARNING: SERIOUS SKIN REACTIONS
- PADCEV can cause severe and fatal cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which occurred predominantly during the first cycle of treatment, but may occur later.
- Closely monitor patients for skin reactions.
- Immediately withhold PADCEV and consider referral for specialized care for suspected SJS or TEN or severe skin reactions.
- Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.
Indication
PADCEV®, in combination with pembrolizumab, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC).
PADCEV, as a single agent, is indicated for the treatment of adult patients with locally advanced or mUC who:
- have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or
- are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.
For more information, please see the U.S. full Prescribing Information including BOXED WARNING for PADCEV here.
About Pfizer Oncology
At Pfizer Oncology, we are at the forefront of a new era in cancer care. Our industry-leading portfolio and extensive pipeline includes game-changing mechanisms of action to attack cancer from multiple angles, including antibody-drug conjugates (ADCs), small molecules, bispecifics and other immunotherapies. We are focused on delivering transformative therapies in some of the world’s most common cancers, including breast cancer, genitourinary cancer and hematologic malignancies, as well as melanoma, gastrointestinal, gynecological and thoracic cancers, which includes lung cancer. Driven by science, we are committed to accelerating breakthroughs to extend and improve patients’ lives.
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. For more information, please visit our website at https://www.astellas.com/en.
About the Pfizer, Astellas and Merck Collaboration
Seagen and Astellas entered a clinical collaboration agreement with Merck to evaluate the combination of Seagen’s and Astellas’ PADCEV® (enfortumab vedotin) and Merck’s KEYTRUDA® (pembrolizumab) in patients with previously untreated metastatic urothelial cancer. As previously announced, Pfizer Inc. successfully completed its acquisition of Seagen on December 14, 2023. KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (known as MSD outside of the United States and Canada).
1 International Agency for Research on Cancer. Cancer Today: bladder globocan 2020 fact sheet (12-2020). https://gco.iarc.fr/today/data/factsheets/cancers/30-Bladder-fact-sheet.pdf.
2 Bladder cancer: The forgotten cancer. Uroweb. (n.d.). https://uroweb.org/news/bladder-cancer-the-forgotten-cancer.
3 National Cancer Institute. What is bladder cancer? https://www.cancer.gov/types/bladder#:~:text=Types%20of%20bladder%20cancer,bladder%20cancers%20are%20urothelial%20carcinomas.
4 American Society of Clinical Oncology. Bladder cancer: introduction (12-2021). https://www.cancer.net/cancer-types/bladder-cancer/introduction.
5 National Cancer Institute. Cancer stat facts: bladder cancer. https://seer.cancer.gov/statfacts/html/urinb.html.
6 Challita-Eid PM, Satpayev D, Yang P, 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.
7 PADCEV [package insert]. Northbrook, IL: Astellas Pharma US, Inc.
SOURCE: Pfizer
