Astellas Pharma, Seagen announce positive results from phase 3 EV-302 trial of Padcev in combo with Keytruda versus chemotherapy in patients with previously untreated advanced bladder cancer

Astellas Pharma Inc. and Seagen Inc. announced positive topline results from the phase 3 EV-302 clinical trial (also known as KEYNOTE-A39) for Padcev (enfortumab vedotin-ejfv) in combination with Keytruda (pembrolizumab) versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC), a form of bladder cancer that has spread to surrounding organs or muscles, or other parts of the body. The EV-302 trial enrolled patients with previously untreated la/mUC who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status.

The EV-302 study met its dual primary endpoints of overall survival (OS) and progression-free survival (PFS), compared to chemotherapy. An Independent Data Monitoring Committee determined that OS crossed the pre-specified efficacy boundary at interim analysis. The safety results of the combination are consistent with those of enfortumab vedotin in combination with pembrolizumab previously reported in cisplatin-ineligible patients with la/mUC.

Ahsan Arozullah, M.D., M.P.H., senior vice president, head of oncology development, Astellas, said: “We are thrilled that the topline results of the EV-302 study demonstrated that the combination of enfortumab vedotin and pembrolizumab improved the dual primary endpoints of OS and PFS. Patients living with metastatic urothelial cancer are in dire need of additional treatment options and this combination has the potential to advance the standard of care. We are extremely grateful to all of the patients who participated in this trial.”

Roger Dansey, M.D., president, research and development, Seagen, said: “This study has the potential to be practice changing and offer a new standard of care for first-line metastatic bladder cancer. We look forward to presenting the results at an upcoming medical conference and discussing with regulators in order to get this medicine to patients as soon as possible.”

Thomas Powles, M.R.C.P., M.D., Professor of Genitourinary Oncology at Queen Mary University of London; Director, Barts Cancer Center, London; EV-302 Primary Investigator, said:  “Over two hundred thousand deaths from urothelial cancer are reported worldwide annually, making it a major cause of morbidity and mortality. The topline results from EV-302 are encouraging for patients with advanced-stage urothelial cancer, which is aggressive and associated with devastating outcomes.”

The EV-302 trial is an open-label, randomized, controlled phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus chemotherapy in patients with previously untreated la/mUC. In this study, patients were randomized to receive either enfortumab vedotin in combination with pembrolizumab or chemotherapy. The dual primary endpoints of this trial are OS and PFS per RECIST v1.1 by blinded independent central review (BICR). Full details will be reported at an upcoming scientific congress.

The EV-302 trial is intended to serve as the basis for global submissions and as the confirmatory trial for the US accelerated approval of this combination. In April 2023, the US Food and Drug Administration (FDA) granted an accelerated approval to Padcev in combination with Keytruda for the treatment of adult patients with la/mUC who are not eligible to receive cisplatin-containing chemotherapy based on the results from the EV-103 trial. The trial is part of an extensive program evaluating this combination in multiple stages of 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.

Globally, approximately 573,000 new cases of bladder cancer and 212,000 deaths are reported annually.

It is estimated that approximately 82,290 people in the US will be diagnosed with bladder cancer in 2023.

It is estimated that approximately 200,000 people in Europe and 24,000 people in Japan are diagnosed with bladder cancer annually.

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.

The EV-302 trial (NCT04223856) is an open-label, randomized, controlled phase 3 study, evaluating the impact of treatment with 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.

Padcev (enfortumab vedotin-ejfv) 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.8 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).

Astellas and Seagen entered a clinical collaboration agreement with Merck to evaluate the combination of Astellas’ and Seagen’s Padcev (enfortumab vedotin-ejfv) and Merck’s Keytruda (pembrolizumab) in patients with previously untreated metastatic urothelial cancer. Keytruda is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. The company is 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.

Founded 25 years ago, Seagen Inc. is a global biotechnology company that discovers, develops, manufactures and commercializes targeted cancer therapeutics, with antibody-drug conjugates (ADCs) at our core.

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