Enfortumab Vedotin Plus Pembrolizumab Receives Priority Review in Japan for First-Line Urothelial Carcinoma


The sNDA for enfortumab vedotin-ejfv plus pembrolizumab in patients with metastatic urothelial cancer has received priority review in Japan.

Ahsan Arozullah, MD, MPH

Ahsan Arozullah, MD, MPH

Japan’s Ministry of Health, Labour, and Welfare has granted priority review to the supplemental new drug application (sNDA) of enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab (Keytruda) for the first-line treatment of patients with previously untreated, locally advanced or metastatic urothelial cancer, according to a news release from Astellas Pharma Inc.1

The decision was based on results from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856). At a median follow-up of 17.2 months, the combination demonstrated a 53% reduction in the risk of death compared with chemotherapy (HR, 0.47; 95% CI, 0.38-0.58; P < .00001). The median overall survival (OS) was 31.5 months (95% CI, 25.4–not reached) for patients treated with the study combination (n = 442) vs 16.1 months (95% CI, 13.9-18.3) in those treated with chemotherapy (n = 444). Notably, the hazard ratio.1,2

Furthermore, the OS was consistently unaffected by PD-L1 status or the presence of visceral metastases. The median progression-free survival (PFS) was 12.5 months (95% CI, 10.4-16.6) and 6.3 months (95% CI, 6.2-6.5) in patients treated with enfortumab vedotin plus pembrolizumab vs chemotherapy, respectively. Notably, this equated to a 55% reduction in the risk of disease progression or death (HR, 0.45; 95%, 0.38-0.54; P < .00001).2

These updated data were read out at the 2023 ESMO Congress, and subsequently led the combination of enfortumab vedotin and pembrolizumab to receive regulatory approval from the FDA on December 15, 2023, following a regulatory accelerated approval to the combination in April 2023.2–4

"The [Ministry of Health, Labour and Welfare of Japan’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,” Ahsan Arozullah, MD, MPH, senior vice president and head of Oncology Development at Astellas, said in the news release. “We are pleased by this review designation and hope to quickly bring this treatment option to those who need it most."

Worldwide, there are approximately 614,000 new cases of bladder cancer resulting in 220,000 reported deaths each year. Specifically in Japan, it is estimated that 25,000 patients receive a bladder cancer diagnosis annually. In 2022, there were 10,000 reported deaths due to the disease. However, enfortumab vedotin represents a significant advancement as the first combination therapy providing an alternative to platinum-based chemotherapy, the current primary treatment for first-line urothelial carcinoma.1

Furthermore, enfortumab vedotin is a novel antibody-drug conjugate (ADC) which targets a protein abundant in bladder cancer cells: Nectin-4. Preclinical studies have shown enfortumab vedotin to work by binding to Nectin-4-expressing cells, leading to the internalization and release of the anti-cancer agent monomethyl auristatin E, resulting in cell cycle arrest and apoptosis.1

Patients enrolled onto the open-label, randomized, controlled study must have presented with previously untreated locally advanced and/or metastatic urothelial carcinoma; must be eligible for platinum therapy and able to receive the study combination; present as PD-(L)1 inhibitor naive; have a group performance status greater than or equal to 30 mL/mina; and have an ECOG performance status of 2 or less.5

In EV-302, patients were randomly assigned 1:1 to receive the study combination with no maximum treatment cycles for enfortumab vedotin and a maximum of 35 cycles for pembrolizumab vs cisplatin or carboplatin plus gemcitabine-containing chemotherapy given for a total of 6 cycles. These patients were treated until disease progression per BICR, clinical progression, unacceptable toxicity, or completion of maximum cycles.5

The coprimary end points of the study were PFS by blinded independent central review (BICR) and OS. Secondary end points incldued ORR per RECIST v1.1 by BICR and investigator assessment, as well as safety.5

“The combination [of enfortumab vedotin plus pembrolizumab] is tolerable and in line with expectations, the [combination] works across broad subgroups of patients, and the control arm performed as expected,” Thomas Powles, MD, MBBS, MRCP, professor of urology cancer at the University of London, and the director of the Barts Cancer Centre in the United Kingdom, said in an interview with OncLive® during the 2023 ESMO Congress following the presentation of data and prior to the United States regulatory approval.

Furthermore, the safety profile of enfortumab vedotin plus pembrolizumab was generally manageable, with no new safety signals observed. Therefore, these results continue to support the study combination as a potential new standard of care for first-line metastatic urothelial carcinoma.5

The combination of enfortumab vedotin plus pembrolizumab is also being reviewed by the Committee for Medicinal Products for Human Use of the European Medicines Agency.1


  1. Padcev™ (enfortumab vedotin [genetical recombination]) with Keytruda® (pembrolizumab [genetical recombination]) granted priority review by Japan’s Ministry of Health, Labour and Welfare for first-line treatment of advanced bladder cancer. News release. Astellas Pharma Inc. February 16, 2024. Accessed February 16, 2024. https://www.astellas.com/en/news/28911
  2. Powles TB, Perez Valderrama B, Gupta S, et al. LBA6 EV-302/KEYNOTE-A39: open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Ann Oncol. 2023;34(suppl 2):S1340. doi:10.1016/j.annonc.2023.10.106
  3. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed February 16, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
  4. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. FDA. April 3, 2023. Accessed February 16, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic
  5. Powles TB, Perez Valderrama B, Gupta S, et al. EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA6.
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