Japan’s Ministry of Health, Labour and Welfare (MHLW) has approved enfortumab vedotin (Padcev®; Astellas Pharma and Seagen) for the treatment of radically unresectable urothelial carcinoma that has progressed after anti-cancer chemotherapy. The New Drug Application received priority review.
Enfortumab vedotin, an antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer, is indicated for the treatment of radically unresectable urothelial carcinoma, a form of urothelial cancer that cannot be treated by surgical removal of the urinary bladder or the kidney and the ureter due to tumor growth.
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).
“Unfortunately, advanced urothelial cancer has a relatively poor prognosis and can be challenging to treat with currently available therapies,” explained Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Head of Development Therapeutic Areas, Astellas.
“The MHLW’s review of enfortumab vedotin in just six months, supported by overall survival data from a pivotal Phase 3 clinical trial, reflects the seriousness of this condition and the potential benefit of enfortumab vedotin for patients in Japan,” Krivoshik added.
The approval is primarily based on the global Phase 3 EV-301, a global, multicenter, open-label, randomized Phase 3 trial designed to evaluate enfortumab vedotin versus physician’s choice of chemotherapy (docetaxel, paclitaxel or vinflunine) in 608 patients with locally advanced or metastatic urothelial cancer who were previously treated with a PD-1/L1 inhibitor and platinum-based therapies.
Participating patients were randomly assigned in a 1:1 ratio to receive enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight on days 1, 8, and 15 of a 28-day cycle) or investigator-chosen chemotherapy (standard docetaxel, paclitaxel, or vinflunine), administered on day 1 of a 21-day cycle. Overall, 301 were assigned to receive enfortumab vedotin and 307 to receive chemotherapy.
The primary endpoint was overall survival, and secondary endpoints included progression-free survival, overall response rate, duration of response, and disease control rate, as well as assessment of safety/tolerability and quality-of-life parameters.
At the time of pre-specified interim analysis, patients who received enfortumab vedotin (n=301) in the trial lived a median of 3.9 months longer than those who received chemotherapy (n=307). Median overall survival was 12.9 vs. 9.0 months, respectively [Hazard Ratio=0.70 (95% Confidence Interval [CI]: 0.56, 0.89), p=0.001]. The most common (≥20%) adverse reactions included alopecia, peripheral sensory neuropathy, pruritus, fatigue, decreased appetite, diarrhea, dysgeusia, and nausea.
Based on an analysis of the outcome data of the study, which was funded by Astellas Pharma US and Seagen, the trial’s investigators concluded that enfortumab vedotin significantly prolonged survival as compared with standard chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based treatment and a PD-1 or PD-L1 inhibitor. The results of the trial, which included sites in Japan, were published in the New England Journal of Medicine.
Urothelial cancer is the most common type of bladder cancer (90 percent of cases), and can also be found in the renal pelvis (where urine collects inside the kidney), ureter (the tube that connects the kidneys to the bladder), and urethra. Globally, approximately 573,000 new cases of bladder cancer and 212,000 deaths are reported annually. 
Each year in Japan, more than 24,300 people are diagnosed with bladder cancer, and an estimated 9,500 die from the disease.  Enfortumab vedotin is the subject of a robust clinical development program aimed at addressing unmet needs across the continuum of urothelial cancer and in other solid tumors.
Astellas and Seagen are co-developing enfortumab vedotin under a 50:50 worldwide development and commercialization collaboration. In the United States, Astellas and Seagen co-promote enfortumab vedotin. In the Americas outside the US, Seagen holds responsibility for commercialization activities and regulatory filings. Outside of the Americas, including in Japan, Astellas holds responsibility for commercialization activities and regulatory filings.
A Study to Evaluate Enfortumab Vedotin Versus (vs) Chemotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301) – NCT03474107
Highlights of Prescribing information
Enfortumab vedotin (Padcev®; Astellas Pharma and Seagen) [Prescribing Information]
 Challita-Eid P, 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.
 Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. doi: 10.1056/NEJMoa2035807. Epub 2021 Feb 12. PMID: 33577729; PMCID: PMC8450892.
 American Society of Clinical Oncology. Bladder cancer: introduction (9-2020). Online. Last accessed on September 22, 2021.
 Cancer Information Service, Projected cancer statistics. Published 2021. Online. Last accessed on September 22, 2021
Featured Image: Astellas Pharma. Exhibition booth during the 2019 annual meeting of the American Society of Medical Oncology (ASCO). Photo Courtesy: © 2019 – 2021 Sunvalley Communication. Used with permission.