The U.S. Food and Drug Administration (FDA) has granted regular approval for enfortumab vedotin-ejfv (Padcev®; Astellas Pharma and Seagen) while, at the same time, approving a new indication for adult patients with locally advanced or metastatic urothelial cancer who are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy. Cisplatin-ineligible patients typically have limited treatment options and a poor prognosis.
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. 
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).
In 2019, the FDA granted accelerated approval for enfortumab vedotin, which is co-developed by Astellas and Seagen, for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/L1 inhibitor and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery, or in a locally advanced or metastatic urothelial cancer setting. The conversion from accelerated approval to regular approval and the label expansion were based on two supplemental Biologics License Applications (sBLAs) reviewed under the Real-Time Oncology Review (RTOR) pilot program.
“The FDA’s decision to convert accelerated approval to regular approval was based on data from the Phase 3 EV-301 trial, which had a primary endpoint of overall survival for patients treated with enfortumab vedotin versus chemotherapy,” said Andrew Krivoshik, M.D., Ph.D., Senior Vice President, and Oncology Therapeutic Area Head, Astellas.
“With enfortumab vedotin, for the first time, physicians can treat advanced urothelial cancer following treatment with a platinum-containing therapy and immunotherapy using an FDA-approved therapy that has demonstrated an overall survival benefit compared with chemotherapy.”
The EV-301 trial compared enfortumab vedotin to chemotherapy in adult patients (n=608) with locally advanced or metastatic urothelial cancer who were previously treated with platinum-based chemotherapy and a PD-1/L1 inhibitor. 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 all-grade adverse reactions (≥20%) included rash, fatigue, peripheral neuropathy, alopecia, decreased appetite, diarrhea, pruritus, nausea, constipation, dysgeusia, musculoskeletal pain, dry eye, pyrexia, abdominal pain, and anemia.
“Enfortumab vedotin is the first and only FDA-approved therapy for patients with locally advanced or metastatic urothelial cancer who have received immunotherapy and cannot receive cisplatin,” said Roger Dansey, M.D., Chief Medical Officer, Seagen.
“Because of the FDA’s Real-Time Oncology Review, we’re able to make enfortumab vedotin available as early as possible to these patients, who have limited treatment options due to their age or comorbid conditions,” Dansey added.
Cohort 2 of the EV-201 trial evaluated enfortumab vedotin in patients (n=89) with locally advanced or metastatic urothelial cancer who had been previously treated with a PD-1/L1 inhibitor, had not received platinum-containing chemotherapy in this setting, and were ineligible for cisplatin. After a median follow-up of 16 months, 51 percent of patients who received enfortumab vedotin had an objective response [95% CI: 39.8, 61.3] per blinded independent central review, with a median duration of response of 13.8 months [95% CI: 6.4, not reached]. The most common all-grade adverse reactions (≥20%) included rash, peripheral neuropathy, alopecia, fatigue, decreased appetite, anemia, diarrhea, pruritus, weight decreased, nausea, dry eye, and dysgeusia.
“Almost half of advanced bladder cancer patients cannot receive cisplatin-based chemotherapy. Many of these patients will receive first-line immunotherapy. If their cancer does not respond — or if it progresses after prior response to immunotherapy — there is an urgent need for more treatment options as there is currently no standard of care,” said Evan Y. Yu, M.D., Division of Oncology, Department of Medicine, University of Washington School of Medicine and a lead investigator for the EV-201 trial, in which all patients were previously treated with immunotherapy.
“A new regulatory approval for enfortumab vedotin is an important clinical advance and can help serve this unmet need,” Yu added.
Globally, approximately 573,000 new cases of bladder cancer and more than 212,000 deaths are reported annually. Enfortumab vedotin is being investigated in a robust development program aimed at addressing unmet needs across the continuum of urothelial cancer and in other solid tumors.
The FDA’s RTOR program aims to explore a more efficient review process to ensure that safe and effective treatments are available to patients as early as possible. The agency’s review was also conducted as part of Project Orbis, an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology drugs among participating international health authorities. Through Project Orbis, health authorities in Australia and Canada are continuing to review data from EV-301 and EV-201 for initial registrations.
The EV-301 trial (NCT03474107) is 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. 
The primary endpoint is overall survival and secondary endpoints include 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. Results were published in the New England Journal of Medicine. 
The EV-201 trial (NCT03219333) is a single-arm, multi-cohort, multicenter, pivotal phase 2 clinical trial of enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1 or PD-L1 inhibitor, including those who have also been treated with platinum-containing chemotherapy (Cohort 1) and those who have not received platinum-containing chemotherapy in this setting and who are ineligible for cisplatin (Cohort 2). The trial enrolled 125 patients in Cohort 1 and 89 patients in Cohort 2 at multiple centers internationally.
The primary endpoint is the confirmed objective response rate per blinded independent central review. Secondary endpoints include assessments of the duration of response, disease control rate, progression-free survival, overall survival, safety, and tolerability. Results of Cohort 2 were published in The Lancet Oncology.
A Study to Evaluate Enfortumab Vedotin Versus (vs) Chemotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301) – NCT03474107
A Study of Enfortumab Vedotin for Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer (EV-201) – NCT03219333
Highlights of prescribing information
Enfortumab vedotin-ejfv (Padcev®; Astellas Pharma and Seagen)[Prescribing Information]
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 World Health Organization, International Agency for Research on Cancer. Globocan 2020 world fact sheet. Online. last Accessed on July 10, 2021.
 Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021; 10.1056/NEJMoa2035807.
 Yu EY, Petrylak DP, O’Donnell PH, et al. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV-201): a multicenter, single-arm, phase 2 trial. The Lancet Oncology. 2021: S1470-2045(21)00094-2.