Astellas Pharma and Seagen have confirmed that the companies have completed the submissions for two supplemental Biologics License Applications (sBLAs) to the U.S. Food and Drug Administration (FDA) for enfortumab vedotin * (Padcev®) for the treatment of patients diagnosed with urothelial cancer, the most common type of bladder cancer (90% of cases), which can also be found in the renal pelvis, ureter and urethra 
Globally, approximately 549,000 new cases of bladder cancer and 200,000 deaths are reported annually.  The standard of care for advanced urothelial carcinoma includes platinum-based chemotherapy and programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors, administered as frontline, second-line, or maintenance therapy.
In December 2019 enfortumab vedotin received accelerated approval in the United States 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 in a locally advanced or metastatic urothelial cancer setting. The drug is currently only approved for use in the United States.
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 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) 
Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials, and in submitting the sBLA, the companies seek to convert enfortumab vedotin’s accelerated approval to regular approval.
The first submission, based on the phase III EV-301 trial (NCT03474107), 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 approximately 600 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 an assessment of safety/tolerability and quality-of-life parameters.
The second submission, based on the pivotal trial EV-201’s (NCT03219333) second cohort, The EV-201 trial is a single-arm, dual-cohort, pivotal phase II 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 128 patients in cohort 1 and 91 patients in cohort 2 at multiple centers internationally. The primary endpoint is 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.
By submitting the sBLA, the companies request an expansion of the current label to include patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1/L1 inhibitor and are ineligible for cisplatin.
The FDA is reviewing both applications under the Real-Time Oncology Review (RTOR) pilot program. The 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 FDA’s review of our applications under Real-Time Oncology Review supports our efforts to expand enfortumab vedotin’s availability as a treatment option for more patients as quickly as possible,” said Andrew Krivoshik, M.D., Ph.D., Senior Vice President, and Oncology Therapeutic Area Head, Astellas.
“Locally advanced or metastatic urothelial cancer is an aggressive disease with limited treatment options,” Krivoshik added.
The sBLA for regular approval of enfortumab vedotin in the U.S. is supported by data from the global EV-301 phase III confirmatory trial, which compared enfortumab vedotin to chemotherapy in adult patients with locally advanced or metastatic urothelial cancer who were previously treated with platinum-based chemotherapy and a PD-1/L1 inhibitor.
The trial’s primary endpoint was the overall survival of patients treated with enfortumab vedotin vs. chemotherapy, and full results were presented at the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) and published in the New England Journal of Medicine 
These results confirmed 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 second submission, for a label expansion in the U.S., is based on results from the second cohort of EV-201, a pivotal phase II clinical trial evaluating PADCEV in patients with locally advanced or metastatic urothelial cancer who had received prior immunotherapy treatment but were not eligible for cisplatin. The trial’s primary endpoint was the objective response rate, and full results were presented at ASCO GU. 
“Advanced bladder cancer patients urgently need more treatment options,” said Roger Dansey, M.D., Chief Medical Officer, Seagen.
“Based on recently presented clinical trial results, PADCEV could address a significant unmet need for more patients with advanced urothelial cancer after initial immunotherapy treatment.”
Note: in the United States, the drug is listed as enfortumab vedotin-ejfv
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 (Padcev®; Astellas Pharma and Seagen) [Prescribing Information]
 American Society of Clinical Oncology. Bladder cancer: introduction (5-2019). Online. Last accessed on February 17, 2021.
 Cancer today: data visualization tools for exploring the global cancer burden in 2020. Online. Last accessed on February 17, 2021.
 PADCEV [package insert] Northbrook, IL: Astellas Pharma Inc.
 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):3003-13.1, 2021.
 Powles T, Rosenberg J, Sonpavde G, et al. Primary Results of EV-301: A Phase 3 Trial of Enfortumab Vedotin vs Chemotherapy in Patients With Previously Treated Locally Advanced or Metastatic Urothelial Carcinoma. ASCO Meeting Library 2021. Online. Last accessed on February 17, 2021.
 Balar AV, McGregor B, Rosenberg J, et al. EV-201 Cohort 2: Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors. ASCO Meeting Library 2021. Online. Last accessed on February 17, 2021.