Tokyo-based Japanese drugmaker Astellas Pharma and Seattle Genetics in Bothel, Washington (USA) confirmed the submission of a Biologics License Application (BLA) for accelerated approval to the U.S. Food and Drug Administration (FDA) for their investigational agent for enfortumab vedotin.
Enfortumab vedotin is an antibody-drug conjugate of ADC that targets Nectin-4, a cell adhesion molecule that is expressed on many solid tumors and is highly expressed in urothelial cancers.
Antibody-drug Conjugates are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker.
With five approved drugs on the market, ADCs have become a powerful class of therapeutic agents in oncology and hematology.
The investigational drug enfortumab vedotin is composed of an anti-Nectin-4 monoclonal antibody attached to a microtubule-disrupting agent, monomethyl auristatin E (MMAE), a very potent antimitotic agent that inhibits cell division by blocking the polymerisation of tubulin. Using Seattle Genetics’ proprietary linker technology, the family of auristatins are synthetic analogues of the antineoplastic natural product Dolastatin 10, ultrapotent cytotoxic microtubule inhibitors that are clinically used as payloads in antibody-drug conjugates.
The drug is being developed for the treatment of patients with locally advanced or metastatic urothelial cancer who have received a PD-1/L1 inhibitor and who have received a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting.
Urothelial cancer is the most common type of bladder cancer (90% of cases). 
In 2018, more than 82,000 people were diagnosed with bladder cancer in the United States. Globally, approximately 549,000 people were diagnosed with bladder cancer last year, and there were approximately 200,000 deaths worldwide.
The submission of the investigational agent is based on results from the first cohort of patients in the EV-201 pivotal phase II clinical trial that were presented as a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology (ASCO) in June 2019.
The EV-201-trial is an ongoing single-arm, pivotal phase II clinical study of enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer (cohort 1).
In the cohort 1 group of 128 patients enrolled at multiple, international centers who have been previously treated with a PD-1/L1 inhibitor and a platinum-containing chemotherapy 
The primary endpoint of the trial is confirmed objective response rate per blinded independent central review. Secondary endpoints include assessments of duration of response, disease control rate, progression-free survival, overall survival, safety and tolerability. EV-201 continues to enroll patients in cohort 2, which includes patients who have not received a platinum-containing chemotherapy or who are ineligible for cisplatin.
Unmet medical need
“There are limited treatment options for patients with advanced urothelial cancer, and we are encouraged by the results observed in the pivotal trial for enfortumab vedotin,” noted Andrew Krivoshik, MD, Ph.D., Senior Vice President and Oncology Therapeutic Area Head at Astellas.
“There is an urgent need for new therapies for patients with advanced urothelial cancer, and we look forward to working with our partner Astellas and the FDA on the review of this application,” explained Roger Dansey, MD, Chief Medical Officer at Seattle Genetics.
Based on preliminary results from a phase I trial (EV-101), the FDA granted enfortumab vedotin Breakthrough Therapy designation for patients with locally advanced or metastatic urothelial cancer whose disease has progressed during or following checkpoint inhibitor therapy.
A global, randomized phase III confirmatory clinical trial (EV-301) is ongoing and is intended to support global registrations. Another ongoing trial, EV-103, is evaluating enfortumab vedotin in earlier lines of treatment for patients with locally advanced or metastatic urothelial cancer, including in combination with pembrolizumab and/or platinum chemotherapy in newly diagnosed patients as well as patients whose cancer progressed from earlier-stage disease.
Seattle Genetics and Astellas are co-developing enfortumab vedotin under a collaboration that was entered into in 2007 and expanded in 2009. Under the collaboration, the companies are sharing costs and profits on a 50:50 basis worldwide.
This article was first published in ADC Review | J. Antibody-drug Conjugates.
 Vlachostergios P, Jakubowski C, Niaz J, et al. (2018). Antibody-Drug Conjugates in Bladder Cancer. Bladder Cancer (Version 4.2018). [Article]
 American Society of Clinical Oncology. Bladder Cancer: Introduction (05-2019) [Article]
 International Agency for Research on Cancer. Cancer tomorrow: bladder. [Article]
 Data on file at Seattle Genetics