FDA Grants Breakthrough Therapy Designation to Enfortumab Vedotin

The FDA granted breakthrough therapy designation to enfortumab vedotin based on results from the dose-escalation cohort and expansion cohort A of the phase Ib/II EV-103 trial.

The FDA has granted breakthrough therapy designation to enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab (Keytruda) for the treatment of patients with unresectable locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy for the first-line setting, according to Seattle Genetics and Astellas Pharma Inc, co-developers of the agent.

The designation was granted based on results from the dose-escalation cohort and expansion cohort A of the phase Ib/II EV-103trial. Initial results from the trial were presented at the European Society of Medical Oncology (ESMO) 2019, and updated findings were presented at the 2020 Genitourinary Cancers Symposium.

EV-103 is an ongoing, multi-cohort, open-label, multicenter phase Ib/II trial of enfortumab vedotin alone or in combination, assessing the safety, tolerability, and efficacy of the antibody-drug conjugate (ADC) in muscle invasive, locally advanced and first- and second-line metastatic urothelial cancer. 

At a median follow-up of 11.5 months, 45 patients with locally advanced or metastatic urothelial carcinoma who were ineligible for platinum-based treatment had received 1.25 mg/kg of enfortumab vedotin in combination with pembrolizumab. Patients demonstrated an overall response rate (ORR) of 73%, including a 15.6% complete response rate and 57.8% partial response rate. Progression-free survival was 12.3 months, and the overall survival at 1 year was 81.6%. As of the data cut-off date, a median duration of response had not been reached. 

Further findings indicated that 55% of the 33 responses were ongoing at the time of analysis, with 83.9% of the responses lasting 6 months or more and 53.7% of responses lasting 12 months or more. 

The most common treatment-emergent side adverse events (AEs) reported were fatigue (58%), alopecia (53%), and peripheral sensory neuropathy (53%). One patient died due to multiple organ failure, an AE also reportedly related to treatment. 

“The FDA’s breakthrough therapy designation reflects the encouraging preliminary evidence for the combination of Padcev and pembrolizumab in previously untreated advanced urothelial cancer to benefit patients who are in need of effective treatment options,” said Andrew Krivoshik, MD, PhD, senior vice president and oncology therapeutic area head at Astellas, said in a press release. “We look forward to continuing our work with the FDA as we progress our clinical development program as quickly as possible.”

Enfortumab vedotin was previously approved by the FDA in December 2019 and is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1 or PD-L1 inhibitor and a platinum chemotherapy before or after surgery or in a locally advanced or metastatic setting. The ADC was approved based on tumor response rate, though continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. 

“This is an important step in our investigation of Padcev in combination with pembrolizumab as a first-line therapy for patients with advanced urothelial cancer who are unable to receive cisplatin-based chemotherapy,” Roger Dansey, MD, chief medical officer for Seattle Genetics, said in the press release. “Based on encouraging early clinical activity, we recently initiated a phase III trial of this platinum-free combination and look forward to potentially addressing an unmet need for patients.” 


1. Seattle Genetics and Astellas Receive FDA Breakthrough Therapy Designation for PADCEV (enfortumab vedotin-ejfv) in Combination with Pembrolizumab in First-Line Advanced Bladder Cancer [news release]. Bothell, Washington and Tokyo. Published February 19, 2020. investor.seattlegenetics.com/press-releases/news-details/2020/Seattle-Genetics-and-Astellas-Receive-FDA-Breakthrough-Therapy-Designation-for-PADCEV-enfortumab-vedotin-ejfv-in-Combination-with-Pembrolizumab-in-First-Line-Advanced-Bladder-Cancer/default.aspx. Accessed February 19, 2020.

2. Cure. Padcev Combination Shows Promise in Patients with Metastatic Bladder Cancer. Cure website. Published February 15, 2020. curetoday.com/articles/padcev-combination-shows-promise-in-patients-with-metastatic-bladder-cancer. Accessed February 19, 2020.