Biologics License Application for enfortumab vedotin has been submitted to the FDA for a potential accelerated approval for use as a treatment for patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.
Andrew Krivoshik, MD, PhD
A Biologics License Application (BLA) for enfortumab vedotin has been submitted to the FDA for a potential accelerated approval as a treatment for patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.1
The BLA submission is based on findings from the pivotal phase II EV-201 trial that were presented as a late-breaking abstract at the 2019 ASCO Annual Meeting.2
“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,” Andrew Krivoshik, MD, PhD, senior vice president and oncology therapeutic area head, Astellas, said in a statement.
Enfortumab vedotin is an investigational antibodydrug conjugate (ADC) that targets Nectin-4, which is a highly expressed protein in urothelial cancers, and is being co-developed in a collaboration between Seattle Genetics and Astellas Pharma.
“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,” said Roger Dansey, MD, chief medical officer at Seattle Genetics, in a statement.
In the single-arm, 2-cohort phase II EV-201 trial, patients who had previously been treated with both platinum chemotherapy and a checkpoint inhibitor were enrolled in the first cohort, and the second cohort included patients who had not received platinum chemotherapy and were ineligible for cisplatin. Patients all received 1.25 mg/kg enfortumab vedotin intravenously on days 1, 8, and 15 of each 28-day cycle.
The primary endpoint of the trial was objective response rate (ORR) by RECIST 1.1 blinded independent central review, and secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety/tolerability.
In the group of patients who had received both immunotherapy and chemotherapy, patients had a median age of 69 years (range, 40-84) and had received a median of 3 (range, 1-6) prior lines of systemic therapy in the locally advanced or metastatic setting but had not received treatment for at least 2 weeks prior to enrolling in the trial. Sixty-five percent of the 125 treated patients had PD-L1 expression combined positive scores (CPS) <10, and 35% had a CPS ≥10.
The ORR was 44% (95% CI, 35.1%-53.2%) with complete responses in 12% and partial responses in 32%. An additional 35 patients (28%) had stable disease. Responses were seen regardless of prior response to checkpoint inhibition or the presence of liver metastases.
The median PFS was 5.8 months (95% CI, 4.9-7.5), the median OS was 11.7 months (95% CI, 9.1not reached), and the median DOR was 7.6 months (range, 0.95-11.30+).
Frequent any-grade treatment-related adverse events (TRAEs) included fatigue (50%), alopecia (49%), and decreased appetite (44%). TRAEs of special interest included rash (all grade, 48%; grade ≥3, 12%), peripheral neuropathy (all grade, 50%; grade ≥3, 3%), and hyperglycemia (all grade, 11%; grade ≥3, 6%).
Treatment discontinuation was seen in 12% of patients due to a TRAE, most frequently due to peripheral neuropathy. One death was reported as treatment related (interstitial lung disease), but was confounded by a suspected pulmonary infection, as per the investigator.
The second cohort of the EV-201 trial continues to enroll patients.
Previously, theFDA granted enfortumab vedotin a breakthrough therapy designationfor the treatment of patients with locally advanced or metastatic urothelial cancer who had previously received an immune checkpoint inhibitor.
A global, randomized phase III trial, known as EV-301 (NCT03474107), has been initiated to confirm the results of the phase II trial. Additionally, the phase I EV-103 trial (NCT03288545) is also ongoing looking at the use of enfortumab vedotin in combinations with pembrolizumab and/or chemotherapy in both newly diagnosed and pretreated patients with urothelial cancer.