The FDA has granted a priority review designation to a biologics license application for enfortumab vedotin for the treatment of patients with locally advanced or metastatic urothelial cancer who have received prior treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.
Roger Dansey, MD
The FDA has granted a priority review designation to a biologics license application (BLA) for enfortumab vedotin for the treatment of patients with locally advanced or metastatic urothelial cancer who have received prior treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.1
The designation is based on results from the first cohort of patients in the phase II EV-201 trial, which showed that enfortumab vedotin elicited an overall response rate (ORR) of 44% in patients with locally advanced or metastatic urothelial cancer, which included a 12% complete response rate.2
Under the Prescription Drug User Fee Act, the FDA will make a decision on the BLA by March 15, 2020.
“The FDA’s filing of the application for enfortumab vedotin and granting of priority review is a significant milestone toward offering a new treatment to patients with advanced urothelial cancer who have a clear unmet need,” Roger Dansey, MD, chief medical officer at Seattle Genetics, the company jointly developing the investigational agent with Astellas Pharma, stated in a press release.
Enfortumab vedotin is a novel investigational antibody-drug conjugate that targets Nectin-4, a protein that is highly expressed in urothelial cancers.
In the single-arm, phase II EV-201 trial, investigators administered enfortumab vedotin to patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1/PD-L1 inhibitor, including those who have also been treated with a platinum-containing chemotherapy (cohort 1) and those who have not received a platinum-containing chemotherapy and who are ineligible for cisplatin (cohort 2). A total 128 patients were enrolled at multiple centers internationally for cohort 1, in which enfortumab vedotin was given at 1.25 mg/kg enfortumab vedotin intravenously on days 1, 8, and 15 of each 28-day cycle.
Seventy percent of the 125 patients treated with enfortumab vedotin were male and the median age was 69 years (range, 40-84). Patients received a median of 3 lines (range, 1-6) of prior systemic treatments in the locally advanced or metastatic setting but had not received treatment for ≥2 weeks prior to enrolling in the study. Moreover, the combined positive scores of PD-L1 expression were <10 in 65% and ≥10 in 35%.
The primary endpoint is confirmed ORR per blinded independent central review, while secondary endpoints include duration of response (DOR), disease control rate, progression-free survival (PFS), overall survival (OS), safety, and tolerability. Patients are continuing to be enrolled in cohort 2.
Additional results showed that the OS was 11.7 months (95% CI, 9.1—not reached), the median PFS was 5.8 months (95% CI, 4.9-7.5), and the median DOR was 7.6 months (range, 0.95-11.30+).
Responses were observed across all subgroups, irrespective of response to prior PD-1/PD-L1 inhibitors or presence of liver metastases (ORR, 38%; 95% CI, 24.7%-52.8%). The median time to response was 1.8 months (range, 1.2-9.2), with 44% of responses ongoing.
Regarding safety, the most common treatment-related adverse events (TRAEs) of any grade were fatigue (50%), alopecia (49%), and decreased appetite (44%), while TRAEs of interest include any case of rash (all grade, 48%; grade ≥3, 12%), any peripheral neuropathy (all grade, 50%; grade ≥3, 3%), and any hyperglycemia (all grade, 11%; grade ≥3, 6%).
The treatment discontinuation rate due to a TRAE was 12%, which was mostly due to peripheral neuropathy. One treatment-related death was reported, which was caused by interstitial lung disease, but was confounded by a suspected pulmonary infection, as per the investigator.
“If approved, enfortumab vedotin will likely play an important role in the treatment of advanced urothelial cancer, and we look forward to working with the FDA as the review process advances,” Andrew Krivoshik, MD, PhD, senior vice president and Oncology Therapeutic Area Head at Astellas, stated in the press release.
The FDA previously granted enfortumab vedotin a breakthrough therapy designation in March 2018 for patients with locally advanced or metastatic urothelial cancer whose disease has progressed during or following checkpoint inhibitor therapy, based on the EV-101 data.