FDA Approval Sought for Enfortumab Vedotin for Urothelial Cancer

Gina Columbus

Roger Dansey, MD, chief medical officer of Seattle Genetics

Roger Dansey, MD

A biologics license application (BLA) has been submitted to the FDA for enfortumab vedotin for the treatment of patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/PD-L1 inhibitor and who have received a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.1

The BLA is based on findings from a cohort of patients enrolled on the single-arm, phase II EV-201 trial, in which the overall response rate (ORR) was 44% with enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer.2 This included a 12% complete response rate.

"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," Roger Dansey, MD, chief medical officer of Seattle Genetics, the developer of the investigational agent, stated in a press release.

Enfortumab vedotin is an antibody-drug conjugate that targets Nectin-4, which is a protein that is highly expressed in urothelial cancers. Previously, the FDA granted the agent a breakthrough therapy designation in March 2018 for patients with locally advanced or metastatic urothelial cancer who experienced disease progression during or following checkpoint inhibitor therapy, which was based on interim results from a phase I dose-escalation/dose-expansion trial exploring the agent in patients with metastatic urothelial carcinoma and other solid tumors.

In the ongoing, two-cohort, phase II EV-201 trial, enfortumab vedotin was evaluated in patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1/PD-L1 inhibitor and a platinum-containing chemotherapy (cohort 1) and those who have not received a platinum-containing chemotherapy or who are ineligible for cisplatin (cohort 2).

In cohort 1, 128 patients were enrolled at multiple centers internationally. Patients received 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 was confirmed ORR per blinded independent central review; secondary endpoints include duration of response (DOR), disease control rate, progression-free survival (PFS), overall survival (OS), safety, and tolerability.

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 (interstitial lung disease), but was confounded by a suspected pulmonary infection, as per the investigator.

Cohort 2 of the EV-201 trial continues to enroll patients, Seattle Genetics stated in the press release.

The ongoing randomized, phase III confirmatory EV-301 trial (NCT03474107) is ongoing and is intended to support global registrations.

Additionally, the ongoing EV-103 trial (NCT03288545) is evaluating enfortumab vedotin in earlier lines of treatment for patients with locally advanced or metastatic urothelial cancer, including in combination with pembrolizumab (Keytruda) and/or platinum chemotherapy in newly diagnosed patients as well as those whose cancer progressed from earlier-stage disease.


  1. Seattle Genetics and Astellas Announce Submission of Biologics License Application to FDA for Enfortumab Vedotin for Patients with Locally Advanced or Metastatic Urothelial Cancer. Seattle Genetics. Published July 16, 2019. https://bit.ly/2LmZCf9. Accessed July 16, 2019.
  2. 2. Petrylak DP, Balar AV, O'Donnell PH, et al. EV-201: results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors. J Clin Oncol. 2019;37(suppl; abstr LBA4505).
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