FDA Approves First Agent to Treat Locally Advanced, Metastatic Urothelial Cancer

Oncology, ONCOLOGY Vol 34 Issue 1, Volume 34, Issue 1

The FDA approved enfortumab vedotin-ejfv (Padcev)-the first drug to treat adult patients with locally advanced or metastatic urothelial cancer who have received prior treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy.

The FDA approved enfortumab vedotin-ejfv (Padcev)-the first drug to treat adult patients with locally advanced or metastatic urothelial cancer who have received prior treatment with a programmed cell death protein 1 (PD-1)/ programmed cell death ligand 1(PD-L1) inhibitor and platinum-containing chemotherapy.1,2

“Typically, for this patient population, there really was not anything that was active (in treating patients), and what we have seen is about 12% of patients have a complete tumor disappearance. Overall, about 40% of patients have what is called a partial response and 84% of patients have some form of tumor reduction,” explained Dr Daniel Petrylak, professor of medicine, medical oncology and urology, and co-leader of Cancer Signaling Networks, at Yale Cancer Center. “So, this is really a remarkable finding. To my knowledge, this is the most active single agent (in treating advanced bladder cancer). It is even more active than drugs they have been using in the earlier setting.”

EV-201 Trial

The FDA based its decision on data from the multicenter, single-arm, phase II pivotal EV-201 trial. This study was designed to evaluate enfortumab vedotin in 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor, including those who were previously treated with platinum-containing chemotherapy (cohort 1) and those who have not received platinum-containing chemotherapy and 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 intravenously on days 1, 8, and 15 of each 28-day cycle.

The primary end point was confirmed overall response rate (ORR) per blinded independent central review, while secondary end points included 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.

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, and a 32% partial response rate. 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 included any case of rash (all grades, 48%; grade ≥3, 12%), any peripheral neuropathy (all grades, 50%; grade ≥3, 3%), and any hyperglycemia (all grades, 11%; grade ≥3, 6%).

Accelerated Approval

The first-in-class antibody-drug conjugate, which is directed against nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer, is approved under the FDA’s Accelerated Approval Program. In this instance, the accelerated approval was based on tumor response rate, the study’s primary end point.

Continued approval of enfortumab vedotin will be contingent upon further evaluation to verify and describe the clinical benefit of the drug in a confirmatory trial. “There are a lot of next steps. This is an exciting drug, and it has a tremendous amount of activity,” Petrylak said. “We are looking to move this up earlier, in the course of disease. There is a trial being done in patients who have had frontline chemotherapy, and we are looking to [add enfortumab vedotin] in the neoadjuvant setting prior to [a patient] having their bladder taken out. And so the thought is that perhaps we will have more activity earlier.” Petrylak added that researchers are also looking to add the agent to other combinations, like checkpoint inhibitors.


1.Seattle Genetics and Astellas announce US FDA grants priority review for enfortumab vedotin Biologics License Application in locally advanced or metastatic urothelial cancer [press release]. Bothell, Washington: Seattle Genetics website; September 16, 2019. https://investor.seattlegenetics.com/press-releases/news-details/2019/Seattle-Genetics-and-Astellas-Announce-US-FDA-Grants-Priority-Review-for-Enfortumab-Vedotin-Biologics-License-Application-in-Locally-Advanced-or-Metastatic-Urothelial-Cancer/default.aspx. Accessed January 10, 2020

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). doi: 10.1200/JCO.2019.37.18_suppl.LBA4505.