FDA Grants Priority Review to Enfortumab Vedotin for Urothelial Cancer

The FDA has granted priority review for 2 supplemental biologics license applications (sBLA) for enfortumab vedotin-ejfv (Padcev) for the treatment of a subset of patients with locally advanced or metastatic urothelial cancer, according to a joint press release by Astellas Pharma, Inc and Seagen, Inc.

Enfortumab vedotin-ejfv, an antibody-drug conjugate, received an accelerated approval in 2019 for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/L1 inhibitor and a platinum-containing chemotherapy before or after surgery for both the locally advanced or metastatic setting. 

The priority review was based on the results of the EV-201 (NCT03219333) and EV-301 trials (NCT03474107). The EV-201 trial supports the conversion of an accelerated approval for enfortumab vedotin to a regular approval for the agent as a monotherapy for locally advanced or metastatic urothelial bladder cancer. The EV-301 study supports the expansion of the indication to include patients with locally advanced or metastatic urothelial cancer after comparing single-agent enfortumab vedotin to chemotherapy in this patient population. Results for both studies were presented during the 2021 Genitourinary Cancer Symposium, and the drug was found to improve outcomes for patients in both studies.

The ongoing phase 2 EV-201 trial enrolled 219 participants and has an estimated completion date of May 2025. The primary outcome was objective response rate (ORR). Secondary outcomes included duration of response (DOR), disease control rate (DCR) at 16 weeks, progression-free survival (PFS), overall survival (OS), and incidents of adverse events (AEs).

During the single-arm study, patients received enfortumab vedotin-ejfv as an infusion on days 1, 9, and 15 every 28 days.

In order to participate, patients must be 18 years old and older and have received prior treatment with a CPI in the locally advanced or metastatic urothelial cancer setting. Additionally, they must also have prior treatment with platinum-containing chemotherapy or be platinum naïve and illegible for treatment with cisplatin. Patients with active central nervous system (CNS) metastases or prior enrollment in an Enfortumab vedotin-ejfv are not eligible to participate.

At the interim analysis, 91 patients were currently enrolled in the study, of which 89 were treated. Patients had a median age of 75 years, with comorbidities including moderate to severe renal impairment. ORR was 52%, including a CR of 20%. Median duration of treatment was 6 months, and median OS and PFS was 5.8 months The Most common AE was alopecia (51%) and peripheral sensory neuropathy (47%). Four treatment-associated deaths were reported.²

EV-301 was a larger study that enrolled 608 participants. The primary outcome of the study of the onging study is OS. Secondary outcomes include PFS, ORR, disease control rate (DCR), AEs, and DOR. During the study, patients were randomized into 1 of 2 arms. In arm 1, patients received Enfortumab vedotin-ejfv on days 1, 8, and 15, of each 28-day cycle. In arm 2 patients received either, docetaxel, vinflunine, or paclitaxel.

In order to participate, patients must be 18 years old or older and has experienced radiographic progression or relapse during or after a PD-1 or PD-L1 inhibitor for locally advanced or metastatic disease. Patients with grade 2 or higher preexisting sensory or motor neuropathy or active CNS metastases are not eligible to participate.

At the interim analysis, 301 patients were assigned to receive Enfortumab vedotin-ejfv and 307 to receive chemotherapy. As of July 2020, 134 deaths had occurred in the Enfortumab vedotin-ejfv group and 167 deaths had occurred in the chemotherapy group. At the interim analysis, the median follow-up was 11.1 months. OS in the experimental group was 12.88 months versus the 8.97 months in the chemotherapy group (HR, 0.70; 95% CI, 0.56-0.89; P =.001). PFS was also long in the experimental group (5.55 months) than the chemotherapy group (3.71 months) (HR, 0.62; 95% CI, 0.51-0.75; P <.001).

The rate of AEs was similar between the two groups. In the experimental group, 93.9% of patients experienced an AE, with 51.4% experiencing an AE of grade 3 or higher. In the chemotherapy group, 91.8% experienced an AE with 49.8% of patients experiencing a grade 3 or higher AE.³

"With our recent regulatory submissions, we intend to provide the highest level of clinical evidence supporting PADCEV use – overall survival data from a randomized phase 3 trial – and expand availability in multiple countries where there is unmet medical need," said Andrew Krivoshik, MD, PhD, senior vice president and oncology therapeutic area head at Astellas said in a press release.

Priority for the 2 enfortumab veditoin BLAs follows an accelerated approval in the United States for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant or adjuvant setting or in a locally advanced or metastatic urothelial cancer setting. The target action date for the applications is August 17, 2021.

_REFERENCES:

_{1. Astellas and Seagen announce U.S. FDA acceptance of two supplemental biologics license applications for PADCEV® (enfortumab vedotin-ejfv) in locally advanced or metastatic urothelial cancer. News release. Seagen. April 19, 2021. Accessed April 19, 2021. https://bit.ly/2RCiU4r.}

_{2.Balar A, McGregor B, Rosenberg J, et al. EV-201 Cohort 2: Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors. J Clin Oncol. 2021;39(suppl 6):394. doi:10.1200/JCO.2021.39.6_suppl.394}

_{3.Powles T, Rosenber J, Sonpavde G, et al. Enfortumab Vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384:1125-1135. doi:10.1056/NEJMoa2035807}