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FDA grants 2 enfortumab vedotin applications priority review in urothelial carcinoma


The FDA has granted priority review to 2 supplemental Biologics License Applications (sBLAs) for enfortumab vedotin-ejfv (Padcev) for use in patients with locally advanced or metastatic urothelial carcinoma, according to Seagen and Astellas Pharma, the developers of the antibody-drug conjugate.1

One sBLA is intended to convert the drug’s accelerated approval in this setting to a full approval. The current approval is for the treatment of 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 second sBLA seeks to expand this approval to include patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1/L1 inhibitor and are ineligible for cisplatin.

The application for conversion to a full approval is based on results from the confirmatory phase 3 EV-301 trial, which were shared during the 2021 Genitourinary (GU) Cancers Symposium.2,3 In the study, enfortumab vedotin reduced the risk of death by 30% versus chemotherapy in patients with heavily pretreated locally advanced or metastatic urothelial carcinoma.

The sBLA for the expanded indication is based on data from cohort 2 of the phase 2 EV-201 trial,4 in which enfortumab vedotin was administered to cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior anti–PD-1/PD-L1 therapy. The confirmed objective response rate (ORR) in these patients was 52%, including a 20% complete response rate. Responses were observed across all prespecified subgroups, including patients with primary tumor sites in the upper tract (ORR = 61%), with liver metastasis (ORR = 48%), and those who did not respond to prior PD-1/PD-L1 inhibitors (ORR = 48%).

The FDA is scheduled to make a decision on these sBLAs on or before August 17, 2021.

"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, Astellas, stated in a press release.

EV-301 trial

The open-label, randomized EV-301 trial (NCT03474107) included 608 patients with histologically or cytologically confirmed urothelial cancer, including patients with squamous differentiation or mixed cell types, were enrolled in the study and randomized 1:1 with stratification to either the enfortumab vedotin (n = 301) arm or the chemotherapy arm (n = 307).

Eligible patients had radiographic progression or relapsed during or after immune checkpoint inhibition for the treatment of advanced urothelial cancer and had received prior platinum-containing chemotherapy; patients also had an ECOG performance status of 0 or 1. Stratification variables included ECOG performance status (0 or 1), region of the world, and the presence or absence of liver metastasis.

Baseline characteristics were balanced between the 2 arms. The median age was 68 years and more than three-fourths of patients were male. Only 14% of patients were from the United States, 60% had an ECOG performance status of 1, two-thirds had a Bellmunt risk score of 0 or 1, 31% had liver metastases, and 87% had 1 or 2 prior lines of therapy. In the enfortumab vedotin arm, 20% responded to prior immune checkpoint inhibition and 16% responded in the chemotherapy arm.

The median OS with enfortumab vedotin was 12.88 months versus 8.97 months with chemotherapy, which translated to a 30% reduction in the risk of death (HR, 0.70; = .00142). Subgroup analyses for OS favored the enfortumab vedotin arm for all groups excepts female patients (HR, 1.17).

Median PFS with enfortumab vedotin was 5.55 months versus 3.71 months with chemotherapy (HR, 0.62; <.00001).

Confirmed ORR in the enfortumab vedotin arm was 40.6%, which included CRs in 4.9%, and the disease control rate (DCR) was 71.9%. In the chemotherapy arm, the ORR was 17.9% with CRs in 2.7%, and a DCR of 53.4% (< .001).

Treatment-related adverse event (TRAE) rates were similar between the 2 arms, with any-TRAE rates of 94% in the investigational arm and 92% in the control arm, and grade ≥3 TRAE rates of 51% and 50%, respectively. Serious TRAEs were reported in 23% of patients in each arm and TRAEs led to treatment discontinuation in 14% of patients in the enfortumab vedotin arm and 11% in the chemotherapy arm.


The single-arm, phase 2 EV-201 trial examined enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer who had 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).

Data for cohort 1 of the trial (n = 128) supported the accelerated approval of enfortumab vedotin. In these patients, the antibody-drug conjugate elicited an ORR of 44%, which included a 12% CR rate, and a 32% partial response rate.

The results for cohort 2, on which the sBLA for expanded is based, included 89 patients. Baseline characteristics showed that patients were a median age of 75, male (74%), and 15% were obese. Two-thirds (67%) of patients exhibited a moderate decrease in kidney function. Looking at the primary site of tumor, 43% had a tumor in the upper tract.

The median time to response was 1.81 months with some patients who have durable responses that extend beyond a year or more. Median DOR was 10.9 months. At a median follow-up of 13.4 months, the median PFS was 5.8 months and median OS was 14.7 months.

In terms of safety, any grade overall TRAEs occurred in 97% of patients and grade 3 or higher TRAEs occurred in 55% of patients. TRAEs led to discontinuations in 16% of patients, and peripheral sensory neuropathy was the most common in 4%. There were 4 deaths that were considered to be treatment related by the investigator and these were a result of acute kidney injury, metabolic acidosis, multiple organ dysfunction syndrome, and pneumonitis.


1. Seagen and Astellas Announce Submission of Two Supplemental Biologics License Applications to the U.S. FDA for PADCEV® (enfortumab vedotin-ejfv) in Locally Advanced or Metastatic Urothelial Cancer. Published April 19, 2021. Accessed April 19, 2021. https://prn.to/3ed3VWh. 2. Powles T, Rosenberg JE, Sonpavde G, et al. Primary results of EV-301: A phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2021;39(suppl 6):393. doi:10.1200/JCO.2021.39.6_suppl.393

3. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. Published online February 12, 2021. N Engl J Med. doi:10.1056/NEJMoa2035807

4. Balar AV, McGregor BA, Rosenberg JE, 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

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