FDA Grants Priority Review to Enfortumab Vedotin/Pembrolizumab in mUC


Positive data from the phase 3 EV-302 trial of enfortumab vedotin with pembrolizumab in locally advanced or metastatic urothelial cancer have shifted the landscape.

  • A supplemental biologics license application (sBLA) for enfortumab vedotin-ejfv (Padcev) with pembrolizumab (Keytruda) in locally advanced or metastatic urothelial cancer (mUC) has been accepted by the FDA.
  • Findings from the phase 3 EV-302 trial (NCT04223856) support this regulatory decision.
  • The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date for May 9, 2024.

The FDA has accepted for priority review a sBLA for the combination of enfortumab vedotin and pembrolizumab for the treatment of adult patients with locally advanced or mUC.1

Findings from the phase 3 EV-302 trial support this regulatory decision as the combination led to improved rates of overall survival (OS) and progression-free survival (PFS) among patients with previously untreated locally advanced mUC compared with platinum-containing chemotherapy. For safety, no new safety issues were identified.

A PDUFA target action date has been set for May 9, 2024 by the FDA. If granted approval, this combination would be the first treatment option for cisplatin-eligible and -ineligible patients.

“The findings of the trial are exceptionally positive. The overall survival shows a 50% reduction in the risk of death. We've never really seen anything like that in bladder cancer before. Progression-free survival was also a 50% reduction in the risk of progression,” Thomas Powles, MD, MBBS, MRCP, professor of genitourinary oncology at Queen Mary University of London, and director, Barts Cancer Center, previously told Targeted OncologyTM.

Bladder Image: © magicmine stock.adobe.com

Bladder Image: © magicmine stock.adobe.com

"We look forward to the FDA's review of this application, which, if approved, will convert the accelerated approval of the combination based on results from the EV-103 study to standard approval for all first-line locally advanced or metastatic urothelial cancer patients, expanding the indication to cisplatin eligible patients. These patients have a critical need for innovative new therapies, as chemotherapy has been the standard of care for over 30 years. We are committed to delivering on our goal of helping patients with advanced urothelial cancer live longer," said Ahsan Arozullah, MD, MPH, senior vice president, head of oncology development, Astellas, in a press release.1

EV-302, an open-label, randomized, controlled, phase 3 study, included 886 patients with previously untreated locally advanced or mUC. Patients were required to have an ECOG performance status of ≤2 and be eligible for cisplatin- or carboplatin-containing chemotherapy. Once enrolled, patients were randomized to receive standard of care chemotherapy for a maximum of 6 cycles (n = 444) or enfortumab vedotin at a dose of 1.25 mg/kg via intravenous (IV) infusion on days 1 and 8 and pembrolizumab (200 mg IV) on day 1 of 3-week cycles (n = 442). The maximum number of pembrolizumab cycles allowed was 35 and there was no maximum number of cycles for enfortumab vedotin.

Across both arms of the study, the median age was 69 years. About three-fourths of patients were male, most were White (69.7% in the combination arm and 65.3% in the control arm), and about 97% of patients in both arms had an ECOG performance status of 0 or 1.2

The co-primary end points were OS and PFS (per blinded independent central review).

Additional findings showed that at a median follow-up of 17.2 months, the combination of enfortumab vedotin plus pembrolizumab reduced the risk of death by 53% vs chemotherapy. In the combination arm, the median OS was 31.5 months (95% CI, 25.4-not reached) vs 16.1 months (95% CI, 13.9-18.3) with chemotherapy (HR, 0.47; 95% CI, 0.38-0.58; P <.00001). Regardless of whether patients in the control arm received cisplatin or carboplatin, the OS benefit was seen.

The median PFS was 12.5 months (95% CI, 10.4-16.6) with the combination vs 6.3 months (95% CI, 6.2-6.5) with chemotherapy. This translated to a 55% reduction in the risk of disease progression or death (HR, 0.45; 95% CI, 0.38-0.54; P <.00001), and the PFS benefit was maintained across all pre-specified subgroups, including those defined by cisplatin eligibility, PD-L1 status, and visceral metastases.

In the combination arm, the confirmed objective response rate (ORR) was 67.7% vs 44.4% in the chemotherapy arm, and the ORR among patients given enfortumab vedotin and pembrolizumab consisted of a complete response (CR) rate of 29.1% and a partial response (PR) rate of 38.7%. In this arm, the stable disease (SD) rate was 18.8% and the progressive disease (PD) rate was 8.7%. This compared with an ORR in the chemotherapy arm that consisted of a CR rate of 12.5%, PR rate of 32%, SD rate of 33.8%, and PD rate 13.6%.

Among patients given the combination vs control, 56% and 70% of patients experienced grade ≥3 treatment-related AEs (TRAEs), and serious TRAEs occurred in 27.7% vs 19.6% of the 2 arms, respectively.

1. FDA grants priority review for supplemental biologics license application (sBLA) of PADCEV® (enfortumab vedotin-ejfv) with KEYTRUDA® (pembrolizumab) for first-line treatment of advanced bladder cancer. News release. Astellas Pharma Inc. November 30, 2023. Accessed December 1, 2023. https://tinyurl.com/22kecyr3
2. Powles TB, Perez Valderrama B, Gupta S, et al. EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA6.
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