FDA Grants Priority Review for Pembrolizumab Combo in Bladder Cancer

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The FDA accepts the supplemental biologics license application for enfortumab vedotin-ejfv and pembrolizumab in patients with urothelial cancer following supporting data from the phase 3 KEYNOTE-A39 trial.

Supporting data for the sBLA came from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), in which the pembrolizumab combination significantly extended the primary endpoints of overall survival (OS) and progression-free survival (PFS) in patients with locally advanced or metastatic urothelial cancercompared withstandard platinum-containing chemotherapy.

Supporting data for the sBLA came from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), in which the pembrolizumab combination significantly extended the primary endpoints of overall survival (OS) and progression-free survival (PFS) in patients with locally advanced or metastatic urothelial cancercompared withstandard platinum-containing chemotherapy.

The FDA has given priority review to a supplemental biologics license application (sBLA) for enfortumab vedotin-ejfv (Padcev) with pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial cancer, according to a press release from Astellas Pharma Inc.1

Supporting data for the sBLA came from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), in which the pembrolizumab combination significantly extended the primary endpoints of overall survival (OS) and progression-free survival (PFS) in patients with locally advanced or metastatic urothelial cancer compared with standard platinum-containing chemotherapy.

At a median follow-up of 17.2 months, the median PFS in the combination arm was 12.5 months compared with 6.3 months in the chemotherapy arm (HR 0.45; 95% CI, 0.38-0.54; P<0.00001).2 Median OS in the combination arm was 31.5 months compared with 16.1 months in the chemotherapy arm (HR 0.47; 95% CI, 0.38-0.58; P<0.00001). The secondary end points of the trial were overall response rate (ORR) and safety. The ORR in the combination arm was 67.7% and 44.4% in the chemotherapy arm (P<0.00001).

"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 [NCT03288545] to standard approval for all [patients with] first-line locally advanced or metastatic urothelial cancer, expanding the indication to cisplatin-eligible patients,” said Ahsan Arozullah, MD, MPH, senior vice president and head of oncology development at Astellas Pharma Inc.1 “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."

This global, open-label, randomized phase 3 KEYNOTE-A39 study randomly assigned886 previously untreated patients with locally advanced or metastatic urothelial cancer who were eligible for cisplatin- or carboplatin-containing chemotherapy. In the experimental arm, patients received 200 mg of intravenous pembrolizumab every 3 weeks plus 125 mg/m2 of intravenous enfortumab vedotin on days 1 and 8 of each 3-week cycle. In the chemotherapy arm, patients received intravenous gemcitabine on day 1 and 8 of each 3-week cycle plus intravenous carboplatin or cisplatin every 3 weeks.2

The most common grade 3 or higher treatment-related adverse effects (TRAEs) in the combination arm were maculopapular rash (7.7%), hyperglycemia (5.0%), and neutropenia (4.8%). The most common high-grade TRAEs in the chemotherapy arm were anemia (31.4%), neutropenia (30.0%), and thrombocytopenia (19.4%). TRAEs at grade 3 or higher that were of interest to researchers included skin reactions (15.5%), peripheral neuropathy (6.8%), and hyperglycemia (6.1%) in the combination arm and severe skin reactions (11.8%) in the chemotherapy arm.

The FDA is said to make a decision on approving the drug combination by May 9, 2024 using the Real-Time Oncology Review (RTOR) program, which aims to use a more efficient review process to help make safe and effective treatments available to patients as quickly as possible. If approved, this combination would be the first to combine an antibody-drug conjugate with a PD-1 inhibitor treatment as an alternative to chemotherapy in this patient population. It will also be the first treatment option for patients who are eligible or ineligible to receive cisplatin.

References

  1. FDA grants priority review for supplemental biologics license application (sBLA) of PADCEV® (enfortumabvedotin-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/39yvtduf
  2. Powles TB, Perez Valderrama B, Gupta S, et al. LBA6 EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumabvedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Ann Oncol. 2023;34:S1340. doi:10.1016/j.annonc.2023.10.106
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