FDA grants Padcev with Keytruda accelerated approval for advanced urothelial carcinoma
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The FDA granted accelerated approval to the combination of enfortumab vedotin-ejfv and pembrolizumab as first-line treatment for cisplatin-ineligible adults with locally advanced or metastatic urothelial carcinoma.
The agency based the approval of enfortumab vedotin-ejfv (Padcev; Astellas Pharma, Seagen), an antibody-drug conjugate directed against Nectin-4, with the PD-1 inhibitor pembrolizumab (Keytruda, Merck) on results of the multicohort phase 1B/phase 2 EV-103/KEYNOTE-869 trial.
The trial’s single-arm dose-escalation cohort and cohort A included patients who received enfortumab vedotin-ejfv with pembrolizumab, whereas cohort K included patients randomly assigned to either the combination or enfortumab vedotin-ejfv monotherapy. Patients had never received systemic therapy for locally advanced or metastatic disease and were not eligible for cisplatin-containing chemotherapy.
Results among 121 patients who received the combination showed a confirmed objective response rate by blinded independent central review of 68% (95% CI, 58.7-76), including a 55% partial response rate and 12% complete response rate.
Median duration of response was 22.1 months (range, 1+ to 46.3+) in the combined dose escalation cohort/cohort A and was not reached in cohort K (range, 1 to 24+ months).
The most common adverse events with enfortumab vedotin-ejfv and pembrolizumab, including laboratory abnormalities, consisted of increased glucose (74%), increased aspartate aminotransferase (73%), rash (71%), decreased hemoglobin (69%), increased creatinine (69%), peripheral neuropathy (65%), decreased lymphocytes (64%), fatigue (60%), increased alanine aminotransferase (60%), decreased sodium (60%), increased lipase (59%), decreased albumin (59%), alopecia (52%), decreased phosphate (51%), decreased weight (48%), diarrhea (45%), pruritus (40%), decreased appetite (38%), nausea (36%) and dysgeusia (35%).
The recommended dose of enfortumab vedotin-ejfv as part of the combination is 1.25 mg/kg (maximum 125 mg for patients 100 kg) via IV infusion over 30 minutes on day 1 and day 8 of a 21-day cycle until disease progression or unacceptable toxicity. The recommended pembrolizumab dose after enfortumab vedotin on the same day is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity or for up to 2 years.
“The accelerated approval for the combination of Padcev and pembrolizumab marks an important milestone for the approximately 8,000 to 9,000 patients in the United States with locally advanced or metastatic urothelial cancer who are not eligible for cisplatin-containing chemotherapy,” Ahsan Arozullah, MD, MPH, senior vice president and head of oncology development for Astellas, said in a joint Astellas-Seagen press release. “This patient population now has an additional treatment option to treat advanced bladder cancer at first diagnosis of metastatic disease.”
The combination previously received FDA breakthrough therapy designation and priority review.
The ongoing phase 3 EV-302/KEYNOTE-A39 trial, which is assessing the clinical benefit of the combination among patients with treatment-naive advanced urothelial cancer, is intended to serve as the pivotal confirmatory trial for accelerated approval in the U.S. and as the basis for global registrations, according to the press release.
References:
- FDA grants accelerated approval for Padcev (enfortumab vedotin-ejfv) with Keytruda (pembrolizumab) for first-line treatment of locally advanced or metastatic urothelial cancer (press release). Available at: www.prnewswire.com/news-releases/fda-grants-accelerated-approval-for-padcev-enfortumab-vedotin-ejfv-with-keytruda-pembrolizumab-for-first-line-treatment-of-locally-advanced-or-metastatic-urothelial-cancer-301788866.html. Published April 3, 2023. Accessed April 3, 2023.
- FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma (press release). Available at: www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic. Published April 3, 2023. Accessed April 3, 2023.
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