The FDA has granted accelerated approval to enfortumab vedotin-ejfv (Padcev®, Astellas Pharma) with pembrolizumab (Keytruda®, Merck) for treatment of locally advanced or metastatic urothelial carcinoma, specifically for patients who are ineligible for cisplatin-containing chemotherapy.
"Both enfortumab vedotin and pembrolizumab are effective monotherapy treatments in patients with locally advanced or metastatic urothelial carcinoma," began Christopher Hoimes, Associate Professor of Medicine at the Duke Cancer Institute, and colleagues, in their publication of the EV-103/KEYNOTE-869 trial (NCT03288545), on which approval was based. "Preclinical studies of vedotin antibody–drug conjugates (ADCs), including enfortumab vedotin, show that these ADCs induce hallmarks of immunogenic cell death, including the release of damage-associated molecular patterns. . . Thus, combining enfortumab vedotin with pembrolizumab may enhance antitumor activity versus either agent alone on the basis of their distinct and complementary engagement of the immune system."
Safety and efficacy were evaluated in the phase 1/2, open-label, multicohort trial in which patients were randomized into a dose-escalation cohort, Cohort A, or Cohort K. Those who were randomized in the dose-escalation cohort and Cohort A, the single-arm cohorts, were treated with the combination of enfortumab vedotin-ejfv plus pembrolizumab, while those randomized in Cohort K were treated with either the combination or enfortumab vedotin-ejfv by itself. Eligibility requirements specified that patients had not received prior systemic therapy for locally advanced or metastatic disease and were ineligible for cisplatin-containing chemotherapy.
The primary end points measured were objective response rate and duration of response as determined by blinded independent central review using RECIST v1.1. Of the 121 patients who received enfortumab vedotin-ejfv plus pembrolizumab, the objective response rate was seen at 68%, 12% of which were complete responses. Duration of response in the dose-escalation cohort and Cohort A was a median of 22 months, and Cohort K's median duration of response was not reached.
The most common adverse events in >20% of patients, including laboratory abnormalities, were increased glucose, increased aspartate aminotransferase, rash, decreased hemoglobin, increased creatinine, peripheral neuropathy, decreased lymphocytes, fatigue, increased alanine aminotransferase, decreased sodium, increased lipase, decreased albumin, alopecia, decreased phosphate, decreased weight, diarrhea, pruritus, decreased appetite, nausea, dysgeusia, decreased potassium, decreased neutrophils, urinary tract infection, constipation, increased potassium, increased calcium, peripheral edema, dry eye, dizziness, arthralgia, and dry skin.
"On the basis of data from these EV-103 cohorts, enfortumab vedotin plus pembrolizumab could provide a highly active and durable first-line platinum-free option for patients whose disease may not be suitable for treatment with a cisplatin-based chemotherapy, pending prospective validation in randomized studies," concluded Dr. Hoimes and colleagues in their report.
The recommended dosage of enfortumab vedotin-ejfv is 1.25 mg/kg, with a maximum of 125 mg for patients ≥100 kg, administered intravenously over 30 minutes on Days 1 and 8 of a 21-day cycle. Pembrolizumab should be administered after enfortumab vedotin-ejfv on the same day at 200 mg every three weeks or 400 mg every six weeks until disease progression, unacceptable toxicity, or up to 24 months.
For More Information
Hoimes CJ, Flaig TW, Milowsky MI, et al (2023). Enfortumab vedotin plus pembrolizumab in previously untreated advanced urothelial cancer. J Clin Oncol, 41(1):22-31. DOI:10.1200/JCO.22.01643
Padcev® (enfortumab vedotin) prescribing information (2023). Astellas Pharma. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761137s018.pdf
Keytruda® (pembrolizumab) prescribing information (2023). Merck. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125514s136.pdf
Clinicaltrials.gov (2023). A study of enfortumab vedotin alone or with other therapies for treatment of urothelial cancer (EV-103). NLM identifier: NCT03288545.
US Food and Drug Administration (2023). FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic
Image credit: CoRus13. Licensed under CC0 1.0.
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