On April 3, the U.S. Food and Drug Administration (FDA) granted accelerated approval to the antibody-drug conjugate enfortumab vedotin-ejfv (Padcev) in combination with the PD-1 inhibitor pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.
EV-103/KEYNOTE-869
Efficacy was evaluated in EV-103/KEYNOTE-869 (ClinicalTrials.gov identifier NCT03288545), a multicohort (dose-escalation cohort, Cohort A, Cohort K) study. The dose escalation cohort and Cohort A were single-arm cohorts treating patients with enfortumab vedotin plus pembrolizumab, while patients in Cohort K were randomly assigned to receive either the combination or enfortumab vedotin alone. Patients had not received prior systemic therapy for locally advanced or metastatic disease and were ineligible for cisplatin-containing chemotherapy. A total of 121 patients received enfortumab vedotin plus pembrolizumab.
The major efficacy outcome measures were objective response rate and duration of response determined by blinded independent central review using Response Evaluation Criteria in Solid Tumors version 1.1. The confirmed objective response rate in 121 patients was 68% (95% confidence interval [CI] = 59%–76%), including 12% with complete responses. The median duration of response for the dose-escalation cohort + Cohort A was 22 months (range = 1+ to 46+ months); duration of response was not reached for Cohort K (range = 1 to 24+months).
The most common adverse reactions occurring in > 20% of patients receiving the combination, 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.
The recommended enfortumab vedotin dose when given with pembrolizumab is 1.25 mg/kg (up to a maximum of 125 mg for patients ≥ 100 kg) administered as an intravenous infusion over 30 minutes on days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity. The recommended pembrolizumab dose, administered 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 up to 24 months.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was granted Priority Review and Breakthrough Therapy designation.
