On April 3, 2023, the U.S. Food and Drug Administration (FDA) granted accelerated approval to enfortumab vedotin-ejfv (Padcev®) with pembrolizumab (Keytruda®) for patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.

FDA Grants Accelerated Approval to Enfortumab Vedotin-Ejfv With Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma

Efficacy was evaluated in EV-103/KEYNOTE-869 (NCT03288545), a multicohort (dose-escalation cohort, cohort A, cohort K) study. The dose-escalation cohort and cohort A were single-arm cohorts in which patients received enfortumab vedotin-ejfv plus pembrolizumab. Patients in cohort K were randomized to receive either the combination or enfortumab vedotin-ejfv alone. Across all of the reported cohorts, none of the patients received prior systemic therapy for locally advanced or metastatic disease and all were ineligible for cisplatin-containing chemotherapy. A total of 121 patients received enfortumab vedotin-ejfv plus pembrolizumab.

The study’s major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR), as determined by blinded independent central review using RECIST v1.1. The confirmed ORR in the 121 patients receiving the study combination was 68% (95% CI = 59, 76), of which 12% were complete responses. The median DOR for the dose-escalation cohort and cohort A was 22 months (range = 1–46+) and for cohort K it was not reached (range = 1–24+). 

The most common adverse reactions reported in more than 20% of patients treated with enfortumab vedotin-ejfv plus pembrolizumab, including laboratory abnormalities, were increased alanine aminotransferase, aspartate aminotransferase, calcium, creatinine, glucose, lipase, and potassium; decreased albumin, appetite, hemoglobin, lymphocytes, neutrophils, phosphate, potassium, and weight; and alopecia, arthralgia, constipation, diarrhea, dry eye, dry skin, dizziness, dysgeusia, edema, fatigue, rash, peripheral neuropathy, pruritus, nausea, and urinary tract infection.  

The recommended enfortumab vedotin-ejfv dose when given with pembrolizumab is 1.25 mg/kg (up to a maximum of 125 mg for patients at least 100 kg) administered as an IV infusion over 30 minutes on days 1 and 8 of a 21-day cycle until patients experience disease progression or unacceptable toxicity. The recommended pembrolizumab dose, administered after enfortumab vedotin on the same day, is 200 mg every three weeks or 400 mg every six weeks for up to 24 months or until patients experience disease progression or unacceptable toxicity.

View the full prescribing information for enfortumab vedotin-ejfv and pembrolizumab.

The review used the Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment. 

The application was granted priority review and breakthrough designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.

For assistance with single-patient investigational new drug applications, contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.