On December 15, 2023, the U.S. Food and Drug Administration (FDA) approved enfortumab vedotin-ejfv (Padcev®) in combination with pembrolizumab (Keytruda®) for patients with locally advanced or metastatic urothelial cancer (la/mUC). FDA previously granted the combination accelerated approval for patients with la/mUC who are ineligible for cisplatin-containing chemotherapy.

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Efficacy was evaluated in EV-302/KN-A39 (NCT04223856), an open-label, randomized trial of 886 patients with la/mUC and no prior systemic therapy for advanced disease. Patients were randomized 1:1 to receive either enfortumab vedotin-ejfv with pembrolizumab or platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin). Randomization was stratified by cisplatin eligibility, PD-L1 expression, and presence of liver metastases.

The major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS) as assessed by blinded independent central review. Researchers observed statistically significant improvements in both measures for patients receiving enfortumab vedotin-ejfv with pembrolizumab compared with platinum-based chemotherapy. Median OS was 31.5 months (95% CI = 25.4, not estimable) for patients who received enfortumab vedotin-ejfv with pembrolizumab and 16.1 months (95% CI = 13.9, 18.3) for those who received platinum-based chemotherapy (HR = 0.47; 95% CI = 0.38, 0.58; p < 0.0001). Median PFS was 12.5 months (95% CI = 10.4, 16.6) for patients who received enfortumab vedotin-ejfv with pembrolizumab and 6.3 months (95% CI = 6.2, 6.5) for those who received platinum-based chemotherapy (HR = 0.45; 95% CI = 0.38, 0.54; p < 0.0001).

The most common adverse reactions, including laboratory abnormalities, reported in at least 20% of patients receiving enfortumab vedotin-ejfv with pembrolizumab were increased aspartate aminotransferase, increased creatinine, rash, increased glucose, peripheral neuropathy, increased lipase, decreased lymphocytes, increased alanine aminotransferase, decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, diarrhea, alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection, and decreased platelets.

The recommended enfortumab vedotin-ejfv dose when given with pembrolizumab is 1.25 mg/kg, up to a maximum of 125 mg for patients weighing 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 when given with enfortumab vedotin-ejfv is 200 mg every three weeks or 400 mg every six weeks, administered as an IV infusion, for up to two years or until patients experience disease progression or unacceptable toxicity.

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

The review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence (OCE). Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. FDA collaborated with the Australian Therapeutic Goods Administration and Health Canada for the review.

The review used the Real-Time Oncology Review pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment. The agency approved the application five months ahead of its FDA goal date. The application was also 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 applications for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.