On December 15, 2023, the Food and Drug Administration (FDA) approved enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial cancer. The FDA previously granted accelerated approval to this combination for patients with locally advanced or metastatic urothelial cancer who are ineligible for cisplatin-containing chemotherapy.
EV-302/KN-A39
Efficacy of the combination was evaluated in EV-302/KN-A39 (ClinicalTrials.gov identifier NCT04223856), an open-label, randomized trial of 886 patients with locally advanced or metastatic urothelial cancer who had received no prior systemic therapy for advanced disease. Patients were randomly assigned 1:1 to receive either enfortumab vedotin-ejfv with pembrolizumab or platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin). Random assignment was stratified by cisplatin eligibility, PD-L1 expression, and presence of liver metastases.
The major efficacy outcome measures were overall survival and progression-free survival as assessed by blinded independent central review. Statistically significant improvements in both overall survival and progression-free survival were demonstrated for enfortumab vedotin-ejfv with pembrolizumab compared with platinum-based chemotherapy. Median overall survival was 31.5 months (95% confidence interval [CI] = 25.4 months to not estimable) for patients who received enfortumab vedotin-ejfv with pembrolizumab and 16.1 months (95% CI = 13.9–18.3 months) for those who received platinum-based chemotherapy (hazard ratio [HR] = 0.47, 95% CI = 0.38–0.58, P < .0001). Median progression-free survival was 12.5 months (95% CI = 10.4–16.6 months) for patients who received enfortumab vedotin-ejfv with pembrolizumab and 6.3 months (95% CI = 6.2–6.5 months) for those who received platinum-based chemotherapy (HR = 0.45, 95% CI = 0.38–0.54, P < .0001).
The most common (reported in ≥ 20%) adverse reactions, including laboratory abnormalities, in 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.
Dosing and Regulatory Details
The recommended enfortumab vedotin-ejfv 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 when given with enfortumab vedotin-ejfv is 200 mg administered as an intravenous infusion every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or 2 years of therapy.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence which provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration and Health Canada.
This 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 the FDA’s assessment. The FDA approved this application 5 months ahead of the FDA goal date. This application was granted Priority Review and Breakthrough Therapy designation.
