On July 9, 2021, the U.S. Food and Drug Administration (FDA) approved enfortumab vedotin-ejfv (Padcev), a Nectin-4 targeted antibody and microtubule inhibitor conjugate, for the treatment of adult patients with previously treated locally advanced or metastatic urothelial carcinoma. These treatments include PD-1 or PD-L1 inhibitors and platinum-based chemotherapy, or for individuals who do not qualify for cisplatin-based chemotherapy and have received one or more prior treatments.
The FDA accelerated the approval of enfortumab wedotin-ejfv in December 2019 for patients with locally advanced or metastatic urothelial cancer who received PD-1 or PD-L1 inhibitors and platinum-containing chemotherapy under neoadjuvant/adjuvant, locally advanced or metastatic conditions.
EV-301
The approval is partly based on the EV-301 trial (ClinicalTrials.gov identifier NCT03474107), an open-label, randomized, multicenter study designed to confirm the clinical benefit granted accelerated approval in 2019. This trial enrolled 608 patients with locally advanced or metastatic urothelial carcinoma who had received prior PD-1 or PD-L1 inhibitors and platinum-based chemotherapy. Patients were randomized 1:1 to receive enfortumab vedotin-ejfv at 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle, or investigator-selective single-agent chemotherapy (docetaxel, paclitaxel, or vinflunine).
The main efficacy endpoint is the total survival, and the key secondary efficacy endpoints are the progress-free survival and the total response rate. The researchers used the solid tumor version 1.1 response evaluation criteria for evaluation.
The median overall survival for patients receiving enfortumab vedotin-ejfv was 12.9 months (95% confidence interval [CI] = 10.6–15.2), compared to 9.0 months (95% CI = 8.1–10.7) for patients receiving chemotherapy (hazard ratio [HR] = 0.70, 95% CI = 0.56–0.89, P = .0014). The median progression-free survival was 5.6 months (95% CI = 5.3–5.8) and 3.7 months (95% CI = 3.5–3.9), respectively (HR = 0.62, 95% CI = 0.51–0.75, P < .0001). The overall response rates were 40.6% (95% CI = 34.9%–46.5%) and 17.9% (95% CI = 13.7%–22.8%), respectively (P < .0001).
EV-201
The efficacy of cisplatin-based chemotherapy was evaluated in cohort 2 of EV-201 (ClinicalTrials.gov identifier NCT03219333), a single-arm, multi-cohort, international trial involving 89 patients with locally advanced or metastatic urothelial carcinoma who had previously received PD-1 or PD-L1 inhibitors and were ineligible for cisplatin-based chemotherapy. The primary efficacy endpoint was confirmed overall response rate, assessed by blinded independent central review, and the key secondary efficacy endpoint was duration of response.
The confirmed overall reaction rate was 51% (95% CI =39.8%-61.3%), of which 22% were complete reactions, and the median reaction duration was 13.8 months (95% CI = 6.4–unpredictable).
Adverse events
The most common adverse reactions, including laboratory abnormalities (≥20%), are skin rash, elevated aspartic acid transaminase, elevated blood sugar, elevated creatinine, fatigue, peripheral neuropathy, lymphopenia, hair loss, decreased appetite, decreased hemoglobin, diarrhea, sodium reduction, nausea, itching, and phosphate reduction., Taste impairment, increased alanine transaminase, anemia, decreased albumin, neutropenia, increased urate, increased lipase, thrombocytopenia, weight loss and dry skin.
The prescribing information in the United States has added black－framed warnings for severe skin reactions, including Stephen-Johnson syndrome and toxic epidermal necrolysis, as well as pneumonia warnings.
Dosage and route of approval
The recommended dose of enfortumab wedotin-ejfv is 1.25 mg/kg (the maximum dose is 125 mg) and is given intravenously for 30 minutes on days 1, 8, and 15 of the 28-day cycle until the disease progresses or the toxicity is unacceptable.
This review was conducted under the Orbis Program, an initiative of the FDA's Center of Excellence in Oncology. The Orbis program project provides a framework for simultaneous submission and review of oncology drugs among international partners. In this review, the FDA cooperated with Health Canada and the Australian Therapeutic Goods Administration.
This review used the real-time oncology review pilot program, which simplifies data submission before submitting the entire clinical application, as well as evaluation assistance, which applicants voluntarily submit to facilitate the FDA's evaluation. The FDA approved the application approximately 5 weeks before the target date set.
The application received designated priority review and breakthrough therapy.
