FDA Grants Regular Approval to Enfortumab Vedotin-ejfv for Locally Advanced or Metastatic Urothelial Cancer

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On July 9, 2021, the U.S. Food and Drug Administration (FDA) approved enfortumab vedotin-ejfv (Padcev), a Nectin-4–directed antibody and microtubule inhibitor conjugate, for adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy, or who are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.

The FDA granted accelerated approval to enfortumab vedotin-ejfv in December 2019 for patients with locally advanced or metastatic urothelial cancer who have received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.


Approval was partially based on the EV-301 trial ( identifier NCT03474107), an open-label, randomized, multicenter study required to confirm the clinical benefit of the 2019 accelerated approval. This trial enrolled 608 patients with locally advanced or metastatic urothelial cancer who received a prior PD-1 or PD-L1 inhibitor and platinum-based chemotherapy. Patients were randomly assigned 1:1 to receive either enfortumab vedotin-ejfv at 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle, or investigator’s choice of single-agent chemotherapy (docetaxel, paclitaxel, or vinflunine).

The primary efficacy endpoint was overall survival, with key secondary efficacy endpoints of progression-free survival and overall response rate, assessed by the investigators using Response Evaluation Criteria in Solid Tumors version 1.1.

Median overall survival was 12.9 months (95% confidence interval [CI] = 10.6­–15.2) for patients receiving enfortumab vedotin-ejfv vs 9.0 months (95% CI = 8.1–10.7) for those receiving chemotherapy (hazard ratio [HR] = 0.70, 95% CI = 0.56–0.89, P = .0014). Median progression-free survival was 5.6 months (95% CI = 5.3–5.8) compared with 3.7 months (95% CI = 3.5–3.9), respectively (HR = 0.62, 95% CI = 0.51–0.75, P < .0001). The overall response rate was 40.6% (95% CI = 34.9%–46.5%) vs 17.9% (95% CI = 13.7%–22.8%), respectively (P < .0001).


Efficacy for patients ineligible for cisplatin-containing chemotherapy was evaluated in cohort 2 of EV-201 ( identifier NCT03219333), a single-arm, multicohort, international trial in 89 patients with locally advanced or metastatic urothelial cancer who received a prior PD-1 or PD-L1 inhibitor and were ineligible for cisplatin-containing chemotherapy. The primary efficacy endpoint was confirmed overall response rate, assessed by blinded independent central review, and the key secondary efficacy endpoint was response duration.

The confirmed overall response rate was 51% (95% CI = 39.8%–61.3%), including 22% with complete responses, and the median response duration was 13.8 months (95% CI = 6.4–not estimable).

Adverse Events

The most common adverse reactions, including laboratory abnormalities (≥ 20%) were rash, increased aspartate aminotransferase, increased glucose, increased creatinine, fatigue, peripheral neuropathy, decreased lymphocytes, alopecia, decreased appetite, decreased hemoglobin, diarrhea, decreased sodium, nausea, pruritus, decreased phosphate, dysgeusia, increased alanine aminotransferase, anemia, decreased albumin, decreased neutrophils, increased urate, increased lipase, decreased platelets, weight loss, and dry skin.

A boxed warning for serious skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, and a warning for pneumonitis were added to the U.S. prescribing information.

Dosing and Approval Pathway

The recommended dose of enfortumab vedotin-ejfv is 1.25 mg/kg (up to a maximum dose of 125 mg) administered as an intravenous infusion over 30 minutes on days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with Health Canada and Australia’s Therapeutic Goods Administration.

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 approximately 5 weeks ahead of the FDA goal date.

This application was granted Priority Review and Breakthrough Therapy designation.


The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.