FDA Grants Accelerated Approval to Enfortumab Vedotin Plus Pembrolizumab for Locally Advanced or Metastatic Urothelial Cancer


A doublet regimen of enfortumab vedotin and pembrolizumab has received accelerated approval for cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer.

The FDA granted accelerated approval to the doublet enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) for the treatment of patients with locally advanced or metastatic urothelial cancer who are not eligible to receive chemotherapy containing cisplatin.1

The approval was supported by data from the phase 1b/2, multicenter, open-label EV-103/KEYNOTE-869 (NCT03288545) study, in which the combination therapy elicited a confirmed objective response rate (n = 121) of 68% (95% CI, 59%-76%) across 3 cohorts of patients. The complete response rate was 12%. In the dose-escalation cohort and cohort A, the median duration of response was 22 months (range, 1-46). In cohort K, the median duration of response was not reached (range, 1-24).1

“The accelerated approval for the combination of [enfortumab vedotin] and pembrolizumab marks an important milestone for the approximately 8000 to 9000 patients in the United States with locally advanced or metastatic urothelial cancer who are not eligible for cisplatin-containing chemotherapy,” Ahsan Arozullah, MD, MPH, senior vice president and head of Oncology Development at Astellas, stated in a news release.2 “This patient population now has an additional treatment option to treat advanced bladder cancer at first diagnosis of metastatic disease.”

EV-103/KEYNOTE-869 was a multicohort trial. In the dose-escalation cohort and cohort A, patients were assigned to treatment with the combination, whereas, in cohort K, patients were randomly assigned to either the combination or enfortumab vedotin alone. To be eligible for the trial, patients could not have received systemic therapy for locally advanced or metastatic disease. Patients also needed to be ineligible for cisplatin-containing therapy.

The recommended dose for enfortumab vedotin is 1.25 mg/kg given as an intravenous injection, across a 30-minute span, on days 1, 8, and 15 of a 28-day treatment cycle. Pembrolizumab should be administered after enfortumab vedotin on the same day and should be given at a dose of 200 mg every 3 weeks of 400 mg every 6 weeks.1,3

Of note, the prescribing label for enfortumab vedotin has a boxed warning for skin reactions, and lists warnings for hyperglycemia and diabetic ketoacidosis, pneumonitis, peripheral neuropathy, ocular disorders, infusion site extravasations, and embryo-fetal toxicity.3

Pembrolizumab is associated with immune-mediated adverse events (AEs), infusions-related reactions, and complications related to allogeneic hematopoietic stem cell transplantation.

Overall, the most common AEs in the trial included increased glucose (74%), increased aspartate aminotransferase (73%), rash (71%), hemoglobin decreased (69%), creatinine increased (69%), peripheral neuropathy (65%), lymphocytes decreased (64%), fatigue (60%), alanine aminotransferase increased (60%), sodium decreased (60%), lipase increased (59%), albumin decreased (59%), alopecia (52%), phosphate decreased (51%), decreased weight (48%), diarrhea (45%), pruritus (40%), decreased appetite (38%), nausea (36%), dysgeusia (35%), potassium decreased (35%), neutrophils decreased (32%), urinary tract infection (30%), constipation (27%), potassium increased (27%), calcium increased (27%), peripheral edema (26%), dry eye (25%), dizziness (23%), arthralgia (23%), and dry skin (21%).

Full approval will be contingent on the results of the phase 3 EV-302 trial (NCT04223856).


  1. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. FDA. April 3, 2023. Accessed April 3, 2023. https://www.fda.gov/drugs/
  2. FDA grants accelerated approval for Padcev (enfortumab vedotin-ejfv) with Keytruda (pembrolizumab) for first-line treatment of locally advanced or metastatic urothelial cancer. News release. Astellas Pharma Inc. April 3, 2023. Accessed April 3, 2023. https://prn.to/42ZQTUO
  3. Padcev. Prescribing information. Astellas Pharma Inc; 2023. Accessed April 3, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761137s018.pdf
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