First-Line Enfortumab Vedotin Plus Pembrolizumab in Cisplatin-Ineligible Patients With Locally Advanced or Metastatic Urothelial Cancer

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As reported in the Journal of Clinical Oncology by O’Donnell et al, findings in a cohort of the phase Ib/II EV-103/KEYNOTE-869 study showed durable responses with first-line enfortumab vedotin-ejfv plus pembrolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. The study supported the April 2023 accelerated approval of enfortumab vedotin plus pembrolizumab in this setting.

Study Details

In the international trial, 149 eligible patients were randomly assigned to receive enfortumab vedotin at 1.25 mg/kg (maximum dose = 125 mg) on days 1 and 8 of a 3-week cycle and pembrolizumab at 200 mg on day 1 of the 3-week cycle (n = 76) or enfortumab vedotin alone (n = 73). The primary endpoint was confirmed objective response rate on blinded independent central review. Data cutoff was in June 2022. No formal statistical comparisons were made between treatment groups.


A confirmed objective response was observed in 49 patients (64.5%, 95% confidence interval [CI] = 52.7%–75.1%) in the enfortumab vedotin plus pembrolizumab group, including complete response in 8 (10.5%), compared with 33 patients (45.2%, 95% CI = 33.5%–57.3%) in the enfortumab vedotin alone group, including complete response in 3 (4.1%). An additional 17 patients (22.4%) and 25 patients (34.2%) had stable disease. Median duration of response was not reached (95% CI = 10.25 months to not reached) in the combination group, compared with 13.2 months (95% CI = 6.14–15.97 months) in the enfortumab vedotin group; maintained response at 12 months was observed in 65.4% and 56.3% of responders.  

In the combination group, progression-free survival on blinded independent central review at 6 and 12 months was 73.8% and 55.1%; overall survival at 6 and 12 months was 88.2% and 80.7%.


  • Enfortumab vedotin plus pembrolizumab produced an objective response in 64.5% of patients, with complete response in 10.5%.
  • Median duration of response in the combination group was not reached, with 65.4% of responses ongoing at 12 months.

Adverse Events

In the combination group, grade ≥ 3 treatment-related adverse events occurred in 63.2% of patients (47.9% in the enfortumab vedotin group), most commonly maculopapular rash (17.1%), fatigue (9.2%), and neutropenia (9.2%). Enfortumab vedotin treatment–related any-grade adverse events of special interest in the combination group included skin reactions (67.1%) and peripheral neuropathy (60.5%).

Serious treatment-related adverse events occurred in 23.7% of the combination group. Treatment-related adverse events led to discontinuation of enfortumab vedotin only in 25.0% of patients, pembrolizumab only in 22.4%, and both in 5.3%. Death due to a treatment-related adverse event occurred in three patients (3.9%) in the combination group; causes consisted of respiratory failure, pneumonitis, and sepsis.

The investigators concluded: “Enfortumab vedotin plus pembrolizumab showed a high confirmed objective response rate with durable responses as first-line treatment in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. Patients who received enfortumab vedotin monotherapy had a response and safety profile consistent with previous studies. Adverse events for enfortumab vedotin plus pembrolizumab were manageable, with no new safety signals observed.”

Jonathan E. Rosenberg, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute and by Astellas Pharma US; Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc; and Seagen Inc. For full disclosures of the study authors, visit

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®.