Enfortumab Vedotin in Platinum- and Anti–PD-1/L1–Pretreated Urothelial Carcinoma


Key Points

  • Objective response was observed in 44% of patients.
  • Good response rates were observed in patients with poor prognostic features, including liver metastases and receipt of three or more prior therapies for advanced disease.

In the phase II EV-201 trial reported in the Journal of Clinical Oncology, Rosenberg et al found the antibody-drug conjugate enfortumab vedotin showed high activity in patients with metastatic urothelial carcinoma who had previously received platinum-based therapy and anti–programmed cell death protein 1 or programmed cell death ligand 1 (PD-1/L1) therapy.

According to the investigators, enfortumab vedotin is the first antibody-drug conjugate targeting Nectin-4, a protein coding gene, in clinical development. Nectin-4 is highly expressed in urothelial carcinoma.

Study Details

The current report provides findings in cohort 1 of the trial; enrollment is ongoing in cohort 2, which includes patients treated with only prior anti–PD-1/L1 therapy.

In the study, 125 evaluable patients with metastatic disease from 51 sites in the United States and Japan were enrolled between October 2017 and July 2018. Patients were treated with enfortumab vedotin 1.25 mg/kg given intravenously on days 1, 8, and 15 of 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or investigator decision.

The primary endpoint was objective response rate per on RECISTv1.1 criteria on blinded independent central review.

Overall, 90% of patients had visceral metastases, with 40% having liver metastases. Patients had received a median of three systemic therapies for locally advanced or metastatic disease; 80% had no response to prior anti–PD-1/L1 treatment. All 120 patients with adequate tissue for testing had tumor biopsies positive for Nectin-4 expression. 

Response Rates

Median follow-up was 10.2 months.

Objective response was observed in 55 patients (44%), with complete response in 15 (12%). An additional 35 patients (28%) had stable disease. Target lesions were reduced in 92 of 110 evaluable patients (84%). Response rates were 56% and 41% in patients with and without response to prior anti–PD-1/L1 treatment, respectively; 38% in those with liver metastases; and 41% in those with three or more prior lines of therapy. Median duration of response was 7.6 months, with 44% of responders having ongoing responses at time of analysis. Estimated median progression-free survival was 5.8 months (95% confidence interval [CI] = 4.9–7.5 months) and estimated median overall survival was 11.7 months (95% CI = 9.1 months–not reached).

Adverse Events

The most common treatment-related adverse events of any grade were fatigue (50%), peripheral neuropathy (50%), alopecia (49%), rash (48%), decreased appetite (44%), and dysgeusia (40%). Treatment-related grade ≥ 3 adverse events occurred in 54% of patients, with the most common being neutropenia (8%), anemia (7%), and fatigue (6%). Treatment-related serious adverse events occurred in 19% of patients, with the most common being febrile neutropenia (4%).  Treatment-related adverse events led to discontinuation of treatment in 12%, with the most common cause being peripheral sensory neuropathy (6%).

The investigators concluded: “Enfortumab vedotin demonstrated a clinically meaningful response rate with a manageable and tolerable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum and anti–PD-1/L1 therapies.”

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 Seattle Genetics and Astellas Pharma. For full disclosures of the study authors, visit

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