Enfortumab Vedotin in Metastatic Urothelial Carcinoma

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In the phase I EV-101 trial reported in the Journal of Clinical Oncology, Rosenberg et al found that the antibody-drug conjugate enfortumab vedotin had no maximum tolerated dose and was active in patients with metastatic urothelial carcinoma at the dose selected for phase II evaluation. The agent is a conjugate of a Nectin-4–directed antibody and a microtubule inhibitor.

The pivotal phase II EV-201 study supported the recent accelerated approval of the agent in patients with locally advanced or metastatic urothelial cancer who have previously received a programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.

Study Details

In the dose-escalation/expansion study, 155 patients who had experienced disease progression on one prior chemotherapy regimen and/or PD-1/PD-L1 inhibitor received escalating doses of enfortumab vedotin up to 1.25 mg/kg on days 1, 8, and 15 of 28-day cycles. Overall, 96% of patients had received prior platinum-containing therapy and 72% had received PD-1/PD-L1 inhibitor therapy.


A maximum tolerated dose of enfortumab vedotin was not established, with the recommended phase II dose being identified as 1.25 mg/kg. Among the 112 patients treated at this dose, the most common treatment-related adverse events of any grade were fatigue (53%), alopecia (46%), decreased appetite (42%), and dysgeusia, nausea, and peripheral sensory neuropathy (38% each). The most common treatment-related grade ≥ 3 adverse events were maculopapular rash (3%) and fatigue (2%).


Among the 112 patients receiving the 1.25-mg/kg dose, the investigator-assessed confirmed objective response rate was 43% and median duration of response was 7.4 months. The response rate among 89 patients with prior PD-1/PD-L1 inhibitor therapy was 43% and median duration of response was 7.3 months.

Median overall survival was 12.3 months, with a 1-year rate of 52%. Median overall survival among the patients with prior PD-1/PD-L1 inhibitor therapy was 12.3 months.

The investigators concluded: “Single-agent [enfortumab vedotin] was generally well tolerated and provided clinically meaningful and durable responses in patients with [metastatic urothelial carcinoma]; survival data are encouraging…. These findings with [enfortumab vedotin] are especially encouraging for patients with [metastatic urothelial carcinoma] who had previously received an anti–PD-(L)1 therapy because there are no currently approved treatments. In addition, because of high Nectin-4 expression in urothelial tumor biopsy samples, … prescreening of Nectin-4 expression in tumor samples before [enfortumab vedotin] administration is not necessary.”

Daniel P. Petrylak, MD, Medical Oncology, Yale New Haven Hospital, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Astellas Pharma and Seattle Genetics. For full disclosures of all study authors, visit

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