EV-101: A Phase I Study of Single-Agent Enfortumab Vedotin in Patients With Nectin-4-Positive Solid Tumors, Including Metastatic Urothelial Carcinoma

Abstract

Purpose: To assess the safety/tolerability and antitumor activity of enfortumab vedotin (EV), a novel investigational antibody-drug conjugate that delivers the microtubule-disrupting agent, monomethyl auristatin E, to cells that express Nectin-4.

Methods: EV-101 is a phase I dose escalation/expansion study that enrolled patients with Nectin-4-expressing solid tumors (eg, metastatic urothelial carcinoma [mUC]) who progressed on ≥ 1 prior chemotherapy regimen and/or programmed death-1 receptor/programmed death ligand-1 [PD-(L)1] inhibitor, including a cohort of patients with mUC who received prior anti-PD-(L)1 therapy. Patients received escalating doses of EV up to 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle. Primary objectives were evaluation of safety/tolerability and pharmacokinetics; antitumor activity was a secondary objective.

Results: Enrolled patients with mUC (n = 155) were heavily pretreated, with 96% having prior platinum-based chemotherapy and 29% receiving ≥ 3 lines of prior treatment. Maximum tolerated dose of EV was not established; however, the recommended phase II dose was identified as 1.25 mg/kg. Rash, peripheral neuropathy, fatigue, alopecia, and nausea were the most common treatment-related adverse events (TRAEs); the most common TRAEs were grade 1-2 in severity. Among the 112 patients with mUC treated with single-agent EV 1.25 mg/kg, the investigator-assessed confirmed objective response rate (ORR) was 43%, and duration of response was 7.4 months. Median overall survival (OS) was 12.3 months, and the OS rate at 1 year was 51.8%. Similar ORR and estimated median OS were observed in patients ≥ 75 years of age with and without prior anti-PD-(L)1 treatment, liver metastases, or upper-tract disease.

Conclusion: Single-agent EV was generally well tolerated and provided clinically meaningful and durable responses in patients with mUC; survival data are encouraging. A pivotal phase II and a confirmatory phase III study are ongoing.

FIG 1.

Antitumor effects of enfortumab vedotin 1.25 mg/kg in patients with metastatic urothelial carcinoma. (A) Change in tumor burden from baseline (investigator assessed). A total of 103 patients had at least 1 measurable postbaseline response assessment. (B) Time to response and duration of response (DoR; investigator-assessed responders only). (C) DoR (investigator assessed). (D) Progression-free survival (investigator assessed). (E) Overall survival (OS; investigator assessed). (*) Patients with liver metastasis at baseline. CR, complete response; PD-(L)1, programmed death-1 receptor/programmed death ligand-1; PR, partial response.

FIG 2.

Survival with enfortumab vedotin (EV) 1.25 mg/kg in patients with metastatic urothelial carcinoma (UC) with prior programmed death-1 receptor/programmed death ligand-1 [PD-(L)1] exposure. (A) Duration of response (investigator-assessed responders and central review). (B) Progression-free survival (PFS; central review). (C) Overall survival (OS; investigator assessed).