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.

Targeted Molecular Therapeutics for Bladder Cancer—A New Option beyond the Mixed Fortunes of Immune Checkpoint Inhibitors?

“…Of note, patients in the EV-101 study who had previously received ICI therapy had an ORR of 42% (95% CI, 31.2–52.5%). In addition, patients with high tumor burdens such as liver metastases had a 36% (95% CI, 20.4–54.9%) ORR [ 59 ].…”

New and Emerging Therapies in the Management of Bladder Cancer

“…EV is an ADC targeting Nectin-4, a cell adhesion molecule highly expressed in nearly all urothelial tumors, conjugated to monomethyl auristatin E, a microtubule-disrupting agent 47 . In the dose expansion portion of the EV-101 trial, 112 mUC patients who failed at least one prior therapy received EV 48 . The confirmed ORR was 43%, including 5% CR, and the median duration of response was 7.4 months.…”

New Salvage Treatments for Metastatic Bladder Cancer

“…Patients with metastatic (M1) Urothelial cancer (UC) have an extremely ominous prognosis, with a 5 year survival rate of <5% after receiving cisplatinbased combination chemotherapy [1][2][3]. Thus, it is highly welcome news that within a year, two publications of Phase II (or I-II) trials of novel agents, erdafitinib [4] and enfortumab vedotin (EV) [5], have reported their efficacy and toxicity in patients with previously treated metastatic or unresectable UC. Each report impressive and similar objective response rates (ORRs) including complete responses (CRs) and prolongation of survival in several groups of patients.…”

“…As opposed to erdafitinib, whose target is only found in a minority of advanced UCs, EV's target, Nectin -4, a trans-membrane immunoglobulin-like protein implicated in cell-cell adhesion [9], and in processes such as immune modulation and host pathogen interactions [9], is expressed by almost all advanced UCs [5,9]. Nectin -4 also has moderate expression in human skin [10][11][12][13].…”

“…Nectin -4 also has moderate expression in human skin [10][11][12][13]. EV is an intravenously administered humanized antibody to Nectin -4 drug conjugate that delivers a micro-tubular dis-rupting agent, Monomethyl Auristatin E (MMAE) to cells expressing Nectin -4 [5,10]. As it turns out, Nectin -4 is so frequently expressed in advanced UC that the investigators felt further testing for Nectin -4 expression was not needed for UC (while it was for other cancers) [5].…”