Abstract
PURPOSETo 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.METHODSEV-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.RESULTSEnrolled 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.CONCLUSIONSingle-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.
Highlights
Nectin-4 is a type 1 transmembrane protein and member of a family of related immunoglobulin-like adhesion molecules implicated in cell-cell adhesion.[1]
Among the 112 patients with metastatic urothelial carcinoma (UC) (mUC) treated with single-agent Enfortumab vedotin (EV) 1.25 mg/kg, the investigator-assessed confirmed objective response rate (ORR) was 43%, and duration of response was 7.4 months
Nectin-4 is highly expressed in cancer cells, in urothelial carcinomas (UCs), with moderate expression observed in normal human skin.[2,3,4,5]
Summary
Nectin-4 is a type 1 transmembrane protein and member of a family of related immunoglobulin-like adhesion molecules implicated in cell-cell adhesion.[1]. Up to 50% of patients with UC are not eligible to receive cisplatinbased chemotherapy because of comorbidities such as renal dysfunction, heart failure, or low Eastern Cooperative Oncology Group performance status.[9] For patients who express programmed death ligand-1 (PD-L1) and are ineligible for cisplatin chemotherapy or any patient not eligible for a platinum-based regimen, antibodies against programmed death-1 receptor (PD-1) or PD-L1 are treatment options.[10] In patients with mUC, objective response rates (ORRs) for currently approved anti–PD-(L)[1] therapies in the second-line setting range from 13% to 21%, with a lower response rate in visceral sites.[10]
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