Abstract OT1-02-04: Enfortumab vedotin 202: Phase 2 study of enfortumab vedotin for previously treated advanced solid tumors, including breast cancer
Authors: Ono Makiko , Bruce Justine Yang , Feinstein Trevor , Muro Kei , Derleth Christina , Gorla Seema , Wu Chunzhang , Novik Yelena 
Published: March 2022

Introduction Despite therapy advances, breast cancer (BC) is a leading cause of cancer death among women. Nectin-4, a cell adhesion molecule, is highly expressed in some epithelial tumors, including breast (Challita-Eid PM, et al. Cancer Res. 2016;76:3003-3013). Nectin-4-directed therapies in BC are a novel approach. Enfortumab vedotin (EV) is an antibody-drug conjugate comprised of a fully human monoclonal antibody directed against Nectin-4, and monomethyl auristatin E (MMAE), a microtubule-disrupting agent, attached to the antibody via a protease-cleavable linker. MMAE release in the cell disrupts the microtubule network, inducing cell cycle arrest and apoptosis. In 2019, EV received accelerated approval by the US FDA for treatment of adults with locally advanced or metastatic (la/m) urothelial cancer (UC) who previously received a PD-1/L1 inhibitor and a platinum-based chemotherapy in the neoadjuvant/adjuvant, la/m setting. In EV-301, a phase 3 trial of patients (pts) with previously treated la/m UC, EV significantly prolonged overall survival (OS) vs chemotherapy (docetaxel, paclitaxel, vinflunine). Methods This multicohort, open-label phase 2 study (NCT04225117) aims to evaluate the efficacy and safety/tolerability of EV in pts with previously treated la/m solid tumors. About 240 pts (~40 pts/cohort) with histologically/cytologically confirmed disease and ECOG performance status of ≤1 are enrolling into 6 tumor-specific cohorts, with a hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) BC and a triple-negative BC (TNBC) cohort. Within the HR+/HER2- BC cohort, pts must have progressed, relapsed, or discontinued therapy for toxicity after 1 (no more than 2) cytotoxic regimen (taxane/anthracycline) for incurable, la/m disease. No limit applies to endocrine therapies. Prior cytotoxic regimen in the neoadjuvant/adjuvant setting counts as prior cytotoxic regimen if disease recurrence occurred within 6 mo of regimen completion. Pts must have progressed, relapsed, or discontinued for toxicity after endocrine/hormonally directed therapy with cyclin-dependent kinase inhibitors. Within the TNBC cohort, the same criteria for HR+/HER2- cytotoxic therapy apply; pts must have progressed/discontinued for toxicity after prior PD-1/L1 inhibitor therapy (if eligible). Nectin-4 expression is not required for eligibility and is being tested for exploratory outcomes. Pts with active CNS metastases, grade ≥2 sensory/motor neuropathy, ongoing grade ≥3 immunotherapy-related hypothyroidism/panhypopituitarism, ongoing immunotherapy-related adverse events requiring high-dose steroids, or uncontrolled diabetes mellitus are excluded. Pts will receive EV 1.25mg/kg (max 125 mg) intravenously on Days 1, 8, and 15 of each 28-day cycle. Treatment continues until disease progression or discontinuation criteria are met. After an end-of-treatment visit, pts have a 30-day safety follow-up, post treatment follow-up with response assessment every 8 wks, and long-term follow-up every 12 wks for survival status. Primary endpoint is investigator-assessed confirmed objective response rate (ORR; per RECIST v1.1); secondary endpoints are duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), OS, and safety/tolerability. Confirmed ORR and DCR will be analyzed with the Clopper-Pearson method for each tumor type, and DoR, PFS, and OS will be analyzed with the Kaplan-Meier method. All pts receiving ≥1 EV dose, have measurable disease at baseline, and have evaluable tumor response data or are not in the follow-up of response at the time of analysis will be included in the efficacy analysis. As of Jun 29, 2021, 150 pts are enrolled (HR+/HER2- BC, n=20; TNBC, n=11). Recruitment is ongoing at ~50 sites in North America and Japan.

Citation Format: Makiko Ono, Justine Yang Bruce, Trevor Feinstein, Kei Muro, Christina Derleth, Seema Gorla, Chunzhang Wu, Yelena Novik. Enfortumab vedotin 202: Phase 2 study of enfortumab vedotin for previously treated advanced solid tumors, including breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-02-04.