Abstract PS5-08-11: Trial in Progress: Phase II Open-Label Study of ARX788 (anti-HER2 Antibody Drug Conjugate (ADC)) for Patients with HER2-Low Locally Advanced Unresectable or Metastatic Breast Cancer

Abstract Background: ARX788 is a next-generation, site-specific ADC composed of a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2) conjugated via a non-natural amino acid linker to a potent tubulin inhibitor payload AS269. The phase I ACE-Breast-01 and ACE-Pan Tumor-01(NCT03255070) studies previously evaluated the safety and efficacy of ARX788 in patients with HER2-positive breast cancer and pan tumor types respectively, with promising efficacy results and with associated ocular adverse events. The clinical benefit of HER2-targeted ADCs for patients with HER2-low breast cancer (HER2 IHC 1+ or 2+ and FISH/ISH negative) has been established for other HER2-targeted ADCs; novel treatment strategies in this population remain an area of high unmet clinical need. Therefore, we hypothesized that ARX788 will also be safe and efficacious for the treatment of patients with HER2-low locally advanced unresectable or metastatic breast cancer, including in patients who have progressed on prior chemotherapies and ADCs. Methods: This is a single-arm, open-label, Phase II clinical trial of ARX788 monotherapy in patients with HER2-low locally advanced unresectable or metastatic breast cancer (NCT06224673). Key eligibility criteria include patients with locally advanced unresectable or metastatic breast cancer, measurable disease, local confirmation of HER2-low status, and receipt of at least one prior line of chemotherapy or ADC therapy in the metastatic setting (no limit on prior lines of therapy). ARX788 monotherapy will be administered at a dose of 1.5mg/kg intravenously every three weeks until progressive disease or intolerable side effects. A total of 30-36 patients will be enrolled in one of two cohorts: 1) hormone receptor (HR) positive/HER2-low (n=20-24) and 2) HR-negative/HER2-low (n=10-12). The primary endpoint is objective response rate (ORR); The proposed sample size will provide ORR estimates with margin of error of 14% and 18% in each cohort respectively at 90% confidence level with anticipated 25% ORR. Secondary endpoints include duration of response (DOR), best overall response (BOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and efficacy of an eye toxicity prevention regimen to prevent grade 2 or higher ocular toxicity. Exploratory endpoints include blood- and tumor-based biomarker analyses and patient-reported outcomes (PROs). Enrollment to all cohorts will begin in the third quarter of 2025. Citation Format: L. A. Huppert, N. D. Pasricha, K. Nathalie, C. Galia, J. Rossi, A. DeLuca, K. Natsuhara, H. Batra-Sharma, M. Majure, M. Melisko, J. Chien, H. Rugo. Trial in Progress: Phase II Open-Label Study of ARX788 (anti-HER2 Antibody Drug Conjugate (ADC)) for Patients with HER2-Low Locally Advanced Unresectable or Metastatic Breast Cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-08-11.