Abstract OT1-02-02: A global, phase 2 study of ARX788 in patients with HER2-positive metastatic breast cancer whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens
Authors: Lu Janice , Kalinsky Kevin M , Tripathy Debu , Sledge George W , Gradishar William , O’Regan Ruth , O’Shaughnessy Joyce , Modi Shanu , Drago Joshua , Park Haeseong , McCartney Amelia , Frentzas Sophia , Shannon Catherine , Cuff Katharine , Eek Richard , Martin Miguel Idzwan , Curigliano Giuseppe , Jerusalem Guy , Huang Chiun-Sheng , Press Michael , Li Matt , Xu Dong , Song Cynthia , Huhn Richard , Yan Jinchun , Hurvitz Sara 
Published: March 2022

Abstract
Background: The HER2 receptor is a cancer driver which is overexpressed on 15-20% of breast cancers. Though historically survival is poor with this disease subtype, HER2+ targeted therapy has improved survival in both early and advanced disease. In spite of this, most patients in the metastatic setting will eventually experience disease progression and death. Therefore, new therapeutic options and innovative treatments are needed for patients with recurrent or refractory disease. ARX788 is a next-generation antibody–drug conjugates (ADC) using a technology platform whereby a HER2 specific monoclonal antibody is conjugated with Amberstatin269, a potent cytotoxic tubulin inhibitor. Site-specific, high homogenous, and stable covalent conjugation in ARX788 leads to slow release and prolonged peak of serum pAF-AS269, which may contribute to the lower systemic toxicity, increased targeted delivery of payload to tumor cells, and lower effective dose compared to other HER2 ADCs.Methods: ACE-Breast-03 (NCT04829604) is a global, single arm, phase 2 study designed to assess anticancer activity and safety of ARX788 in patients with metastatic HER2 positive breast cancer. Patients whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens are eligible. Patients must have adequate organ function and any brain metastasis must demonstrate radiographic stability and lack of steroid dependence. Approximately 200 subjects with advanced HER2-positive breast cancer will be enrolled. ARX788 will be administered as an intravenous (IV) infusion at 1.5 mg/kg as the initial dose on Day 1 of the first 4-week cycle and followed by 1.3 mg/kg at every subsequent 4-week cycle. Efficacy will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 via imaging every 8 weeks (±7 days) on study and endpoints include objective response rate (ORR), duration of response (DOR), time to response (TTR), best overall response (BOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The safety and tolerability profile will be assessed. Blood samples will be collected at specified time points to determine serum concentrations of ARX788 (intact ADC), total antibody, and metabolite pAF-AS269. Biomarkers (e.g., cell-free DNA, serum HER2 extracellular domain, and circulating tumor cells) at baseline and on-treatment will be analyzed for exploratory research. Descriptive statistics will be used to evaluate anticancer activity, safety, and tolerability. The study is currently recruiting patients. Please contact breast03trialinquiry@ambrx.com for additional information.
Citation Format: Janice Lu, Kevin M Kalinsky, Debu Tripathy, George W Sledge, William Gradishar, Ruth O’Regan, Joyce O’Shaughnessy, Shanu Modi, Joshua Drago, Haeseong Park, Amelia McCartney, Sophia Frentzas, Catherine Shannon, Katharine Cuff, Richard Eek, Miguel Idzwan Martin, Giuseppe Curigliano, Guy Jerusalem, Chiun-Sheng Huang, Michael Press, Matt Li, Dong Xu, Cynthia Song, Richard Huhn, Jinchun Yan, Sara Hurvitz. A global, phase 2 study of ARX788 in patients with HER2-positive metastatic breast cancer whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens [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 OT1-02-02.