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Abstract Background: HER2 overexpression and/or amplification confers aggressive tumor behavior and decreased survival in patients with breast cancer. Targeting of HER2 is a validated therapeutic strategy, and trastuzumab deruxtecan (T-DXd) has emerged as a preferred treatment in the second-line setting. However, effective treatment following progression on T-DXd remains a major unmet medical need. ARX788 is a next-generation antibody-drug conjugate (ADC) using a technology platform whereby a HER2-specific monoclonal antibody is conjugated to amberstatin 269 (AS269), a potent cytotoxic tubulin inhibitor. Site-specificity, high homogeneity, and stable covalent conjugation of ARX788 leads to the slow release and prolonged peak of serum pAF-AS269, which may contribute to the lower systemic toxicity and increased targeted delivery of payload to tumor cells, at a lower effective dose compared with other HER2 ADCs. Methods: ACE-Breast-03 (NCT04829604) is a global, phase 2 study designed to assess anticancer activity and safety in approximately 40 patients with unresectable or metastatic HER2 positive breast cancer who have been previously treated with T-DXd. Eligibility criteria include measurable disease by RECIST v1.1, radiographically stable brain metastases, no more than three prior lines of treatment in the metastatic setting, and HER2 positivity as determined by central review. If recently progressed on T-DXd or trastuzumab emtansine (T-DM1), a new biopsy for HER2 status is required. Patients will be administered 1.5 mg/kg of ARX788 every three weeks. Efficacy will be assessed using RECIST v1.1 at nine-week intervals after starting ARX788 until progression or start of new cancer treatment. Objective response rate is the primary endpoint, with disease control rate, progression-free survival, overall survival, best overall response, duration of response, and time to response as additional endpoints. The safety and tolerability profile will also be evaluated. PK analysis will determine serum concentrations of ARX788, total antibody, and pAF-AS269. Potential predictive and/or prognostic biomarkers will be analyzed for exploratory purposes. Descriptive statistics will be used to evaluate anticancer activity, safety, and tolerability. The study is currently recruiting patients. Citation Format: Kashif Ali, Laila Agrawal, Anu Thummala, Kevin Kalinsky, Sami Ali, Sibel Blau, Margaret Block, Michael Danso, Denise Yardley, Jay Andersen, Adrienne Gropper-Waks, Priya Jayachandran, Igor Makhlin, Petros Nikolinakos, Joyce O'Shaughnessy, Sandra Aung, Colin Hessel, Hope Rugo, William Gradishar, Debu Tripathy. ACE-Breast-03: A phase 2 study of ARX788, a novel next-generation anti-HER antibody-drug conjugate in HER2-positive metastatic breast cancer patients previously treated with trastuzumab deruxtecan abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-02.
Ali et al. (Thu,) studied this question.