Abstract P2-10-20: ACE-BREAST-03: A phase 2 trial evaluating ARX788, an anti-HER2 antibody drug conjugate (ADC), for the treatment of HER2+ metastatic breast cancer (mBC) in patients who have been previously treated with trastuzumab deruxtecan (T-DXd)

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Abstract Background: HER2-targeted ADCs revolutionized treatment for patients with HER2+ mBC. The HER2-targeted ADC, T-DXd, improved PFS and OS vs T-DM1 as second- line treatment for HER2+ mBC and is now the preferred treatment option in this setting. However, improved treatment options are needed for patients with disease progression on T-DXd. Novel technological advances in design of the antibody, linker, and payload of ADCs may further improve the safety/tolerability and efficacy, widening the therapeutic window to address resistance to other anti-HER2 therapies. ARX788 is a next-generation anti-HER2 ADC stably conjugated to AS269 (a potent tubulin inhibitor). Proprietary site-specific oxime conjugation chemistry, enabled by incorporation of synthetic amino acids into the antibody construct, maximizes the delivery of the cytotoxic payload to tumor cells and minimizes systemic exposure to free payload. A phase 2/3 study in China demonstrated that ARX788 had significantly improved PFS compared with the combination of lapatinib and capecitabine (HR 0.64 [0.49, 0.82], p = 0.0006) in patients treated with prior trastuzumab and taxane (ASCO 2024 Abstract 1020). In addition, ARX788 has shown antitumor activity in heavily pretreated patients with HER2+ and HER2-low mBC, including those with prior T-DXd exposure. Methods: ACE-Breast-03 (NCT04829604) is a phase 2 trial evaluating ARX788 in patients previously treated with T-DXd. The primary efficacy endpoint is response rate by RECIST v1.1. Approximately 40 patients will be enrolled. Eligible patients have HER2+ mBC and up to 5 prior treatment regimens for mBC, including T-DXd. Patients with stable brain metastases who are off steroids are eligible. Treatment includes 1.5 mg/kg Q3W ARX788 until unacceptable toxicity or disease progression. Tumor status is assessed every 9 weeks through 27 weeks and every 12 weeks thereafter. The study is currently enrolling in the US. Citation Format: Joyce O’Shaughnessy, Kashif Ali, Sami M. Ali, Kevin Kalinsky, Margaret Block, Priya Jayachandran, Debu Tripathy, Laila Agrawal, Sibel Blau, Michael A. Danso, Denise Yardley, Jay Andersen, Adrienne Gropper Waks, Igor Makhlin, Petros Nikolinakos, Richard Zuniga1, Janice M. Lu, William John Gradishar, Kamel Abou Hussein, Hope S. Rugo. ACE-BREAST-03: A phase 2 trial evaluating ARX788, an anti-HER2 antibody drug conjugate (ADC), for the treatment of HER2+ metastatic breast cancer (mBC) in patients who have been previously treated with trastuzumab deruxtecan (T-DXd) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-10-20.

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