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TPS1123 Background: HER2-targeted ADCs revolutionized treatment for patients with HER2+ mBC. The HER2-targeted ADC, T-DXd, improved PFS and OS vs T-DM1 (trastuzumab emtansine) as second-line treatment for HER2+ mBC and is now the preferred treatment option in this setting. However, new 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 of free payload. 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 must have central laboratory-confirmed HER2+ mBC; new pre-treatment biopsies may be required. Patients with treated and stable brain metastases who are off steroids are eligible. Treatment includes 1.5 mg/kg Q3W ARX788 for up to 26 cycles or until 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. Clinical trial information: NCT04829604 .
Tripathy et al. (Sat,) studied this question.