Safety and efficacy of ZN-A-1041, a highly blood-brain barrier (BBB)–permeable HER2 tyrosine kinase inhibitor (TKI), + trastuzumab deruxtecan (T-DXd) or pertuzumab-trastuzumab (PH) in HER2-positive metastatic breast cancer (HER2+ mBC): Phase Ic expansion results from the ZN-A-1041-101-US trial.

1055 Background: Brain metastases (BMs) are a common site of progression in HER2+ mBC due to limited BBB penetration of systemic therapies. ZN-A-1041 is an oral, selective HER2 TKI designed for high intact BBB permeability. We report ZN-A-1041-101-US (NCT05593094) Phase Ic expansion results of ZN-A-1041 + T-DXd in patients (pts) with HER2+ mBC refractory to prior treatments (txs), or + PH as maintenance therapy after first-line taxane + H ± P induction. Phase Ia and Ib (dose-escalation as single agent or in combination therapies) results have been reported (Anders ASCO 2023). Methods: The study enrolled pts with HER2+ mBC, with or without BMs (including leptomeningeal disease). Pts in Phase Ic received ZN-A-1041 800 mg twice daily (BID) + PH (Arm C), or were randomized to ZN-A-1041 800 mg or 600 mg BID, + T-DXd 5.4 mg/kg every 3 weeks (Arms A and B, respectively). Primary objectives: safety and tolerability. Secondary objectives included systemic objective response rate (ORR) and disease control rate (DCR) per Response Evaluation Criteria in Solid Tumours version 1.1. Results: As of July 31, 2025 (last pt in), enrollment in Arms A, B, and C was 24, 23, and 20 pts, respectively; median age was 57, 54, and 46 years; 50, 36, and 70% had de novo stage IV disease. Baseline central nervous system (CNS) metastases were present in 58, 59, and 16% of pts. Median prior lines of therapy for metastatic disease was 1, 1, and 0. Median ZN-A-1041 tx duration was 23.0, 24.6, and 42.9 weeks. The most frequent all-grade tx-emergent adverse events (TEAEs) across Arms A, B, and C, respectively, were nausea (83, 96, and 47%), diarrhea (62, 77, and 68%), and vomiting (46, 64, and 47%); diarrhea (17, 9, and 5%) was the most frequent Grade ≥3 TEAE. Preliminary systemic efficacy is summarized in the Table. Intracranial lesion shrinkage was observed in pts with BMs across all tx arms. Conclusions: ZN-A-1041 showed manageable safety profiles and promising clinical activity when combined with standard anti-HER2 therapies in pts with HER2+ mBC, both with or without CNS metastases. High disease control in pts pretreated with T-DXd and notable continued responses in the PH maintenance setting support further clinical evaluation of these combinations. Clinical trial information: NCT05593094 . Arm n ORR, % (95% CI) Complete response, % of pts DCR, % (95% CI) A: ZN-A-1041 800mg + T-DXd 20 65.0 (40.8, 84.6) 10.0 95.0 (75.1, 99.9) B: ZN-A-1041 600mg + T-DXd 21 76.2 (52.8, 91.8) 9.5 90.5 (69.6, 98.8) C: ZN-A-1041 800mg + PH 13* 30.8 (9.1, 61.4) 5.6 100 (75.3, 100.0) *Efficacy reported for 13 pts with measurable disease receiving maintenance therapy with ZN-A-1041 + PH after taxane + H ± P induction. CI, confidence interval.