ZN-A-1041 (BBB-permeable HER2 TKI) + T-DXd drives 65%–76% ORR in HER2+ mBC (incl CNS mets)

ZN-A-1041 is an oral, selective HER2 tyrosine kinase inhibitor designed for high intact blood–brain barrier permeability; in the Phase Ic ZN-A-1041-101-US trial (NCT05593094), it was combined with trastuzumab deruxtecan (T-DXd; HER2 ADC) in pretreated HER2+ metastatic breast cancer (Arms A/B; median 1 prior metastatic line; baseline CNS metastases 58%–59%) or with pertuzumab–trastuzumab (PH) as post-taxane induction maintenance (Arm C; baseline CNS metastases 16%). In evaluable patients, systemic ORR was 65.0% with ZN-A-1041 800 mg BID + T-DXd (n=20) and 76.2% with 600 mg BID + T-DXd (n=21), with DCR 95.0% and 90.5% respectively; PH maintenance showed ORR 30.8% (n=13 with measurable disease) and DCR 100%, and intracranial lesion shrinkage was observed across arms. Safety was GI-heavy (nausea 47%–96%, diarrhea 62%–77%, vomiting 46%–64%); the most common Grade ≥3 TEAE was diarrhea (5%–17%)—notably, the abstract does not report the ILD/pneumonitis rate that typically frames T-DXd risk–benefit, and without PFS/DoR or a T-DXd-alone control it’s hard to say if responses exceed what’s expected for T-DXd–based therapy in this disease setting.