Trastuzumab deruxtecan efficacy, FcRn-facilitated penetration of the blood-tumor barrier, and distribution to tumor cells in HER2+ brain metastasis model systems

BACKGROUND: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) approved for metastatic HER2+ and HER2-low/ultralow breast cancer. It has shown impressive clinical activity for HER2+ brain metastases. We conducted preclinical brain metastasis experiments to understand T-DXd efficacy. METHODS: Nude mice were intracardially injected with either JIMT1-BR (HER2-2+) or SUM190-BR (HER2-3+) brain-tropic breast cancer cells and dosed with 3 or 10 mg/kg T-DXd or 10 mg/kg control-ADC, with endpoints of metastasis number and size, in both the metastasis prevention and treatment of established disease settings. RESULTS: In the JIMT1-BR model, T-DXd at both doses reduced metastasis number by 48% to 88% and size by 32% to 88%; a reduction of HER2 expression by lesions remaining at the experimental endpoint and heterogeneous T-DXd distribution were observed. A distinct dose effect was observed in SUM190-BR with the 3 mg/kg dose inhibiting size and number by 24% to 39% and 10 mg/kg by 72% to 79%; HER2 expression was maintained together with heterogeneous T-DXd distribution. In both models widespread reduced tumor Ki-67 was observed, while increased cleaved caspase-3 primarily costained with T-DXd. We used an in vitro model of the blood-brain and blood-tumor barriers (BBB/BTB) to ask how T-DXd crossed. Data demonstrated T-DXd endocytosis and transcytosis of brain endothelial cells partially reliant on the neonatal Fc receptor (FcRn). BTB transcytosis was accompanied by increased endothelial RAB11FIP5 expression in vitro and in vivo. CONCLUSIONS: The data confirm T-DXd activity in HER2+ brain metastases and identify important correlates, including heterogeneous uptake, variable HER2 expression at endpoint, tumor cell cytotoxicity, decreased proliferation, and BTB transcytosis.