Preclinical evaluation of trastuzumab deruxtecan in a new HER2+ leptomeningeal colonization model.

Leptomeningeal metastases are devastating complications of advanced HER2+ breast cancer, with limited therapeutic options. We developed a xenograft model of human HER2+ breast cancer cell line JIMT1-BR3-LM4 leptomeningeal colonization by four iterative cycles of intrathecal injection. The model reliably produced leptomeningeal lesions in brain and spinal cord and tumor cells in the CSF, as confirmed by endpoints of BLI, MRI, pathologic analysis and immunofluorescent staining. Upon RNA-seq, the LM model exhibited significant transcriptional changes as compared to the starting brain-tropic line. In a preclinical experiment, two doses of trastuzumab deruxtecan (T-DXd) were compared to human IgG, trastuzumab (T), nab-paclitaxel (nab-P) and T+nab-P for leptomeningeal metastasis. T-DXd demonstrated efficacy in terms of BLI imaging of the brain (P < 0.0001) and spine (P = 0.008), leptomeningeal lesion number and size in the brain (P = 0.06); efficacy was dose-dependent. T-DXd 10 mg/kg reduced leptomeningeal tumor Ki67 positivity (P = 0.0008) and increased apoptosis (P < 0.0001). In the brain, a comparison of leptomeningeal and parenchymal lesion number showed a reduction by T-DXd of 53% and 72%, respectively, compared to human IgG, with comparable effects on tumor proliferation and apoptosis. T-DXd also extended median survival to 38 days compared with 20 -24 days in control IgG or T+nab-P, with some mice surviving beyond 60 days (P = 0.003). These findings support ongoing clinical translation of T-DXd for HER2+ leptomeningeal metastasis and highlight the value of this model for future therapeutic development.