Epertinib (S-222611) is really a potent, reversible, and selective tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), human EGFR2 (HER2), and human EGFR4. We developed experimental brain metastasis models by intraventricular injection (intraventricular injection mouse model IVM) of HER2-positive cancer of the breast (MDA-MB-361-luc-BR2/BR3) or T790M-EGFR-positive cancer of the lung (NCI-H1975-luc) cells. Following a single dental administration, epertinib and lapatinib concentrations in brain metastatic regions were examined by quantitative imaging mass spectrometry. Within the NCI-H1975 cancer of the lung IVM, the power of epertinib in brain metastasis was similar to those of lapatinib. However, within the MDA-MB-361 cancer of the breast IVM, the power of epertinib in brain metastasis was >10 occasions greater compared to lapatinib. In addition, the epertinib tumor-to-normal brain ratio was ~4 occasions greater compared to lapatinib. Bloodstream-tumor barrier (BTB) permeability was assessed in every brain metastatic region. Within the cancer of the lung model, fluorescently labeled dextran was better detected in brain metastatic regions compared to brain parenchyma. However, in cancer of the breast models, dextran fluorescence intensity in brain metastatic regions and brain parenchyma were comparable, suggesting the BTB continued to be largely intact. Epertinib could be guaranteed like a therapeutic agent for HER2-positive cancer of the breast with brain metastasis.