Abstract 4008: TAS2940, a novel brain-penetrable pan-ERBB inhibitor, exhibits tumor regression and prolongs survival in intracranial models bearing ERBB aberrations

Background: Primary and metastatic brain tumors have significant unmet medical needs as few drugs can penetrate the blood-brain barrier (BBB). Brain metastasis is more common in non-small cell lung cancer (NSCLC) and breast cancer than in other cancers. Genetic alterations in ERBB family genes are frequently observed in those cancers, with about half of HER2/EGFR aberrations metastasizing in the brain. EGFR aberrations have been also observed in glioblastoma. Several pan-ERBB inhibitors are clinically available or under clinical development, such as afatinib, neratinib, and poziotinib. However, none are highly brain-penetrable as they are pumped out via the BBB. Here, we report TAS2940 as a novel potent pan-ERBB inhibitor that elicits brain penetrability and anti-tumor effects in brain metastasis models. Methods: The kinase selectivity of TAS2940 was evaluated in a panel of 257 kinases. Autophosphorylation of wild-type and mutant ERBB in stably expressing cell lines was evaluated using a quantitative immunofluorescence assay. The growth inhibitory effect on cell lines expressing HER2/EGFR aberrations was evaluated based on quantitation of the cellular ATP concentration. Cell lines were transplanted subcutaneously or intracranially in BALB/cAJcl-nu/nu mice. HER2 tyrosine kinase inhibitors, including TAS2940, were then orally administered once daily followed by evaluation of tumor volume and body weight. Results: TAS2940 showed potent and selective inhibition against ERBB family proteins over more than 250 kinases on enzymatic assay. TAS2940 also showed preferential cytotoxicity in cells harboring HER2/EGFR genetic alterations in vitro, while sparing cells without ERBB genetic aberrations. TAS2940 showed potent anti-proliferative activity in cells containing HER2 genetic alterations or EGFR exon 20 insertions, commonly found in NSCLC or breast cancer, as well as EGFRvIII alterations, frequently observed in glioblastoma. In vivo xenograft tumor models with various EGFR genetic alterations showed that TAS2940 exerted anti-tumor effects, such as growth retardation or regression. We further examined brain penetration by assessing the brain to blood concentration of TAS2940 in mice with intact BBBs, showing higher brain penetrability compared to other ERBB inhibitors. Evaluation of TAS2940 in intracranial brain metastasis mouse models resulted in tumor regression and prolonged survival. Conclusion: TAS2940 is a novel potent and selective pan-ERBB inhibitor with h