YH25448, an Irreversible EGFR-TKI with Potent Intracranial Activity in EGFR Mutant Non-Small Cell Lung Cancer.

Abstract

Given that osimertinib is the only approved third-generation EGFR-TKI against <i>EGFR</i> activating and resistant T790M mutated non-small cell lung cancer (NSCLC), additional mutant-selective inhibitors with a higher efficacy, especially for brain metastases, with favorable toxicity profile are still needed. In this study, we investigated the antitumor efficacy of YH25448, an oral, mutant-selective, irreversible third-generation EGFR-TKI in preclinical models. Antitumor activity of YH25448 was investigated <i>in vitro</i> using mutant <i>EGFR</i>-expressing Ba/F3 cells and various lung cancer cell lines. <i>In vivo</i> antitumor efficacy, ability to penetrate the blood-brain barrier (BBB), and skin toxicity of YH25448 were examined and compared with those of osimertinib using cell lines and PDX model. Compared with osimertinib, YH25448 showed a higher selectivity and potency in kinase assay and mutant <i>EGFR</i>-expressing Ba/F3 cells. In various cell line models harboring <i>EGFR</i> activating and T790M mutation, YH25448 effectively inhibited EGFR downstream signaling pathways, leading to cellular apoptosis. When compared <i>in vivo</i> at equimolar concentrations, YH25448 produced significantly better tumor regression than osimertinib. Importantly, YH25448 induced profound tumor regression in brain metastasis model with excellent brain/plasma and tumor/brain area under the concentration-time curve value. YH25448 rarely suppressed the levels of p-EGFR in hair follicles, leading to less keratosis than osimertinib in animal model. The potent systemic and intracranial activity of YH25448 has been shown in an ongoing phase I/II clinical trial for advanced <i>EGFR</i> T790M mutated NSCLC (NCT03046992). Our findings suggest that YH25448 is a promising third-generation EGFR inhibitor, which may be more effective and better tolerated than the currently approved osimertinib.