P3.02b-119 YH25448, a Highly Selective 3rd Generation EGFR TKI, Exhibits Superior Survival over Osimertinib in Animal Model with Brain Metastases from NSCLC: Topic: EGFR RES

Currently-available EGFR TKIs are ineffective for the treatment of brain metastases (BrM) due to limited blood-brain barrier (BBB) penetration. YH25448 is a potent, highly mutant-selective and irreversible 3rd generation EGFR TKI that is able to penetrate the BBB, and targets both the T790M mutation and activating EGFR mutations while sparing wild type (wt). The biochemical and pharmacological activity of YH25448 were characterized through in vitro kinase assays, and functional cell assays. The animal model with brain metastases from NSCLC was established by implanting luciferase-transfected NCI-H1975 human NSCLC cells carrying the L858R/T790M mutation both subcutaneously and intracranially into nude mice. In this animal model, YH25448 was compared with osimertinib in terms of tumor growth inhibition, survival, weight loss and clinical signs. The correlation of PK profiles (plasma, CSF and tumor tissues) with biological activity using inhibition of EGFR phosphorylation (pEGFR) in the tumor tissue was evaluated. YH25448 selectively inhibited EGFR single and double mutant kinase activity with IC50 values of 2 nM for L858R/T790M against 76 nM for wt-EGFR. In the cell proliferation assays, GI50 values were 6 nM, 5 nM, and 711 nM for H1975 cells (L858R/T790M), PC9 cells (del19) and H2073 cells (wt), respectively. In primary cancer cells from patients harboring EGFR mutations, YH25448 showed more potent inhibition of cancer cell growth compared to osimertinib. YH25448 treatment at the once-daily doses of 1-25 mg/kg resulted in dose-dependent tumor regression in both subcutaneous and intracranial lesions in mice implanted with H1975 cells. Given its high selectivity against wild type and wide safety margin, there were no changes in body weight and no abnormal clinical signs. At 10-25 mg/kg, YH25448 achieved more significant, complete tumor growth inhibition and longer overall survival compared to same doses of osimertinib. Dose-dependent inhibition of pEGFR expression in tumor tissue by YH25448 treatment was well translated into the in vivo efficacy. Plasma half-life of YH25448 was 5.9-6.8 hr and tumor to plasma AUC0-last ratio was 3.0-5.1. YH25448 also showed excellent penetration of the BBB, achieving CSF concentrations exceeding the IC50 value for pEGFR inhibition. The strong in vitro potency and high selectivity of YH25448 for mutant EGFR translated into robust in vivo efficacy. These findings indicate that YH25448 will be able to address the urgent unmet needs for EGFR mutant-positive patients with brain metastases.