Lung cancer patients harboring a mutation in the epidermal growth factor receptor (EGFR) gene exhibit an initial dramatic response to the first-generation EGFR tyrosine kinase inhibitors Erlotinib and Gefitinib but acquired resistance is almost inevitable after a progression-free period of approximately ten months. A secondary point mutation that substitutes at amino acid position 790 (T790M) is a molecular mechanism that produces a drug-resistant variant of the targeted kinase. The T790M mutation is present in about half of the lung cancer patients with acquired resistance.
GNS-1480 (Lazertinib,YH25448), our third-generation EGFR mutant-selective inhibitor is not only potent against various EGFR mutant including T790M and L858M but also spares wild-type EGFR. Furthermore, it strongly inhibits PD-L1 and inflammatory cytokine in lung cancer cell harboring EGFR double mutant del19 and T790M which leads to a therapeutic advantage in the aspect of immuno-oncology. GNS-1480 is also brain penetrant and showed good efficacy in orthotopic brain metastatic model (below). It is now partnered with Yuhan Corporation in Korea for preclinical and clinical development. GNS-1480 (Lazertinib,YH25448) is in clinical phase 1/2.
In s.c. H1975 xenograft mouse, oral dosing of GNS-1480 shows complete tumor regression at ten mpk/day (QD, 14 days) & 3 mpk/day (QD and bid, 14 days). Strong tumor growth inhibition is shown in a dose-dependent manner (0.3-1 mpk/day). GNS-1480 shows three-fold higher efficacy than AZD9291 in dose level and no body weight change was observed.
Furthermore, at mouse brain metastasis model of subcutaneous and intracranial dual implantation model with H1975-luciferase, 3mpk/day (QD, 12 days) dosing showed markedly reduced tumor regression in the brain and subcutaneous tumor.