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 (Yuhan code: 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 and subsequently partnered with Shandong Luoxin Pharmaceuticals for Chinese territory and clinical development.
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.