GNS-1480 (Lazertinib)

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), 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 clinical development. It was approved in Korea by the Korean Ministry of Food and Drug Safety in January 2021 and is currently in global clinical phase 3 for mono-therapy and combo-therapy with Johnson & Johnson’s Amivantamab, a fully human bispecific antibody that targets EGFR and mesenchymal epithelial transition factor (MET) mutations.
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.
In the interim results from the CHRYSALIS study (NCT02609776) announced in ESMO 2020, 20 patients in the treatment-naïve group receiving the combination of Amivantamab and Lazertinib achieved a 100 percent ORR (95 percent CI, 83 – 100). Among 45 Osimertinib-relapsed, chemotherapy-naïve patients, the combination of Amivantamab and Lazertinib resulted in a 36 percent ORR (95 percent CI, 22 – 51), with one complete response and 15 partial responses.