Lazertinib (formerly known as GNS-1480; YH-25448; GNS1480; YH25448; LECLAZA) is an oral, highly mutant-selective and irreversible 3rd generation EGFR TKI (Tyrosine-kinase inhibitors) approved in 2021 for the treatment of lung cancer (NSCLC). It inhibits Del19/T790M, L858R/T790M, Del19, L85R and Wild type EGFR with IC50 values of 1.7 nM, 2 nM, 5 nM, 20.6 nM and 76 nM, respectively. Lazertinib is a brain-penetrant EGFR-TKI targeting the T790M mutation and activating EGFR mutations Ex19del and L858R, while sparing wild type-EGFR. Lazertinib has the potential for the treatment of locally advanced or metastatic NSCLC patients with EGFR mutations and has been approved in January 2021 for that purpose. Lazertinib 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, Lazertinib showed more potent inhibition of cancer cell growth compared to osimertinib. Lazertinib 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, Lazertinib 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 Lazertinib treatment was well translated into the in vivo efficacy. Plasma half-life of Lazertinib was 5.9-6.8 hr and tumor to plasma AUC0-last ratio was 3.0-5.1. Lazertinib also showed excellent penetration of the BBB, achieving CSF concentrations exceeding the IC50 value for pEGFR inhibition.