Lazertinib is a potent, highly mutant-selective, blood-brain barrier permeable, orally available and irreversible third-generation EGFR tyrosine kinase inhibitor[1]. Lazertinib selectively and potently inhibits the T790M, L858R, and Del19 mutations of EGFR, while its inhibitory activity against wild - type EGFR is relatively low[2]. Lazertinib inhibits EGFR phosphorylation and prevents downstream signaling of the mitogen-activated protein kinase (MAPK) and PI3K/Akt/mTOR (PAM) pathways, thereby halting cancer cell growth and proliferation, and is commonly used in the research of non-small cell lung cancer (NSCLC)[3-4].
In vitro, treatment of Ba/F3 cells harboring Del19, L858R, Del19/T790M, and L858R/T790M mutations with Lazertinib(5, 10, 100nM; 72h) showed a dose-dependent inhibition of EGFR phosphorylation and reduced cell viability with mean IC50 values in the low nanomolar range (3.3-5.7nM)[5]. Treatment of the non-small cell lung cancer (NSCLC) cell line H1975 with Lazertinib(0-100nM; 72h) demonstrated significant anti-proliferative activity with an IC50 value of less than 1nM, while in the glioblastoma (GBM) cell line U87-EGFRvIII, the IC50 value of Lazertinib was greater than 100nM[6].
In vivo, combination treatment of Lazertinib (10mg/kg; p.o.; 29 days) and amivantamab in uncommon EGFR-mutant NSCLC mice demonstrates potent antitumor activity by overcoming resistance to EGFR-TKIs, enhancing amivantamab's on-target expression, and upregulating of EGFR/MET expression[7].
References:
[1] Cho BC, Felip E, Hayashi H, et al. MARIPOSA: phase 3 study of first-line amivantamab + lazertinib versus osimertinib in EGFR-mutant non-small-cell lung cancer. Future Oncol. 2022;18(6):639-647.
[2] Shah D, Shah D, Ndandji S, Kar S. Lazertinib: a novel EGFR-TKI therapy for non-small cell lung cancer. Expert Opin Drug Metab Toxicol. 2025;21(7):789-800.
[3] Hong MH, Choi YJ, Ahn HK, et al. Lazertinib in EGFR-Variant Non-Small Cell Lung Cancer With CNS Failure to Prior EGFR Tyrosine Kinase Inhibitors: A Nonrandomized Controlled Trial. JAMA Oncol. 2024;10(10):1342-1351.
[4] Cho BC, Lu S, Felip E, et al. Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC. N Engl J Med. 2024;391(16):1486-1498.
[5] Yun J, Hong MH, Kim SY, et al. YH25448, an Irreversible EGFR-TKI with Potent Intracranial Activity in EGFR Mutant Non-Small Cell Lung Cancer. Clin Cancer Res. 2019;25(8):2575-2587.
[6] Yang H, Yan R, Jiang Y, et al. Design, synthesis and biological evaluation of 2-amino-4-(1,2,4-triazol)pyridine derivatives as potent EGFR inhibitors to overcome TKI-resistance. Eur J Med Chem. 2020;187:111966.
[7] Oh SY, Park S, Lee S, et al. The potential of lazertinib and amivantamab combination therapy as a treatment strategy for uncommon EGFR-mutated NSCLC. Cell Rep Med. 2025;6(2):101929.
Lazertinib是一种有效的、高度突变选择性的、能穿透血脑屏障的、口服的、不可逆的第三代EGFR酪氨酸激酶抑制剂[1]。Lazertinib选择性地强效抑制T790M、L858R和Del19突变的EGFR，而对野生型EGFR的抑制活性相对较低[2]。Lazertinib抑制EGFR磷酸化，并阻止丝裂原活化蛋白激酶（MAPK）和PI3K/Akt/mTOR（PAM）通路的下游信号传导，从而抑制癌细胞的生长和增殖，常用于非小细胞肺癌（NSCLC）的研究[3-4]。
在体外，Lazertinib（5，10，100nM；72小时）处理携带Del19、L858R、Del19/T790M和L858R/T790M突变的Ba/F3细胞，显示出剂量依赖性的EGFR磷酸化抑制，并降低细胞活力，平均IC50值在低纳摩尔范围（3.3-5.7nM）内[5]。用Lazertinib（0-100nM；72小时）处理非小细胞肺癌（NSCLC）细胞系H1975，显示出显著的抗增殖活性，IC50值小于1nM；而在胶质母细胞瘤（GBM）细胞系U87-EGFRvIII中，Lazertinib的IC50值大于100nM[6]。
在体内，Lazertinib（10mg/kg；口服；29天）与amivantamab联合治疗不常见EGFR突变NSCLC小鼠可通过克服对EGFR-TKIs的耐药性，增强amivantamab的靶向表达，并上调EGFR/MET表达，表现出强大的抗肿瘤活性[7]。