Lu Zhiqin, Yi Yali, Wang Linxiao, Luo Yuxi, Luo Daya, Xiong Le, Shu Yun, Luo Hui, Li Jing, Zhu Wufu, Zeng Zhimin, Liu Anwen
Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China; Jiangxi key laboratory of clinical translational cancer research, Nanchang, Jiangxi Province, China; Radiation Induced Heart Damage Institute of Nanchang University, Nanchang, Jiangxi Province, China.
Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi Province, China.
Transl Oncol. 2024 Jan;39:101834. doi: 10.1016/j.tranon.2023.101834. Epub 2023 Nov 24.
This study compared the clinical efficacy of first-, second-, and third-generation tyrosine kinase inhibitors (TKIs) in previously untreated non-small cell lung cancer (NSCLC) patients harboring uncommon epidermal growth factor receptor (EGFR) exon 19delins variants.
We retrospectively analyzed the clinical outcomes of NSCLC patients with EGFR exon 19delins mutations who were treated with third- and first-generation EGFR TKIs. In vitro and in vivo studies were conducted to verify the sensitivity of these mutations to distinct generations of TKIs. Molecular simulation was used to investigate the structural characteristics of the EGFR mutant molecules.
In a multicenter cohort of 1,526 patients, 37 (2.4 %) had uncommon EGFR 19delins mutations. Twenty-four patients were treated with first-generation EGFR TKIs, and third-generation TKIs were administered to ten patients as frontline therapy. Patients carrying EGFR exon 19delins mutations who were given third-generation TKIs exhibited comparatively shorter progression-free survival (PFS) and overall survival (OS) in relation to those who received first-generation EGFR inhibitors; median PFS: 6.9 months vs. 19.1 months (p < 0.001), Median OS: 19.1 months vs. 32.6 months (p < 0.001). In vivo and in vitro studies revealed that uncommon EGFR 19delins variants exhibit limited sensitivity to third-generation EGFR inhibitors in contrast to first- and second-generation EGFR inhibitors. The molecular binding affinity of third-generation EGFR TKIs toward uncommon EGFR 19delins mutations was less than that of first- and second-generation EGFR inhibitors.
Uncommon EGFR 19delins variants respond poorly to third-generation EGFR inhibitors in NSCLC. Uncommon EGFR 19delins mutations may serve as an unfavorable predictive factor for the efficacy of third-generation EGFR TKI therapy, offering potential guidance for future clinical decision-making.
本研究比较了第一代、第二代和第三代酪氨酸激酶抑制剂（TKIs）在既往未接受过治疗、携带不常见表皮生长因子受体（EGFR）外显子19缺失/插入（delins）变异的非小细胞肺癌（NSCLC）患者中的临床疗效。
我们回顾性分析了接受第三代和第一代EGFR TKIs治疗的EGFR外显子19delins突变NSCLC患者的临床结局。进行了体外和体内研究，以验证这些突变对不同代TKIs的敏感性。使用分子模拟来研究EGFR突变分子的结构特征。
在一个包含1526例患者的多中心队列中，37例（2.4%）有不常见的EGFR 19delins突变。24例患者接受第一代EGFR TKIs治疗，10例患者接受第三代TKIs作为一线治疗。与接受第一代EGFR抑制剂的患者相比，接受第三代TKIs治疗的携带EGFR外显子19delins突变的患者的无进展生存期（PFS）和总生存期（OS）相对较短；中位PFS：6.9个月对19.1个月（p<0.001），中位OS：19.1个月对32.6个月（p<0.001）。体外和体内研究表明，与第一代和第二代EGFR抑制剂相比，不常见的EGFR 19delins变异对第三代EGFR抑制剂的敏感性有限。第三代EGFR TKIs对不常见EGFR 19delins突变的分子结合亲和力低于第一代和第二代EGFR抑制剂。
在NSCLC中，不常见的EGFR 19delins变异对第三代EGFR抑制剂反应不佳。不常见的EGFR 19delins突变可能是第三代EGFR TKI治疗疗效的不良预测因素，为未来临床决策提供潜在指导。
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