PO.CL07.02 · 临床研究
从实验台到病床：一种CNS穿透性的全能型EGFR抑制剂WSD0922-FU，靶向原发突变和C797S获得性耐药突变，重塑EGFR突变型NSCLC的治疗格局
From bench to bedside: A CNS penetrant and Omnipotent EGFR inhibitor, WSD0922-FU targeting primary mutations and the C797S acquired resistance mutation shapes the treatment landscape of EGFR mutant NSCLC
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
随着第三代共价EGFR酪氨酸激酶抑制剂（TKI）奥希替尼作为携带经典EGFR突变肿瘤一线治疗的广泛采用，以及二代测序（NGS）应用的扩大，EGFR突变型非小细胞肺癌（NSCLC）的分子格局已发生实质性演变。因此，获得性耐药模式也发生了转变：曾经占主导地位、与第一代EGFR TKI相关的EGFR-T790M耐药突变发生率下降，而EGFR-C797S已成为一线第三代EGFR TKI治疗后的主要耐药机制。与此同时，越来越多的证据凸显了EGFR-L858R与EGFR-Ex19del突变肿瘤对一线第三代EGFR TKI治疗反应的差异。通过NGS进行的全面基因组分析持续完善我们对经典、非经典和旁路耐药改变谱的理解，尤其是那些涉及C797S或与之共存的改变。我们利用配对的组织和血浆样本，提供真实世界证据以刻画经典和非经典EGFR突变以及包括C797S在内的旁路信号改变的分子格局。我们进一步描述了WSD0922-FU的活性特征——这是一种专门设计用于应对不断演变的EGFR突变格局的分子，并有涵盖临床前至临床研究的转化数据支持。我们的数据表明，WSD0922-FU不仅对经典EGFR突变以及奥希替尼后的靶上耐药机制（包括C797S）具有强效活性，而且对一系列影响胞内和胞外结构域的非经典EGFR改变（Q701L、E709X、L718X、G719X、S768I、V769M、L792X、V834X）以及EGFRvIII也具有强效活性。总体而言，这些发现为WSD0922-FU的临床开发策略提供了依据，使其有望作为经典EGFR突变的一线治疗、奥希替尼治疗后CNS转移患者的二线选择，以及奥希替尼耐药后携带C797S肿瘤的靶向治疗。
查看英文原文 English abstract
The molecular landscape of EGFR-mutated non-small cell lung cancer (NSCLC) has evolved substantially with the widespread adoption of the third-generation covalent EGFR tyrosine kinase inhibitor (TKI) osimertinib as first-line therapy for tumors harboring classical EGFR mutations, along with the expanded use of next-generation sequencing (NGS). Consequently, patterns of acquired resistance have shifted: the once-predominant EGFR-T790M resistance mutation associated with first-generation EGFR TKIs has decreased in incidence, while EGFR-C797S has emerged as a major resistance mechanism following front-line third-generation EGFR TKI therapy. In parallel, increasing evidence highlights differential therapeutic responses to first-line third-generation EGFR TKIs between tumors with EGFR-L858R and EGFR-Ex19del mutations. Comprehensive genomic profiling through NGS continues to refine our understanding of the spectrum of classical, non-classical, and bypass resistance alterations, particularly those involving or co-occurring with C797S. Using paired tissue and plasma samples, we provide real-world evidence characterizing the molecular landscape of classical and non-classical EGFR mutations, as well as bypass signaling alterations that include C797S. We further describe the activity profile of WSD0922-FU, a molecule specifically designed to address the evolving EGFR mutational landscape, supported by translational data spanning preclinical to clinical studies. Our data demonstrate that WSD0922-FU exhibits potent activity not only against classical EGFR mutations and on-target resistance mechanisms following osimertinib-including C797S-but also against a range of non-classical EGFR alterations affecting both intracellular and extracellular domains (Q701L, E709X, L718X, G719X, S768I, V769M, L792X, V834X) as well as EGFRvIII. Collectively, these findings inform the clinical development strategy for WSD0922-FU as a potential first-line therapy for classical EGFR mutations, a second-line option for patients with CNS metastases after osimertinib, and a targeted treatment for tumors harboring C797S following osimertinib resistance.
利益披露 Disclosure
W. Zhong, None..
Y. Liu, None..
C. Yu, None..
X. Wang, None.