Decoding the Evolutionary Response to Ensartinib in Patients With ALK-Positive NSCLC by Dynamic Circulating Tumor DNA Sequencing

• DOI: 10.1016/j.jtho.2021.01.1615
• Publication Date: 2021-02-15T17:37:12Z
• Authors: Yunpeng Yang; Jie Huang; Tao Wang; Jianya Zhou; Jing Zheng; Jifeng Feng; Wu Zhuang; Jianhua Chen; Jun Zhao; Wei Zhong; Yanqiu Zhao; Yiping Zhang; Yong Song; Yi Hu; Zhuang Yu; Youling Gong; Yuan Chen; Feng Ye; Shucai Zhang; Lejie Cao; Yun Fan; Gang Wu; Yubiao Guo; Chengzhi Zhou; Kewei Ma; Jian Fang; Weineng Feng; Yunpeng Liu; Zhendong Zheng; Gaofeng Li; Huijie Wang; Shundong Cang; Ning Wu; Wei Song; Xiaoqing Liu; Shijun Zhao; Lieming Ding; Li Mao; Giovanni Selvaggi; Larry Zhu; Shanshan Xiao; Xiaobin Yuan; Zhilin Shen; Li Zhang
• Keywords: Circulating tumor DNA

IntroductionBy implementing dynamic circulating tumor DNA (ctDNA) analysis, we explored the impact of TP53 mutations on evolution and resistance mechanisms to ensartinib in patients with ALK-positive NSCLC.MethodsIn a multicenter phase 2 trial, NSCLC who progressed crizotinib were treated ensartinib. Blood samples for ctDNA analysis collected at baseline, cycle 3 day 1, progression disease (PD) analyzed 212-gene panel.ResultsA total 440 from 168 patients. Baseline (20.2%) significantly correlated inferior progression-free survival (4.2 mo versus 11.7 mo, p < 0.0001). Patients had higher mutation load than those without baseline (13.79 ± 3.72 4.67 0.39, 0.001). Although there was no significant difference between these groups 1 (5.89 2.25 0.62, = 0.425), mutated developed more PD (7.07 1.25 3.20 0.33, 0.003). Frequency abundance secondary ALK G1269A, G1202R, E1210K increased markedly baseline. In mutations, identified ALK-independent including bypass signaling activation, downstream effector protein reactivation, epithelial-mesenchymal transformation, epigenetic dysregulation.ConclusionsOur study highlighted advantage monitoring evolution. promoted genetic accelerated occurrence resistance. We also unveiled ALK-dependent mechanisms, mainly by