Refined Stratification Based on Baseline Concomitant Mutations and Longitudinal circulating tumor DNA Monitoring in Advanced EGFR-mutant Lung Adenocarcinoma under Gefitinib Treatment.

Duan, Jianchun; Xu, JiaChen; Wang, Zhijie; Bai, Hua; Cheng, Ying; An, Tongtong; Gao, Hongjun; Wang, Kai; Zhou, Qing; Hu, Yanping; Song, Yong; Ding, Cuimin; Peng, Feng; Liang, Li; Hu, Yi; Huang, Cheng; Zhou, Caicun; Shi, Yuankai; Han, Jiefei; Wang, Di; Tian, Yanhua; Yang, Zhenlin; Zhang, Li; Chuai, Shaokun; Ye, Junyi; Zhu, Guanshan; Zhao, Junhui; Wu, Yi-Long; Wang, Jie

INTRODUCTION The optimal treatment for EGFR-mutant lung adenocarcinoma (LUAD) remains challenging due to intratumor heterogeneity. We aimed to explore a refined stratification mode based on the integrated analysis of ctDNA tracking. METHODS ctDNA was prospectively collected at baseline and every eight weeks in advanced treatment-naïve EGFR-mutant LUAD patients under gefitinib treatment enrolled in a phase II trial, and analyzed using next-generation sequencing of a 168-gene panel. RESULTS Three subgroups categorized by baseline co-mutations: EGFR-sensitizing mutations (59, 32.8%), EGFR-sensitizing mutations with tumor suppressor mutations (97, 53.9%) and EGFR-sensitizing mutations with other driver mutations (24, 13.3%), exhibited distinct progression-free survival (PFS) and overall survival (OS) [PFS 13.2 (11.3-15.2) vs. 9.3 (7.6-10.5) vs. 4.0 (2.4-9.3) months; OS 32.0 (29.2-41.5) vs. 21.7 [(19.3-27.0) vs. 15.5 (10.5-33.7) months], providing evidence for initial stratification. 63.7% of the patients achieved week-8 ctDNA-clearance, with significant difference among three subgroups (74.5% vs. 64.0% vs. 29.4%, P=0.004, fisher's exact test). Patients without week-8 ctDNA-clearance had worse PFS [clearance vs. non-clearance 11.2 (9.9-13.2) vs. 7.4 (5.6-9.6) months, P=0.016, cox regression], especially in the second subgroup [5.8 (5.6-11.5) months], suggesting the necessity of adaptive stratification during treatment. During follow-up, 56.0% and 20.8% of the patients eventually harbored p.T790M and non-p.T790M mutations, with significant difference in non-p.T790M mutations among three subgroups (7.5% vs. 15.7% vs. 80.0%, P<0.001, fisher's exact test), giving clues to post-line treatment. CONCLUSIONS The patients with baseline co-mutations and ctDNA non-clearance at first visit might require combined therapy due to limited survival benefit of EGFR-TKI monotherapy. We proposed a refined stratification mode for the whole-course management of EGFR-mutant LUAD.