The allele frequency of EGFR T790M in ctDNA predicted clinical outcomes of Osimertinib in non-small cell lung cancer patients from a real-world study
Authors: Fu Xiao , Shi Tingting , Liu Mengjie , Zheng Xiaoqiang , Zheng Haoran , Fan Chaoxin , Zhang Rui , Chen Xue , Jiang Lili , Wang Wenjuan , Yang Yujuan , Liang Xuan , Ruan Zhiping , Tian Tao , Yao Yu 
Published: June 2022

Abstract
Background: The clinical and molecular factors that associated with the response to Osimertinib in the patients who have acquired resistance to the first or second-generation of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is elusive.Objectives: The purpose of this study is to investigate the clinical relevance to the allele frequency (AF) of T790M in circulating tumor DNA (ctDNA) by targeted next generation sequencing (NGS), and to analyze the prognostic value of T790M AF in patients with advanced non-small cell lung cancer (NSCLC) receiving Osimertinib after resistance to the first-or second-generation of EGFR-TKIs.Materials and methods: We retrospectively screened 3011 advanced NSCLC patients in the First Affiliated Hospital of Xi’an Jiaotong University from November 2015 to March 2021. 586 of them experienced the first- or second-generation EGFR-TKIs resistance and had complete follow-up information, 146 of them took NGS gene test and 48 were detected EGFR T790M in ctDNA. The associations among T790M AF, clinical characteristics and objective response rate (ORR) of Osimertinib was performed by Students’ t-test or one-way ANOVA. The patients were divided into T790M-high and T790M-low groups according to a receiver operation curve (ROC) determined cut-off value. The correlation between T790M AF and ORR of Osimertinib was performed by Students’ t-test, and the association between clinical factors and ORR of Osimertinib was assessed by Pearson’s χ2 test or Fisher’s exact test, when appropriate. The survival curves were calculated by the Kaplan-Meier method and analyzed by the log-rank test. Cox proportional hazards regression models were also used to evaluate the association between clinical characteristics, T790M AF and survival endpoints.Results: Age (P=0.004), EGFR active mutations (P<0.001), EGFR T790M AF (P=0.014), prior EGFR-TKIs (P=0.024) and liver metastasis before Osimertinib treatment (P=0.031) were significantly associated with progression-free survival (PFS). Multivariate analysis revealed that age (hazard ratio: 0.32, 95%CI: 0.13-0.75, P=0.009) and the AF of EGFR T790M (hazard ratio: 0.39, 95%CI: 0.17-0.90, P=0.027) were independent prognostic factors for PFS in EGFR T790M positive advanced NSCLC patients receiving Osimertinib. EGFR active mutations (P<0.001) was significantly associated with overall survival (OS). EGFR T790M AF tended to be related to OS (P=0.066). Moreover, high EGFR T790M AF (HR: 0.31, 95%CI: 0.10-0.92, P=0.035) and EGFR active mutations (HR: 2.28, 95%CI: 1.07-4.90, P=0.015) were independently predictive factors of OS in multivariate analysis.Conclusion: EGFR T790M AF in ctDNA independently predicted PFS and OS in T790M-positive advanced NSCLC who received Osimertinib after resistance to the first- or second-generation of EGFR-TKIs.