Co-occurring EGFR p.E709X Mutation Mediates Primary Resistance to the Third-Generation EGFR-TKIs in EGFR p.G719X-Mutant Patients with Advanced NSCLC

Author:

Pang Lanlan1ORCID,Huang Yihua1ORCID,Zhuang Weitao1ORCID,Zhang Yaxiong1ORCID,Liao Jun1ORCID,Hao Yue2ORCID,Hao Feng3ORCID,Wang Guoqian3ORCID,Chen Ze-xin Chase4ORCID,Zhu Yu4ORCID,Li Mengzhen5ORCID,Song Zhengbo2ORCID,Deng Bo Peng6ORCID,Li Jing1ORCID,Zhang Li1ORCID,Fang Wenfeng1ORCID

Affiliation:

1. 1Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.

2. 2Department of Clinical Trial, Zhejiang Cancer Hospital, Hangzhou, China.

3. 3KYinno Biotechnology Co., Ltd, Beijing, China.

4. 4Guangdong Research Center of Organoid Engineering and Technology, Guangzhou, China.

5. 5Mygene Diagnostics Co., Ltd. China.

6. 6Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, China.

Abstract

Abstract Purpose: The current National Comprehensive Cancer Network (NCCN) guidelines recommend afatinib or osimertinib as the preferred first-line treatment strategy for patients with advanced NSCLC harboring EGFR p.G719X mutation. However, in the absence of head-to-head trials comparing afatinib with osimertinib in EGFR p.G719X-mutant patients, it is unclear which regimen is the preferred treatment option. Experimental Design: A large cohort of 4,228 treatment-naïve patients with lung cancer who underwent targeted next-generation sequencing (NGS) testing was screened for EGFR p.G719X mutation. A multicenter cohort involving 68 EGFR p.G719X-mutant patients with advanced NSCLC and NGS profiling was retrospectively enrolled to evaluate clinical responses to afatinib (n = 37) and the third-generation EGFR-TKIs (n = 31). Ba/F3 cells stably expressing the EGFR p.G719A mutation were created to investigate the response to EGFR-TKIs in vitro. Results: Concurrent EGFR p.E709X mutations, being the most frequent co-occurring EGFR mutation in EGFR p.G719X-mutant NSCLC (∼30%), exerted a detrimental effect on outcomes in patients treated with third-generation EGFR-TKI [G719X/E709X vs. G719X; objective response rate (ORR): 0.00% vs. 47.62%, P < 0.001; mPFS: 7.18 vs. 14.2 months, P = 0.04, respectively]. Conversely, no significant difference was found in the treatment efficacy of afatinib between EGFR p.G719X/E709X and EGFR p.G719X patients (G719X/E709X vs. G719X; ORR: 71.43% vs. 56.67%, P = 0.99; mPFS: 14.7 vs. 15.8 months, P = 0.69, respectively). In vitro experiments elucidated a resistant drug sensitivity and poor inhibition of EGFR phosphorylation in Ba/F3 cells expressing EGFR p.G719A/E709K mutation upon the third-generation EGFR-TKI treatment. Conclusions: Co-occurring EGFR p.E709X mutation mediated primary resistance to the third-generation EGFR-TKIs in EGFR p.G719X-mutant patients but remained sensitive to afatinib. A personalized treatment strategy should be undertaken based on the coexisting EGFR p.E709X mutation status.

Funder

National Natural Science Foundation of China

Huangpu Technology Bureau, Guangzhou, China

Publisher

American Association for Cancer Research (AACR)

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