EGFR uncommon alterations in advanced non-small cell lung cancer and structural insights into sensitivity to diverse tyrosine kinase inhibitors

Haiyan Xu; Guangjian Yang; Runze Liu; Yaning Yang; Weihua Li; Junling Li; Xuezhi Hao; Puyuan Xing; Yan Wang

doi:10.3389/fphar.2022.976731

EGFR uncommon alterations in advanced non-small cell lung cancer and structural insights into sensitivity to diverse tyrosine kinase inhibitors

Front Pharmacol. 2022 Sep 16:13:976731. doi: 10.3389/fphar.2022.976731. eCollection 2022.

Authors

Haiyan Xu¹, Guangjian Yang², Runze Liu³, Yaning Yang⁴, Weihua Li⁵, Junling Li⁴, Xuezhi Hao⁴, Puyuan Xing⁴, Yan Wang⁴

Affiliations

¹ Department of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² Department of Respiratory Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, Shandong, China.
³ Guangdong Provincial Key Laboratory of Advanced Drug Delivery Systems and Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China.
⁴ Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁵ Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Abstract

Background: Approximately 10% of patients with non-small cell lung cancer (NSCLC) harbor uncommon epidermal growth factor receptor (EGFR) alterations. This study aims to investigate the therapeutic responses and predict the binding activity of different tyrosine kinase inhibitors (TKIs) for EGFR uncommon alterations. Methods: Between May 2014 and June 2021, clinical outcomes of NSCLC patients harboring EGFR uncommon alterations who received diverse treatment modalities: first-generation (1G) EGFR-TKI, second-generation (2G) EGFR-TKI afatinib, chemotherapy, and 1G TKI in combination with chemotherapy as the initial therapy were retrospectively analyzed, and structural analysis for the binding activity of major uncommon subtypes G719A, S768I, and L861Q to different TKIs were predicted. Results: A total of 102 NSCLC patients harboring EGFR uncommon alterations with treatment and survival outcomes were included and analyzed. The majority of patients presented compound mutations (54.9%), and G719X plus S768I was the predominant subtype (n = 33, 32.3%). There was a significant difference in median progression-free survival (mPFS) between therapeutic patterns (p = 0.015) and EGFR alteration subtypes (p = 0.017). Rather than almonertinib and furmonertinib, afatinib, dacomitinib and osimertinib revealed favorable binding activity to G719A mutation. In contrast, S768I and L861Q mutation indicated an unaffected binding activity to these diverse kinds of EGFR TKIs. Conclusion: Together with afatinib, 1G-TKIs combined with chemotherapy might be another effective option for NSCLC patients harboring EGFR uncommon alterations. Based on computational findings, afatinib, dacomitinib, and osimertinib might confer favorable activity to G719A, S768I, and L861Q, whereas almonertinib and furmonertinib revealed less activity to G719A.

Keywords: epidermal growth factor receptor; non-small cell lung cancer; targeted therapy; tyrosine kinase inhibitor; uncommon alteration.