Journal Article

Osimertinib for EGFR‐Mutant NSCLC Patients With Acquired T790M and EGFR Amplification After First‐Generation EGFR‐TKI Resistance

Xu, Yingqi, Zhong, Hua, Zhang, Yidan, Xia, Jinjing, Zhong, Runbo, Xu, Jianlin

2025

Overview

Third‐generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) is the standard therapy for patients harboring T790M after first‐generation EGFR‐TKI resistance. However, the impact of acquired EGFR amplification on the efficacy of third‐generation EGFR‐TKI against T790M remains uncertain. We aimed to investigate whether the presence of acquired EGFR amplification after first‐generation EGFR‐TKI resistance influences the efficacy of third‐generation EGFR‐TKI in patients with advanced non‐small‐cell lung cancer (NSCLC). We reviewed data from 275 advanced NSCLC patients harboring T790M after first‐generation EGFR‐TKI resistance. Patients were categorized into two groups based on the presence or absence of acquired EGFR amplification identified through next‐generation sequencing (NGS) after first‐line EGFR‐TKI treatment. We evaluated the efficacy of osimertinib used as a second‐line treatment. Among these patients, 59 exhibited acquired EGFR amplification, while 216 did not. The median progression‐free survival (PFS) was 12.20 months in the EGFR amplification group and 12.03 months in the non‐amplification group (p = 0.011), with median overall survival (OS) of 33.90 months and 23.30 months, respectively (p = 0.164). Multivariate analysis of PFS revealed that acquired EGFR amplification and EGFR 19del were independent prognostic factors for patients with T790M undergoing osimertinib. Additionally, subgroup analysis indicated a prolonged PFS in patients with EGFR 19del compared to those with EGFR 21L858R (p = 0.034) in the EGFR amplification group. Following first‐generation EGFR‐TKI resistance, advanced EGFR‐mutant NSCLC patients harboring both acquired T790M and EGFR amplification are likely to experience enhanced PFS with osimertinib. This phenomenon is particularly noteworthy among individuals with EGFR 19del. Acquired EGFR amplification may coincide with T790M after first‐generation EGFR‐TKI resistance, accounting for 21.5% of cases in our study. Patients with both acquired T790M and EGFR amplification after first‐generation EGFR‐TKI may derive enhanced benefits from 3rd EGFR‐TKI. Patients with both acquired T790M and EGFR amplification, particularly those with EGFR 19del, exhibited a longer PFS.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Acrylamides - therapeutic use / Adult / Aged / Aged, 80 and over / Aniline Compounds - therapeutic use / Antineoplastic Agents - therapeutic use / Biopsy / Cancer / Cancer therapies / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - mortality / Carcinoma, Non-Small-Cell Lung - pathology / Drug Resistance, Neoplasm - genetics / EGFR / EGFR amplification / EGFR‐TKI / Epidermal growth factor receptors / ErbB Receptors - antagonists & inhibitors / ErbB Receptors - genetics / Female / Gene Amplification / Genes / Genetic testing / High-Throughput Nucleotide Sequencing / Humans / Indoles / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - mortality / Lung Neoplasms - pathology / Male / Metastasis / Middle Aged / Multivariate analysis / Mutants / Mutation / Non-small cell lung carcinoma / NSCLC / Original / ORIGINAL ARTICLE / Progression-Free Survival / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Protein-tyrosine kinase receptors / Pyrimidines / Retrospective Studies / T790M / Tomography / Tyrosine kinase inhibitors / Variables