Journal Article

Outcomes in non‐small cell lung cancer with uncommon epidermal growth factor receptor L858 substitutions under first‐line epidermal growth factor receptor tyrosine kinase inhibitors: A large real‐world cohort study

Zhu, Minyi, Qu, Hao, Zhang, Jingying, Wu, Wei, Zhu, Junfei, Li, Hengyuan, Yuan, Minchi, Pang, Jiaohui, Feng, Zhi, Xiao, Yao, Shao, Youyou, Zhao, Xiaotian, Xia, Guojie, Liu, Meng

2024

Overview

Atypical L858R or other L858X mutations in the epidermal growth factor receptor (EGFR) gene, beyond the classical EGFRL858R mutation caused by c.2573 T > G, have been identified in non‐small cell lung cancer (NSCLC), yet their genomic features and survival benefits with EGFR tyrosine kinase inhibitor (TKI) treatment have not been fully explored. We retrospectively enrolled 489 NSCLC patients with baseline tumor tissue/plasma samples carrying uncommon EGFRL858R (N = 124), EGFRL858Q/M (N = 17), or classical EGFRL858R mutations (N = 348). The comparison of molecular features was performed using treatment‐naïve tumor tissues. Survival benefits and resistance mechanisms of first‐line EGFR TKI treatment were studied in an advanced disease subcohort. NSCLCs harboring uncommon EGFRL858R had lower TP53 mutation prevalence (p = 0.04) and chromosome instability scores (p = 0.02) than those with classical EGFRL858R. Concomitant EGFRL861Q mutations were enriched in NSCLCs with EGFRL858Q/M (p < 0.01), with cooccurrence in those carrying EGFRL858M. Patients with uncommon EGFRL858R experienced improved progression‐free survival (PFS) compared to those with classical EGFRL858R (median: 13.0 vs. 10.0 months, hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.41–0.80). The association remained significant when adjusting for sex, age, histological subtype, TKI category, and anti‐vascular therapy (HR: 0.55, 95% CI: 0.39–0.77). Furthermore, EGFRL858Q/M patients showed enhanced first‐line PFS (vs. classical EGFRL858R, HR: 0.26, 95% CI: 0.10–0.67), potentially benefiting more from afatinib. Additionally, NSCLCs with uncommon EGFRL858R and classical EGFRL858R had similar resistance profiles to EGFR TKIs. In conclusion, NSCLCs carrying atypical EGFR L858 aberrations, which had fewer TP53 mutations and higher chromosome stability, exhibited improved PFS under first‐line EGFR TKIs than those with the classical EGFRL858R. This study reveals that NSCLC patients with uncommon EGFR L858R mutations experience improved outcomes with EGFR TKIs compared to those with the classical EGFR L858R mutation, evidenced by longer PFS, fewer TP53 mutations, and higher chromosome stability. Furthermore, patients with EGFR L858Q/M showed enhanced first‐line PFS, potentially benefiting more from afatinib.

• Publisher: John Wiley & Sons, Inc
• Subject: Biopsy / Cancer therapies / Chromosomes / Disease resistance / EGFR / EGFR L858R / EGFR tyrosine kinase inhibitor / Epidermal growth factor / Epidermal growth factor receptors / first‐line treatment / Genes / Kinases / Lung cancer / Mutation / Non-small cell lung carcinoma / non‐small cell lung cancer / p53 Protein / Patients / Protein-tyrosine kinase receptors / Small cell lung carcinoma / Tumors / Tyrosine kinase inhibitors