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

Atypical L858R or other L858X mutations in the epidermal growth factor receptor (EGFR) gene, beyond the classical EGFR^L858R 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 EGFR^L858R (N = 124), EGFR^L858Q/M (N = 17), or classical EGFR^L858R 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 EGFR^L858R had lower TP53 mutation prevalence (p = 0.04) and chromosome instability scores (p = 0.02) than those with classical EGFR^L858R. Concomitant EGFR^L861Q mutations were enriched in NSCLCs with EGFR^L858Q/M (p < 0.01), with cooccurrence in those carrying EGFR^L858M. Patients with uncommon EGFR^L858R experienced improved progression-free survival (PFS) compared to those with classical EGFR^L858R (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, EGFR^L858Q/M patients showed enhanced first-line PFS (vs. classical EGFR^L858R, HR: 0.26, 95% CI: 0.10–0.67), potentially benefiting more from afatinib. Additionally, NSCLCs with uncommon EGFR^L858R and classical EGFR^L858R 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 EGFR^L858R.