Prognostic impact and treatment options for EGFR-mutant non-small cell lung cancer with concurrent EGFR amplification

The prognostic role of EGFR amplification in treatment-naïve EGFR-mutant NSCLC remains controversial, and the efficacy of different EGFR-TKIs in this population is unclear.

This retrospective study enrolled 781 patients with locally advanced or metastatic EGFR-mutant NSCLC who received first-line EGFR-TKIs monotherapy. Patients were stratified by EGFR amplification status. Survival outcomes were analyzed using Kaplan-Meier and multivariate Cox models, with IPTW adjustment. Subgroup analyses were performed by EGFR mutation type and the EGFR-TKI generation.

Patients with EGFR mutations and concurrent EGFR amplification demonstrated a trend toward shorter OS compared to those with EGFR mutation alone (37.3 vs. 32.7 months), although the difference was not statistically significant (P = 0.14). Within the EGFR L858R subgroup, patients with co-occurring EGFR amplification had significantly shorter median PFS (8.9 vs. 12.4 months, P = 0.004) and OS (21.5 vs. 31.2 months, P = 0.03). In the patients with EGFR L858R mutation and concurrent EGFR amplification, second-generation TKIs exhibited better PFS (11.1 vs. 7.0 months, P = 0.046) and OS (32.4 vs. 15.4 months, P = 0.021) than third-generation TKIs.

Our study demonstrated that baseline EGFR amplification defines a clinically distinct, aggressive subtype of treatment-naïve patients with concurrent EGFR L858R mutation and EGFR amplification. Second-generation TKIs showed superior efficacy over third-generation TKIs in this specific population. These findings refine prognostic stratification and support biomarker-guided first-line therapy selection for EGFR L858R-mutant NSCLC with co-occurring EGFR amplification.