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

Abstract

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.

Keywords: EGFR; EGFR amplification; EGFR‐TKI; NSCLC; T790M.

FIGURE 1

Flow diagram showing the screening of patients with advanced NSCLC with EGFR sensitive mutations who had T790M mutation with or without EGFR amplification after first‐generation EGFR‐TKI.

FIGURE 2

Kaplan–Meier estimates of the two groups. (A) Progression‐free survival and (B) Overall survival.

FIGURE 3

Cox regression hazard model related to (A) PFS and (B) OS of third‐generation EGFR‐TKI therapy. PFS, progression‐free survival; OS, overall survival.

FIGURE 4

Subgroup analysis of PFS(A) and OS(B) in the EGFR amplification group receiving third‐generation EGFR‐TKI. PFS, progression‐free survival; OS, overall survival.