Aggressive Progression to EGFR Tyrosine Kinase inhibitors in Advanced NSCLC Patients: Concomitant Mutations, Prognostic Indicator and Subsequent Management

Abstract

Background—EGFR tyrosine kinase (TKIs) are recommend as the first-line treatment for non-small cell lung cancer (NSCLC) patients with EGFR mutation. However, some patients experience aggressive progression (PFS≤6 months) on the first-line EGFR TKI therapy. Therefore, our study is to analyze the potential influencing factors including clinical features, biomarkers, concomitant mutations et al. Methods—A total of 1,073 NSCLC patients with EGFR mutation in a multi-center study from January 2019 to December 2021. The datum pathological and molecular characteristics were collected. The area under the receiver operating characteristic (ROC) curve was used to evaluate the predictive effect of Ki-67 on the first-line TKI. The curve of progression-free survival (PFS) was conducted by Kaplan-Meier method and tested by bilateral log-rank. Cox regression model was used to predict and evaluate PFS of different variables. Chi-square or Fisher analysis was used for correlation between groups. Results—55 patients who show aggressive progression on the first-line TKI therapy were analyzed in this study, while 71 with slow progression (PFS＞6 months). Concomitant mutationsincluding AXIN2, P2CG and RAD51C mutations occurred only in the aggressively progressive group (P=0.029). Correlation between Ki-67 index and the aggressive progression of the first-line TKI therapy was significant statistically different (P<0.05). In the second-line therapy, the PFS of chemotherapy in combination with other treatments was better than single TKIs in the first ten months. Conclusion—NSCLC harbored EGFR and concomitant mutations (such as AXIN2, PLCG2 and RAD51C), and / or Ki-67 high expression may indicate the aggressive progression to the first-line EGFR-TKI.

Optimal First-Line Treatment for EGFR-Mutated NSCLC: A Comparative Analysis of Osimertinib and Second-Generation EGFR-TKIs

“…Numerous small-scale studies have examined the independent predictive factors for shorter PFS in rstline EGFR-TKI treatment of EGFR-mutated NSCLC. These factors include poor ECOG PS, 32 carrying the T790M mutation before treatment, 33 concomitant mutations (e.g., in axin 2 [AXIN2], phospholipase C gamma 2 [PLCG2], and RAD51 paralog C [RAD51C]) and/or high marker of proliferation Ki-67 (MKI67) expression, 34 tumor protein p53 (TP53) co-mutations, 35 and dynamic plasma EGFR mutation status. 36 However, the results of these studies lack consistency and are not easily applied in clinical practice.…”