The concomitant gene alterations impact the therapeutic efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors in advanced non-small cell lung cancer patients with epidermal growth factor receptor sensitive mutation

Abstract

Objective: To investigate if concomitant gene alterations impact the therapeutic efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) sensitive mutation. Methods: From November 2016 to December 2017, 51 patients (19 males and 32 females, age 37-85 years) with histology or cytology diagnosed,locally advanced or metastatic NSCLC from Zhongshan Hospital Fudan University were prospectively recruited in the study. All patients harboring EGFR sensitive mutation detected by a 123 lung cancer specific gene panel of next-generation sequencing(NGS) analysis were under treatment of EGFR-TKIs. Multi-factors analysis of the correlation between EGFR-TKIs efficacy and concomitant gene alterations were analyzed by multivariate Cox regression model. Results: 82% of the NSCLC patients with EGFR mutation presented concomitant gene alterations with an average number of 2.1. Patients not harboring concomitant gene alterations had a longer median progression free survival (mPFS: not reached vs 8.8 m, P=0.008). Those who had less than 2 concomitant genes had a higher objective response rate[ORR: 52% (17/33) vs 33% (6/18) , P=0.251]and better mPFS (13.8 vs 8.0 m, P=0.003). The top 3 concomitant gene alterations were TP53 gene mutation(55%, 28/51), EGFR gene amplification (26%, 13/51) and RB1 gene mutation (18%,9/51) respectively. The mPFS of EGFR-TKI treatment in patients with either one of these 3 concomitant genes was 8.0, 8.0, and 6.0 months respectively, significantly shorter than those without one of the 3 gene alterations (13.8, 13.1, and 10.8 months respectively). Multivariate Cox regression revealed that concomitant gene abnormalities (P=0.036) and accompanied by RB1 gene mutation (P=0.025) were independent risk factors for the survival benefit of EGFR-TKI in the treatment of advanced NSCLC with EGFR-sensitive mutation. Conclusions: The efficacy of EGFR-TKI decreased significantly in advanced NSCLC with EGFR-sensitive mutation who had concomitant gene abnormalities, especially accompanied by more than 2 of the 3 gene alterations (TP53 gene mutation, EGFR gene amplification or RB1 gene mutation). This study suggested that the concomitant gene alterations should be an important issue for consideration when applying a personalized combination therapy for advanced NSCLC harboring EGFR sensitive mutation.