Concurrent Genetic Alterations Predict the Progression to Target Therapy in EGFR-Mutated Advanced NSCLC

Abstract

Introduction: EGFR-mutant NSCLC displays diverse outcomes to tyrosine kinase inhibitor (TKI) treatment. Because co-occurring genomic alterations might describe different biological subsets of patients with this cancer, exploring co-occurring genomic alterations that impact patients' outcomes using a comprehensive gene panel is potentially important.

Methods: This retrospective cohort study was conducted with the panel-sequencing data acquired from January 2014 to May 2017, and clinical outcome data collected until February 2018. This study includes all eligible patients who possess panel-sequencing data before treatment with first-/second-generation EGFR-TKIs (cohort 1) or third-generation EGFR-TKIs following initial EGFR-TKI failure (cohort 2).

Results: Seventy-five patients (mean [SD] age, 58.5 [11.0] years; 68.0% women) were included in cohort 1, and 82 patients (mean [SD] age, 57.3 [9.1] years; 67.1% women) were included in cohort 2. In cohort 1, alterations in TP53 were independently associated with worse progression-free survival (PFS) (hazard ratio [HR]: 2.02; 95% confidence interval [CI]: 1.04-3.93; p = 0.038) in multivariate analysis. In cohort 2, TP53 mutation was associated with significantly worse PFS (8.9 versus 12.8 months; p = 0.029). RB1 mutation was significantly associated with worse (median PFS, 1.9 versus 11.7 months; p < 0.001). PTEN mutation was associated with significantly worse PFS (2.6 versus 10.3 months; p = 0.001). MDM2 amplification was associated with worse PFS (6.6 versus 10.4 months; p = 0.025). In cohort 2, multivariate analysis revealed that alterations in TP53 (HR: 2.23; 95% CI: 1.16-4.29; p = 0.017), RB1 (HR: 5.62; 95% CI: 1.96-16.13; p = 0.001), PTEN (HR: 5.84; 95% CI: 1.56-21.85; p = 0.009), and MDM2 (HR: 2.46; 95% CI: 1.02-5.94; p = 0.046) were independently associated with worse PFS.

Conclusions: Co-occurring genomic alterations detected by panel sequencing are associated with the clinical outcomes of EGFR-TKI treatment in NSCLC.

Keywords: Biomarker; Epidermal growth factor receptor; Molecular sequencing; NSCLC; Tyrosine kinase inhibitor.