<p>Predictors of Acquired <em>T790M</em> Mutation in Patients Failing First- or Second-Generation <em>Epidermal</em> <em>Growth</em> <em>Factor</em> <em>Receptor</em>-Tyrosine Kinase Inhibitors</p>

Abstract

Background This study aims to determine the predictors of acquired exon 20 T790M mutation in advanced non-small cell lung cancer (NSCLC) patients harbouring sensitizing epidermal growth factor receptor ( EGFR) mutation following the failure of first- or second-generation EGFR -tyrosine kinase inhibitor (TKI). Methods This is a retrospective observational study of NSCLC patients with sensitising EGFR mutation experiencing disease progression (PD) whilst on first- or second-generation EGFR -TKIs with subsequent investigations to detect acquired T790M mutation at the University of Malaya Medical Centre from 1st January 2015 to 31st December 2017. Results A total of 87 patients were included. Upon PD, acquired T790M mutation was found in 55 (63.2%) patients and was significantly more common in patients who achieved partial response (PR) whilst on the EGFR- TKIs (p = 0.008) or had new lung metastasis upon PD (p = 0.048). It was less frequent in patients who developed new symptomatic brain lesions (p = 0.021). Patients with exon 19 deletion were more likely to acquire T790M mutation compared to those with exon 21 L858R point mutation (p = 0.077). Multivariate analysis revealed PR whilst on EGFR -TKI treatment was an independent predictor of acquiring T790M mutation (p = 0.021), whereas development of new symptomatic brain lesions (p = 0.034) or new lymph node metastases (p = 0.038) upon PD was independently against acquiring T790M mutation. Patients with exon 19 deletion were more likely to acquire T790M mutation compared to those with exon 21 L858R point mutation (odds ratio: 2.3, 95% confidence interval: 0.84–6.25, p = 0.104). Conclusion The best tumour response of PR to first- or second-generation EGFR -TKI treatment independently predicts acquired T790M mutation. Patients with exon 19 deletion are likely to acquire T790M mutation. This would prove useful for clinicians to prognosticate and plan subsequent treatments for patients with advanced NSCLC harbouring EGFR mutations.

Risk Stratification Using a Novel Nomogram for 2190 EGFR-Mutant NSCLC Patients Receiving the First or Second Generation EGFR-TKI

“…Generally, pretreatment of individuals harboring the exon 19 deletion is associated with a higher risk of developing the acquired T790M resistance mutation than pretreatment of individuals harboring the L858 mutation [ 22 ]. In addition, the clinical tumor response [ 23 ] and a longer duration of EGFR-TKI treatment (≥12 months) [ 24 , 25 , 26 , 27 ] were reported to be associated with a higher frequency of T790M mutation acquisition. Therefore, patients in the low-risk groups with predicted PFS ≥12 months may be presumed to have a higher chance of acquiring the T790M mutation and are suitable for sequential osimertinib use, although acquired T790M and sequential osimertinib were not evaluated in the current study.…”

A Novel KIF5B-EGFR Fusion Variant in Non-Small-Cell Lung Cancer and Response to Afatinib: A Case Report

“…of cases. 19,20 In this study, blood-based NGS testing revealed the acquisition of T790M. Osimertinib, a thirdgeneration EGFR-TKI, has demonstrated high efficacy in patients with T790M-positive advanced NSCLC in whom disease had progressed during prior first-or secondgeneration TKI therapy.…”

Optimizing Patient Outcomes Through Sequential EGFR TKI Treatment in Asian Patients With EGFR Mutation-Positive NSCLC

“…In the multivariate analysis of molecular and clinical predictors, the presence of EGFR Ex19del mutations (vs Ex21 L858R mutations), younger age (< 65 years), the absence of metastases (brain or intrathoracic lymph nodes), and lower fluorodeoxyglucose (FDG) uptake on FDG-PET/CT imaging (indicative of lower metabolic rate of viable tumor cells) were independently associated with a higher probability of acquiring T790M mutation following treatment failure on first- or second-generation EGFR TKIs. 117 - 120 In addition, Chua et al conducted an in-depth analysis of genetic and transcriptome alterations shaping the EGFR TKI resistance trajectories. The study results showed that the presence of TP53 wild-type, aging mutational signatures, and the absence of whole-genome doubling were predictive for the emergence of T790M-positive resistance.…”