Acquired T790M Mutation in Patients Failing Treatment with First or Second-Generation EGFR-Tyrosine Kinase Inhibitors

Background: The majority of patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small cell lung cancer (NSCLC) develop resistance to first- or second-generation EGFR-tyrosine kinase inhibitor (TKI) after a median treatment period of 12 months. This study aimed to determine the prevalence and predictors of acquired T790M mutation as a resistance mechanism among these patients. Method: This was a retrospective study of patients with sensitising EGFR-mutant advanced NSCLC who experienced disease progression (PD) while on first- or second-generation EGFR-TKI treatment and underwent investigations to determine the resistance mechanisms in University of Malaya Medical Centre from 1st January 2015 to 31st December 2017. Result: Of 87 patients, acquired T790M mutation was detected in 55 (63.2%) patients at PD. T790M mutation was significantly more frequent in patients who achieved partial response (PR) as the best response (p ¼ 0.008) or had new lung metastasis (p ¼ 0.048); and significantly less frequent in patients who developed new symptomatic brain metastases (p ¼ 0.021). Patients with exon 19 deletion were more likely to acquire T790M mutation compared to those with exon 21 L858R point mutation (p ¼ 0.077). In multivariate analysis, PR with EGFR-TKI treatment was a significant independent predictor of acquired T790M mutation (p ¼ 0.021) while having new symptomatic brain metastases (p ¼ 0.034) or new lymph node metastases (p ¼ 0.038) were significant independent predictors against acquired T790M mutation. Conclusion: Acquired T790M mutation was a common resistance mechanism leading to first- or second-generation EGFR-TKI treatment failure. Patients with tumours harbouring exon 19 deletion mutation were more likely to acquire T790M mutation. A best tumour response of PR to EGFR-TKI treatment was an independent predictor of acquiring this resistance. This information is helpful to clinicians in the early prognostication and management planning for patients with EGFR-mutant NSCLC