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

Chai, Chee Shee and Liam, Chong Kin and Poh, Mau Ern and Ong, D. B. L. and Cheah, P. L. and Pang, Yong Kek and Ho, G. F. and Alip, A. (2019) Acquired T790M Mutation in Patients Failing Treatment with First or Second-Generation EGFR-Tyrosine Kinase Inhibitors. Journal of Thoracic Oncology, 14 (10). S1038. ISSN 1556-0864

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Abstract

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.

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