Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors

Abstract

Background: Over the past years, EGFR tyrosine kinase inhibitors (TKI) revolutionized treatment response. 1stgeneration (reversible) EGFR TKI and later the 2nd-generation irreversible EGFR TKI Afatinib were aimed to improve treatment response. Nevertheless, diverse resistance mechanisms develop within the first year of therapy. Here, we evaluate the prevalence of acquired resistance mechanisms towards reversible and irreversible EGFR TKI. Methods: Rebiopsies of patients after progression to EGFR TKI therapy (> 6 months) were targeted to histological and molecular analysis. Multiplexed targeted sequencing (NGS) was conducted to identify acquired resistance mutations (e.g. EGFR p.T790M). Further, Fluorescence in situ hybridisation (FISH) was applied to investigate the status of bypass mechanisms like, MET or HER2 amplification. Results: One hundred twenty-three rebiopsy samples of patients that underwent first-line EGFR TKI therapy (PFS ≥6 months) were histologically and molecularly profiled upon clinical progression. The EGFR p.T790M mutation is the major mechanism of acquired resistance in patients treated with reversible as well as irreversible EGFR TKI. Nevertheless a statistically significant difference for the acquisition of T790M mutation has been identified: 45% of afatinib-vs 65% of reversible EGFR TKI treated patients developed a T790M mutation (p-value 0.02). Progression free survival (PFS) was comparable in patients treated with irreversible EGFR irrespective of the sensitising primary mutation or the acquisition of p.T790M. Conclusions: The EGFR p.T790M mutation is the most prominent mechanism of resistance to reversible and irreversible EGFR TKI therapy. Nevertheless there is a statistically significant difference of p.T790M acquisition between the two types of TKI, which might be of importance for clinical therapy decision.

Comparison of afatinib and erlotinib combined with bevacizumab in untreated stage IIIB/IV epidermal growth factor receptor-mutated lung adenocarcinoma patients: a multicenter clinical analysis study

“…In the analysis of previous large cohort studies, the acquired EGFR-T790M mutation rate was higher in NSCLC patients taking first-generation EGFR-TKIs (gefitinib and erlotinib) than in those taking the second-generation EGFR-TKI afatinib. 42 , 43 The secondary EGFR-T790M mutation rates in our study were similar to those in previous cohort studies, and our results indicated that the addition of bevacizumab to first- and second-generation EGFR-TKIs did not affect the frequency or the trend of acquired EGFR-T790M mutation after disease progression.…”

Comparison of T790M Acquisition After Treatment With First- and Second-Generation Tyrosine-Kinase Inhibitors: A Systematic Review and Network Meta-Analysis

“…After removing duplicate studies and excluding titles and abstracts, 56 studies were considered for full-text evaluation, and 27 studies were excluded for different reasons (Table S3). Finally, 29 studies [including 23 multi-cohort studies (5,11, and six single-cohort studies (43)(44)(45)(46)(47)(48)] were included in the risk of bias assessment and singlearm meta-analysis, and 20 multi-cohort studies were included in the network meta-analysis. Among the studies identified in the search results, acquired T790M acquisition rates after treatment with gefitinib, erlotinib, icotinib, or afatinib were noted.…”

Outcomes in Patients With Lung Adenocarcinoma With Transformation to Small Cell Lung Cancer After EGFR Tyrosine Kinase Inhibitors Resistance: A Systematic Review and Pooled Analysis

“…The main resistance mechanism of EGFR-TKIs is the emergence of secondary EGFR-T790M mutations. Among the first-/second-generation EGFR-TKIs-resistant patients, 50% of patients have secondary EGFR-T790M mutations (13)(14)(15). Repeated biopsy cohort studies have shown that approximately 3%-10% of acquired EGFR-TKIs resistance is related to histological transformation to SCLC (16,17).…”