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

Svenja Wagener-Ryczek,Carina Heydt,Markus Falk,Reinhard Büttner,Sabine Merkelbach-Bruse,Jana Fassunke,Christina Alidousty,Sebastian Michels,Michaela Angelika Ihle,Jürgen Wolf,Juliane Süptitz,Lukas Heukamp,Markus Tiemann

doi:10.1186/s12885-020-06920-3

Abstract

BackgroundOver the past years, EGFR tyrosine kinase inhibitors (TKI) revolutionized treatment response. 1st-generation (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.MethodsRebiopsies 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.ResultsOne 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.ConclusionsThe 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.

Highlights

Introductionepidermal growth factor receptor (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
Over the past years, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) revolutionized treatment response. 1stgeneration EGFR TKI and later the 2nd –generation irreversible EGFR TKI Afatinib were aimed to improve treatment response
Progression free survival (PFS) or partial response for at least 6 months (PFS > 6 months) under EGFR TKI therapy was chosen as criteria to include only patients without pre-existing EGFR p.T790M mutations. 21% of EGFR-mutated and subsequently Afatinib-treated patients progressed in less than 6 month

Summary

Introduction

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. 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. We evaluate the prevalence of acquired resistance mechanisms towards reversible and irreversible EGFR TKI. Administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) to patients with activating mutations in the EGFR gene, especially exon 19 deletions and exon 21 p.L858R point mutations, has significantly improved treatment and outcome of advanced-stage lung cancer patients [2]. Five to 50% of patients with lung adenocarcinomas carry activating mutations within the EGFR gene with huge differences between geographical distribution and populations [3]. Activating mutations confer patients susceptible to treatment with EGFR-tyrosine kinase inhibitors (TKIs). Acquired resistance to TKIs and secondary progression is being observed after a median time of 8 to 14 months in most patients [4]

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