Outcome of EGFR-mutated NSCLC patients with MET-driven resistance to EGFR tyrosine kinase inhibitors.

Simon Baldacci,Eric Dansin,Zoulika Kherrouche,Maurice Pérol,Julien Mazieres,Marie Wislez,Julien Labreuche,David Tulasne,Pascale Tomasini,Charlotte Leduc,Florian Guisier,Isabelle Monnet,Alexis B Cortot,Etienne Giroux Leprieur,Clarisse Audigier-Valette,Nicolas Girard,Pascal Dô,Denis Moro-Sibilot

doi:10.18632/oncotarget.21707

Abstract

BackgroundSeveral mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC have been described including the T790M mutation and MET amplification. Whereas T790M mutation confers prolonged survival and sensitivity to 3rd generation TKIs, data are lacking on clinical features and outcome of MET-driven resistant EGFR-mutated NSCLC patients.MethodsPatients with metastatic EGFR-mutated NSCLC displaying high MET overexpression or MET amplification, detected on a biopsy performed after progression on EGFR TKI, were identified in 15 centers. Clinical and molecular data were retrospectively collected.ResultsForty two patients were included. The median overall survival (OS), and the median post EGFR TKI progression overall survival (PPOS) were 36.2 months [95%CI 27.3-66.5] and 18.5 months [95%CI 10.6-27.4] respectively. Nineteen out of 36 tumors tested for MET FISH had MET amplification. A T790M mutation was found in 11/41 (26.8%) patients. T790M-positive patients had a better OS than T790M-negative patients (p=0.0224). Nineteen patients received a MET TKI. Objective response was reported in 1 out of 12 evaluable patients treated with a MET inhibitor as a single agent and in 1 of 2 patients treated with a combination of MET and EGFR TKIs.ConclusionMET-driven resistance to EGFR TKI defines a specific pattern of resistance characterized by low objective response rate to MET inhibitors given alone and overlapping with T790M mutations. Further studies are warranted to define adequate therapeutic strategies for MET-driven resistance to EGFR TKI.

Highlights

RESULTSEGFR mutations are found in 10% of non small cell lung cancer (NSCLC) in Caucasians and 40% in Asians [1]
MET-driven resistance to EGFR tyrosine kinase inhibitors (TKIs) defines a specific pattern of resistance characterized by low objective response rate to MET inhibitors given alone and overlapping with T790M mutations
Treatment of advanced EGFR-mutated NSCLC patients relies on EGFR tyrosine kinase inhibitors (TKIs), which demonstrated superiority over chemotherapy as first-line therapy [2,3,4,5]

Summary

Introduction

RESULTSEGFR mutations are found in 10% of non small cell lung cancer (NSCLC) in Caucasians and 40% in Asians [1]. Besides T790M mutation, bypass activation of other tyrosine kinase receptors including MET or HER2 is the second most common mechanism of resistance to EGFR TKI. MET amplification has been detected in 5 to 22% of patients with an acquired resistance to EGFR TKI [9,10,11,12,13,14]. High MET overexpression with a 3+ immunoscore (IHC3+) by immunohistochemistry was recently found in 27% of EGFR mutated NSCLC with acquired resistance to EGFR TKI [17]. Several mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC have been described including the T790M mutation and MET amplification. Whereas T790M mutation confers prolonged survival and sensitivity to 3rd generation TKIs, data are lacking on clinical features and outcome of MET-driven resistant EGFR-mutated NSCLC patients

Methods

Results

Conclusion