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. 2017 Oct 9;8(62):105103-105114.
doi: 10.18632/oncotarget.21707. eCollection 2017 Dec 1.

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

Simon Baldacci  1   2 , Julien Mazieres  3 , Pascale Tomasini  4 , Nicolas Girard  5 , Florian Guisier  6 , Clarisse Audigier-Valette  7 , Isabelle Monnet  8 , Marie Wislez  9 , Maurice Pérol  10 , Pascal Dô  11 , Eric Dansin  12 , Charlotte Leduc  13 , Etienne Giroux Leprieur  14 , Denis Moro-Sibilot  15 , David Tulasne  2 , Zoulika Kherrouche  1   2 , Julien Labreuche  16 , Alexis B Cortot  1   2
Affiliations

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

Simon Baldacci et al. Oncotarget. .

Abstract

Background: 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: Patients 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.

Results: Forty 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.

Conclusion: MET-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.

Keywords: EGFR; MET; non small cell lung cancer; resistance; tyrosine kinase inhibitors.

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Conflict of interest statement

CONFLICTS OF INTEREST A B. Cortot reported conflicts of interest with : Astra-Zeneca, Boehringer-Ingelheim, Roche, Novartis, BMS, MSD, Pfizer Simon Baldacci reported conflicts of interest with : Lilly, GSK, Pfizer, Roche Nicolas Girard reported conflicts of interest with : Astra-Zeneca, Boehringer-Ingelheim, Roche, Novartis, BMS, MSD, Pfizer Clarisse Audigier-Valette reported conflicts of interest with : Astra-Zeneca, Boehringer-Ingelheim, Roche, Novartis, BMS, MSD, Pfizer Florian Guisier reported conflicts of interest with : Boehringer-Ingelheim, BMS

Figures

Figure 1
Figure 1. Flow chart of MET overexpression and MET amplification status on post EGFR TKI initiation sample
IHC : Immunohistochemistry ; FISH : Fluorescence In Situ Hybridization ; TKI : tyrosine kinase inhibitor.
Figure 2
Figure 2. Overall survival according to T790M status and MET amplification status
(A) Kaplan Meier estimates of overall survival in MET non amplified (blue) and MET amplified (red) patients. (B) Kaplan Meier estimates of overall survival in T790M-negative (blue) and T790M-positive (red) patients.
Figure 3
Figure 3. Duration of treatment with MET inhibitors
(A) Patients treated with a MET inhibitor as a single agent; (B) Patients treated with a MET inhibitor in combination with an EGFR TKI. ID : identification number, Red: progressive disease as best response according to RECIST criteria ; Orange : stable disease as best response according to RECIST criteria ; Green : partial response as best response according to RECIST criteria, White : no tumor response evaluation available ; Arrow indicates that the MET inhibitor therapy is still ongoing.
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