Oncotarget

Research Papers:

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

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

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Oncotarget. 2017; 8:105103-105114. https://doi.org/10.18632/oncotarget.21707

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Abstract

Simon Baldacci1,15, Julien Mazieres2, Pascale Tomasini3, Nicolas Girard4, Florian Guisier5, Clarisse Audigier-Valette6, Isabelle Monnet7, Marie Wislez8, Maurice Pérol9, Pascal Dô10, Eric Dansin11, Charlotte Leduc12, Etienne Giroux Leprieur13, Denis Moro-Sibilot14, David Tulasne15, Zoulika Kherrouche1,15, Julien Labreuche16 and Alexis B. Cortot1,15

1CHU Lille, Thoracic Oncology Department, Univ. Lille, Siric ONCOLille, Lille, France

2Toulouse University Hospital, Université Paul Sabatier, Toulouse, France

3Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Multidisciplinary Oncology & Therapeutic Innovations Department, Marseille, France

4Louis Pradel Hospital, Hospices Civils de Lyon, Lyon, France

5Rouen University Hospital, Thoracic oncology unit & Normandy University, IRIB, LITIS Lab, EA 4103 QuantIF team, Rouen, France

6Service de Pneumologie, Centre Hospitalier Sainte Musse, Toulon, France

7Centre Hospitalier Intercommunal de Créteil, Créteil, France

8APHP Hôpital Tenon, Paris, France

9Department of Medical Oncology, Centre Léon Bérard, Lyon, France

10Centre Régional de Lutte Contre le Cancer François Baclesse, Caen, France

11Centre Oscar Lambret, Lille, France

12CHU Strasbourg, Strasbourg, France

13APHP – Hôpital Ambroise Paré, Boulogne-Billancourt, France

14Unité d’Oncologie Thoracique, Service de Pneumologie, CHU Grenoble-Alpes, La Tronche, France

15Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161, M3T, Mechanisms of Tumorigenesis and Targeted Therapies, Lille, France

16EA 2694 University of Lille, Lille, France

Correspondence to:

Alexis B. Cortot, email: alexis.cortot@chru-lille.fr

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

Received: February 21, 2017    Accepted: August 04, 2017    Published: October 09, 2017

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.


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