title: [Resistances to targeted therapies and strategy for following therapeutic lines in metastatic NSCLC].
abstract: EGFR, ALK, ROS1 Tyrosine Kinase Inhibitors (TKis) have changed natural history of 12 to 15% of patients with metastatic Non-Small Cell Lung Cancer (NSCLC) and molecular alterations (mutations or translocations) in these genes. Median Progression Free Survival (PFS) of these patients has increased from 12 months with a platinum-based chemotherapy associated with bevacizumab, to 18 months with TKIs, overall survival reaching several years in these patients. However, rare primary resistance have been described in less than 10% of patients with EGFR or ALK-mutated cancer, whereas secondary resistance occur systematically. New generations TKIs are currently in clinical development, which are active on tumor clones harboring a resistance mutation, and some of them diffuse perfectly well into brain, a classical sanctuary for metastasis. Strategies are developed to delay secondary resistance apparition, to prolong PFS, and then overall survival. These strategies use combinations, as soon as first linesetting, of TKIs with either an anti-angiogenic drug (bevacizumab), or with an immunological checkpoint inhibitors, or with Heat-Shock Protein (Hsp) inhibitors. In order to delay acquired resistance to EGFR TKIs, the French Intergroup (IFCT) has launched a combination trial of EGFR TKIs with an anti-estrogen (fulvestrant) in postmenopausal women, whereas other trials associate EGFR TKIs with EFGR monoclonal antibody cetuximab, or with a monoclonal antibody targeting c-met.
authors.affiliation: Service de pneumologie et oncologie thoracique, Université de Caen-Basse Normandie, Hôpital de la Côte-de-Nacre, 14033 Caen CS 3001, France; UMR Inserm 1086 Cancers et préventions, Université de Caen-Basse Normandie, Hôpital de la Côte-de-Nacre, 14033 Caen CS 3001, France.
authors.forename: Solenn
authors.initials: S
authors.lastname: Brosseau
authors.affiliation: Service de pneumologie et oncologie thoracique, Université de Caen-Basse Normandie, Hôpital de la Côte-de-Nacre, 14033 Caen CS 3001, France.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Oulkhouir
authors.affiliation: Service de pneumologie et oncologie thoracique, Université de Caen-Basse Normandie, Hôpital de la Côte-de-Nacre, 14033 Caen CS 3001, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Naltet
authors.affiliation: Service de pneumologie et oncologie thoracique, Université de Caen-Basse Normandie, Hôpital de la Côte-de-Nacre, 14033 Caen CS 3001, France; UMR Inserm 1086 Cancers et préventions, Université de Caen-Basse Normandie, Hôpital de la Côte-de-Nacre, 14033 Caen CS 3001, France; Centre de recherche clinique/Essais de phases précoces, Université de Caen-Basse Normandie, Hôpital de la Côte-de-Nacre, 14033 Caen CS 3001, France. Electronic address: zalcman-g@chu-caen.fr.
authors.forename: Gérard
authors.initials: G
authors.lastname: Zalcman
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D000068258:Bevacizumab; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D000068818:Cetuximab; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D004958:Estradiol / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077267:Fulvestrant; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D058990:Molecular Targeted Therapy; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D014178:Translocation, Genetic
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D018931:Antineoplastic Agents, Hormonal; D047428:Protein Kinase Inhibitors; D000077267:Fulvestrant; D000068258:Bevacizumab; D004958:Estradiol; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: ALK; Acquired resistance; EGFR; Inhibiteur de tyrosine-kinase; Primary resistance; ROS1; Résistance primaire; Résistance secondaire; Tyrosine kinase inhibitors