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Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSé phase II trial.

  • Moro-Sibilot, D1
  • Cozic, N2
  • Pérol, M3
  • Mazières, J4
  • Otto, J5
  • Souquet, P J6
  • Bahleda, R7
  • Wislez, M8
  • Zalcman, G9
  • Guibert, S D10
  • Barlési, F11
  • Mennecier, B12
  • Monnet, I13
  • Sabatier, R14
  • Bota, S15
  • Dubos, C16
  • Verriele, V17
  • Haddad, V18
  • Ferretti, G19
  • Cortot, A20
  • And 4 more
  • 1 Thoracic Oncology Unit, Grenoble-Alpes University Hospital, Grenoble; Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris. Electronic address: [email protected]
  • 2 Department of Biostatistics and Epidemiology, Gustave Roussy Cancer Campus, INSERM U1018, ESP, Paris-Saclay and Paris-Sud Universities, Villejuif.
  • 3 Department of Medical Oncology, Léon Bérard Cancer Centre, Lyon.
  • 4 Pneumology Department, Toulouse University Hospital and Paul Sabatier University, Toulouse.
  • 5 Department of Medicine, Antoine Lacassagne Cancer Centre, Nice.
  • 6 Department of Pneumology and Thoracic Oncology, Lyon Sud Hospital Center, Hospices Civils de Lyon, Pierre Bénite.
  • 7 Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Villejuif.
  • 8 Pneumology Department, Tenon Hospital, AP-HP and "Pierre and Marie Curie" University, Paris.
  • 9 Thoracic Oncology Department-CIC INSERM 1425, Bichat University Hospital, AP-HP, Paris; Paris-Diderot University, Paris.
  • 10 Hematology Department, Pontchaillou, Rennes.
  • 11 Multidisciplinary Oncology & Therapeutic Innovations Department, APHM and Aix Marseille University, INSERM, CNRS, CRCM, Marseille.
  • 12 Pneumology Department, Strasbourg University Hospital, Strasbourg.
  • 13 Pneumology Department, CHIC Creteil, Créteil.
  • 14 Department of Medical Oncology, Inserm 1068, CNRS UMR7258, CRCM, Paoli-Calmettes Institute and Aix-Marseille University, Marseille.
  • 15 Pneumology Department, Charles Nicolle Hospital, Rouen University Hospital, Rouen.
  • 16 Pneumology Department, François Baclesse Cancer Centre, Caen.
  • 17 Anatomy and Pathological Cytologies Department, Paul Papin Cancer Centre, ICO, Angers.
  • 18 Department of Tumour Biology, Léon Bérard Cancer Centre, Lyon.
  • 19 Radiology and Medical Imaging Department, Grenoble-Alpes University Hospital, Grenoble.
  • 20 Department of Thoracic Oncology, Lille University Hospital and University of Lille, Lille.
  • 21 Molecular Genetic Unit: Hereditary Diseases and Oncology, Grenoble-Alpes University Hospital, Grenoble.
  • 22 Research and Development UNICANCER, Paris.
  • 23 French National Cancer Institute, Boulogne-Billancourt.
  • 24 Clinical Research Division, Gustave Roussy Cancer Campus, Villejuif, France. , (France)
Published Article
Annals of Oncology
Oxford University Press
Publication Date
Dec 01, 2019
DOI: 10.1093/annonc/mdz407
PMID: 31584608


In 2013, the French National Cancer Institute initiated the AcSé program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC). Advanced NSCLC patients with c-MET ≥6 copies, c-MET-mutated, or ROS-1-translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance. From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET ≥6 copies, 74 c-MET-mutation, and 78 ROS-1-translocated tumour. Finally, 25 patients in the c-MET ≥6 copies cohort, 28 in the c-MET-mutation cohort, and 37 in the ROS-1-translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET ≥6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET-≥6 copies cohort, 36% in the c-MET-mutated, and 69.4% in the ROS-1-translocation cohort. Safety data were consistent with that previously reported. Crizotinib activity in patients with ROS1-translocated tumours was confirmed. In the c-MET-mutation and c-MET ≥6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified. NCT02034981. © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]

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