Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial.
Por:
Rosell R, Dafni U, Felip E, Curioni-Fontecedro A, Gautschi O, Peters S, Massutí B, Palmero R, Aix SP, Carcereny E, Früh M, Pless M, Popat S, Kotsakis A, Cuffe S, Bidoli P, Favaretto A, Froesch P, Reguart N, Puente J, Coate L, Barlesi F, Rauch D, Thomas M, Camps C, Gómez-Codina J, Majem M, Porta R, Shah R, Hanrahan E, Kammler R, Ruepp B, Rabaglio M, Kassapian M, Karachaliou N, Tam R, Shames DS, Molina-Vila MA, Stahel RA and BELIEF collaborative group
Publicada:
1 may 2017
Ahead of Print:
10 abr 2017
Categoría:
Pulmonary and respiratory medicine
Resumen:
BACKGROUND: The tyrosine kinase inhibitor erlotinib improves the outcomes of patients with advanced non-small-cell lung carcinoma (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. The coexistence of the T790M resistance mutation with another EGFR mutation in treatment-naive patients has been associated with a shorter progression-free survival to EGFR inhibition than in the absence of the T790M mutation. To test this hypothesis clinically, we developed a proof-of-concept study, in which patients with EGFR-mutant NSCLC were treated with the combination of erlotinib and bevacizumab, stratified by the presence of the pretreatment T790M mutation. METHODS: BELIEF was an international, multicentre, single-arm, phase 2 trial done at 29 centres in eight European countries. Eligible patients were aged 18 years or older and had treatment-naive, pathologically confirmed stage IIIB or stage IV lung adenocarcinoma with a confirmed, activating EGFR mutation (exon 19 deletion or L858R mutation). Patients received oral erlotinib 150 mg per day and intravenous bevacizumab 15 mg/kg every 21 days and were tested centrally for the pretreatment T790M resistance mutation with a peptide nucleic acid probe-based real-time PCR. The primary endpoint was progression-free survival. The primary efficacy analysis was done in the intention-to-treat population and was stratified into two parallel substudies according to the centrally confirmed pretreatment T790M mutation status of enrolled patients (T790M positive or negative). The safety analysis was done in all patients that have received at least one dose of trial treatment. This trial was registered with ClinicalTrials.gov, number NCT01562028. FINDINGS: Between June 11, 2012, and Oct 28, 2014, 109 patients were enrolled and included in the efficacy analysis. 37 patients were T790M mutation positive and 72 negative. The overall median progression-free survival was 13·2 months (95% CI 10·3-15·5), with a 12 month progression-free survival of 55% (95% CI 45-64). The primary endpoint was met only in substudy one (T790M-positive patients). In the T790M-positive group, median progression-free survival was 16·0 months (12·7 to not estimable), with a 12 month progression-free survival of 68% (50-81), whereas in the T790M-negative group, median progression-free survival was 10·5 months (9·4-14·2), with a 12 month progression-free survival of 48% (36-59). Of 106 patients included in the safety analysis, five had grade 4 adverse events (one acute coronary syndrome, one biliary tract infection, one other neoplasms, and two colonic perforations) and one died due to sepsis. INTERPRETATION: The BELIEF trial provides further evidence of benefit for the combined use of erlotinib and bevacizumab in patients with NSCLC harbouring activating EGFR mutations. FUNDING: European Thoracic Oncology Platform, Roche.
Filiaciones:
Rosell R:
Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain
Dafni U:
Frontier Science Foundation-Hellas & National and Kapodistrian University of Athens, Athens, Greece
Felip E:
Vall d'Hebron University Hospital, Institute of Oncology, Barcelona, Spain
Curioni-Fontecedro A:
University Hospital Zurich, Clinic of Oncology, Zurich, Switzerland
Swiss Group of Clinical Cancer Research, Bern, Switzerland
Gautschi O:
Cantonal Hospital Lucerne, Medical Oncology, Lucerne, Switzerland
Swiss Group of Clinical Cancer Research, Bern, Switzerland
Peters S:
Centre Hospitalier Universitaire Vaudois, Département d'Oncologie, Lausanne, Switzerland
Swiss Group of Clinical Cancer Research, Bern, Switzerland
:
Hospital General Universitario Alicante, Oncología Médica, Alicante, Spain
Palmero R:
Catalan Institute of Oncology, Hospital Duran i Reynals, Bellvitge, Spain
Aix SP:
Hospital Universitario 12 de Octubre, Oncología Médica, Madrid, Spain
Carcereny E:
Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain
Früh M:
Cantonal Hospital St Gallen, Oncology and Hematology, St Gallen, Switzerland
Swiss Group of Clinical Cancer Research, Bern, Switzerland
Pless M:
Cantonal Hospital Winterthur, Medical Oncology, Winterthur, Switzerland
Swiss Group of Clinical Cancer Research, Bern, Switzerland
Popat S:
Medical Oncology, Royal Marsden Hospital, London, UK
Kotsakis A:
University General Hospital of Heraklion, Medical Oncology, Heraklion, Crete, Greece
Cuffe S:
Cancer Trials Ireland and St James's Hospital, Medical Oncology, Dublin, Ireland
Bidoli P:
Ospedale San Gerardo, Oncologia Medica, Monza, Italy
Favaretto A:
Istituto Oncologico Veneto, IRCCS, Padova, Italy
Froesch P:
Instituto Oncologica Della Svizzera Italiana, Bellinzona, Switzerland
Swiss Group of Clinical Cancer Research, Bern, Switzerland
Reguart N:
Hospital Clínic, Medical Oncology & Genomics and Targeted Therapeutics in Solid Tumors, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
Puente J:
Thoracic, Urologic & Melanoma Cancer Unit Medical Oncology Department Hospital Clinico Universitario San Carlos, Madrid, Spain
Coate L:
University Hospital Limerick and Cancer Trials Ireland, Limerick, Ireland
Barlesi F:
Aix Marseille University
Assistance Publique Hôpitaux de Marseille, Marseille, France
Rauch D:
Okologiezentrum Thun-Berner Oberland, Thun, Switzerland
Swiss Group of Clinical Cancer Research, Bern, Switzerland
Thomas M:
Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research, Heidelberg, Germany
Camps C:
University Hospital Valencia, Valencia, Spain
Gómez-Codina J:
Hospital La Fe, Valencia, Spain
Majem M:
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Porta R:
Insitut Catalan d'Oncologia and University of Girona, Girona, Spain
Shah R:
Kent Oncology Centre, Maidstone, UK
Hanrahan E:
Cancer Trials Ireland and St Vincent's University Hospital, Dublin, Ireland
Kammler R:
European Thoracic Oncology Platform Coordinating Office, Bern, Switzerland
Ruepp B:
European Thoracic Oncology Platform Coordinating Office, Bern, Switzerland
Rabaglio M:
European Thoracic Oncology Platform Coordinating Office, Bern, Switzerland
Kassapian M:
Frontier Science Foundation-Hellas, Athens, Greece
Karachaliou N:
Institute of Oncology Rosell, University Hospital Sagrat Cor, Barcelona, Spain
Tam R:
Oncology Biomarker Development, Genentech, South San Francisco, CA, USA
Shames DS:
Oncology Biomarker Development, Genentech, South San Francisco, CA, USA
Molina-Vila MA:
Pangaea Biotech S L, Quirón Dexeus University Hospital, Barcelona, Spain
Stahel RA:
University Hospital Zurich, Clinic of Oncology, Zurich, Switzerland
Swiss Group of Clinical Cancer Research, Bern, Switzerland
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