Rafael Rosell1, Urania Dafni2, Enriqueta Felip3, Alessandra Curioni-Fontecedro4, Oliver Gautschi5, Solange Peters6, Bartomeu Massutí7, Ramon Palmero8, Santiago Ponce Aix9, Enric Carcereny1, Martin Früh10, Miklos Pless11, Sanjay Popat12, Athanasios Kotsakis13, Sinead Cuffe14, Paolo Bidoli15, Adolfo Favaretto16, Patrizia Froesch17, Noemí Reguart18, Javier Puente19, Linda Coate20, Fabrice Barlesi21, Daniel Rauch22, Michael Thomas23, Carlos Camps24, Jose Gómez-Codina25, Margarita Majem26, Rut Porta27, Riyaz Shah28, Emer Hanrahan29, Roswitha Kammler30, Barbara Ruepp30, Manuela Rabaglio30, Marie Kassapian31, Niki Karachaliou32, Rachel Tam33, David S Shames33, Miguel A Molina-Vila34, Rolf A Stahel35. 1. Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain. 2. Frontier Science Foundation-Hellas & National and Kapodistrian University of Athens, Athens, Greece. 3. Vall d'Hebron University Hospital, Institute of Oncology, Barcelona, Spain. 4. University Hospital Zurich, Clinic of Oncology, Zurich, Switzerland; Swiss Group of Clinical Cancer Research, Bern, Switzerland. 5. Cantonal Hospital Lucerne, Medical Oncology, Lucerne, Switzerland; Swiss Group of Clinical Cancer Research, Bern, Switzerland. 6. Centre Hospitalier Universitaire Vaudois, Département d'Oncologie, Lausanne, Switzerland; Swiss Group of Clinical Cancer Research, Bern, Switzerland. 7. Hospital General Universitario Alicante, Oncología Médica, Alicante, Spain. 8. Catalan Institute of Oncology, Hospital Duran i Reynals, Bellvitge, Spain. 9. Hospital Universitario 12 de Octubre, Oncología Médica, Madrid, Spain. 10. Cantonal Hospital St Gallen, Oncology and Hematology, St Gallen, Switzerland; Swiss Group of Clinical Cancer Research, Bern, Switzerland. 11. Cantonal Hospital Winterthur, Medical Oncology, Winterthur, Switzerland; Swiss Group of Clinical Cancer Research, Bern, Switzerland. 12. Medical Oncology, Royal Marsden Hospital, London, UK. 13. University General Hospital of Heraklion, Medical Oncology, Heraklion, Crete, Greece. 14. Cancer Trials Ireland and St James's Hospital, Medical Oncology, Dublin, Ireland. 15. Ospedale San Gerardo, Oncologia Medica, Monza, Italy. 16. Istituto Oncologico Veneto, IRCCS, Padova, Italy. 17. Instituto Oncologica Della Svizzera Italiana, Bellinzona, Switzerland; Swiss Group of Clinical Cancer Research, Bern, Switzerland. 18. Hospital Clínic, Medical Oncology & Genomics and Targeted Therapeutics in Solid Tumors, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain. 19. Thoracic, Urologic & Melanoma Cancer Unit Medical Oncology Department Hospital Clinico Universitario San Carlos, Madrid, Spain. 20. University Hospital Limerick and Cancer Trials Ireland, Limerick, Ireland. 21. Aix Marseille University; Assistance Publique Hôpitaux de Marseille, Marseille, France. 22. Okologiezentrum Thun-Berner Oberland, Thun, Switzerland; Swiss Group of Clinical Cancer Research, Bern, Switzerland. 23. Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research, Heidelberg, Germany. 24. University Hospital Valencia, Valencia, Spain. 25. Hospital La Fe, Valencia, Spain. 26. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 27. Insitut Catalan d'Oncologia and University of Girona, Girona, Spain. 28. Kent Oncology Centre, Maidstone, UK. 29. Cancer Trials Ireland and St Vincent's University Hospital, Dublin, Ireland. 30. European Thoracic Oncology Platform Coordinating Office, Bern, Switzerland. 31. Frontier Science Foundation-Hellas, Athens, Greece. 32. Institute of Oncology Rosell, University Hospital Sagrat Cor, Barcelona, Spain. 33. Oncology Biomarker Development, Genentech, South San Francisco, CA, USA. 34. Pangaea Biotech S L, Quirón Dexeus University Hospital, Barcelona, Spain. 35. University Hospital Zurich, Clinic of Oncology, Zurich, Switzerland; Swiss Group of Clinical Cancer Research, Bern, Switzerland. Electronic address: rolf.stahel@usz.ch.
Abstract
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.
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.
Authors: Howard L West; James Moon; Antoinette J Wozniak; Philip Mack; Fred R Hirsch; Martin J Bury; Myron Kwong; Dorothy D Nguyen; Dennis F Moore; Jieling Miao; Mary Redman; Karen Kelly; David R Gandara Journal: Clin Lung Cancer Date: 2017-07-06 Impact factor: 4.785