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Molecular correlates of response to capmatinib in advanced non-small-cell lung cancer: clinical and biomarker results from a phase I trial Schuler, Martin Berardi, R. Lim, Darren Wan-Teck de Jonge, M. Azaro Pedrazzoli, Analía Beatriz Bauer, Todd Institut Català de la Salut [Schuler M] Department of Medical Oncology, West German Cancer Center, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany. [Berardi R] Clinica Oncologica, Università Politecnica delle Marche—Ospedali Riuniti, Ancona, Italy. [Lim WT] Division of Medical Oncology, National Cancer Centre Singapore, Singapore. [de Jonge M] Medical Oncology, Erasmus MC Cancer Center, Rotterdam, The Netherlands. [Bauer TM] Drug Development Unit, Sarah Cannon Research Institute, and Tennessee Oncology, PLCC, Nashville, USA. [Azaro A] Unitat d’Investigació de Teràpia Molecular, Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Departament de Farmacologia, Universitat Autònoma de Barcelona, Bellaterra, Spain Vall d'Hebron Barcelona Hospital Campus Pulmons - Càncer - Aspectes genètics DISEASES::Respiratory Tract Diseases::Lung Diseases::Lung Neoplasms::Carcinoma, Bronchogenic::Respiratory Tract Diseases::Carcinoma, Non-Small-Cell Lung DISEASES::Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Mutation ENFERMEDADES::enfermedades respiratorias::enfermedades pulmonares::neoplasias pulmonares::carcinoma broncogénico::enfermedades respiratorias::carcinoma de pulmón de células no pequeñas ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::mutación Mutació del MET; Capmatinib Mutación del MET; Capmatinib MET mutation; Capmatinib Background Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%–4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC. Patients and methods Eligible patients [≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats. Results Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4–33.0). In patients with MET GCN ≥6 (n = 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN ≥6 was 9.3 months (95% confidence interval, 3.8–11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%). Conclusions MET GCN ≥6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC (NCT01324479). This study was funded by Novartis Pharmaceuticals Corporation. 2021-10-20T08:03:21Z 2021-10-20T08:03:21Z 2020-06 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Schuler M, Berardi R, Lim WT, de Jonge M, Bauer TM, Azaro A, et al. Molecular correlates of response to capmatinib in advanced non–small-cell lung cancer: clinical and biomarker results from a Phase I trial. Ann Oncol. 2020 Jun;31(6):789–97. 0923-7534 https://hdl.handle.net/11351/6421 10.1016/j.annonc.2020.03.293 32240796 000535705600012 http://hdl.handle.net/11351/6421 eng Annals of Oncology;31(6) https://doi.org/10.1016/j.annonc.2020.03.293 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess application/pdf application/pdf Elsevier Scientia