1. Molecular correlates of response to capmatinib in advanced non-small-cell lung cancer: clinical and biomarker results from a phase I trial
- Author
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Todd M. Bauer, Wan-Teck Lim, Analia Azaro, Tae Min Kim, N. Nwana, Dae Ho Lee, Angelo Delmonte, Xiaoming Cui, J-Y. Han, Mira Wollner, Rossana Berardi, Maya Gottfried, M.J.A. de Jonge, Martin Schuler, Arndt Vogel, M. Akimov, S. Ghebremariam, Monica Giovannini, David S. Hong, 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, and Medical Oncology
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms [DISEASES] ,Lung Neoplasms ,Nausea ,Peripheral edema ,Medizin ,Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES] ,Pulmons - Càncer - Aspectes genètics ,NSCLC ,03 medical and health sciences ,0302 clinical medicine ,neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares [ENFERMEDADES] ,SDG 3 - Good Health and Well-being ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,medicine ,Humans ,Lung cancer ,fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS] ,Performance status ,Triazines ,business.industry ,Imidazoles ,Respiratory Tract Diseases::Lung Diseases::Lung Neoplasms::Carcinoma, Bronchogenic::Respiratory Tract Diseases::Carcinoma, Non-Small-Cell Lung [DISEASES] ,Hematology ,Proto-Oncogene Proteins c-met ,MET exon 14 ,medicine.disease ,enfermedades respiratorias::enfermedades pulmonares::neoplasias pulmonares::carcinoma broncogénico::enfermedades respiratorias::carcinoma de pulmón de células no pequeñas [ENFERMEDADES] ,Confidence interval ,030104 developmental biology ,Capmatinib ,Tolerability ,MET mutation ,030220 oncology & carcinogenesis ,Benzamides ,Mutation ,Vomiting ,Biomarker (medicine) ,medicine.symptom ,business ,Biomarkers ,MET amplification - Abstract
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.
- Published
- 2020