Sistema de Salut de Catalunya
Institut Català de la Salut
[Bang YJ] Seoul National University College of Medicine, Seoul, Korea. [Su WC] National Cheng Kung University Hospital, Tainan, Taiwan. [Schuler M] Department of Medical Oncology, West German Cancer Center, University DuisburgEssen and German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany. [Nam DH] Samsung Medical Center, Seoul, Korea. [Lim WT] National Cancer Centre, Singapore. [Bauer TM] Sarah Cannon Research Institute/ Tennessee Oncology, PLLC, Nashville, Tennessee, USA. [Azaro A] Servei d’Oncologia Mèdica, Unitat d’Investigació de Teràpia Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Departament de Farmacologia, Universitat Autònoma de Barcelona, Bellaterra, Spain
Vall d'Hebron Barcelona Hospital Campus
2021-11-05T06:58:36Z
2021-11-05T06:58:36Z
2020-02
Amplificació del MET; Capmatinib; Tumors sòlids
Amplificación MET; Capmatinib; Tumores sólidos
MET amplification; Capmatinib; Solid tumors
Capmatinib is an oral, ATP-competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose-escalation results for capmatinib in advanced MET-positive solid tumor patients and dose expansion in advanced non-lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose-limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, Ctrough >EC90 (90% inhibition of c-MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose-expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near-complete immunohistochemically determined phospho-MET inhibition (H-score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high-level MET GCN (GCN ≥6) and MET-overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D.
Novartis Pharmaceuticals Corporation
Article
Published version
English
Proteïnes quinases - Inhibidors - Ús terapèutic; Càncer - Tractament; DISEASES::Neoplasms; Other subheadings::Other subheadings::Other subheadings::/drug therapy; CHEMICALS AND DRUGS::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Tyrosine Kinases::Receptor Protein-Tyrosine Kinases::Proto-Oncogene Proteins c-met; Other subheadings::Other subheadings::Other subheadings::/antagonists & inhibitors; ENFERMEDADES::neoplasias; Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia; COMPUESTOS QUÍMICOS Y DROGAS::enzimas y coenzimas::enzimas::transferasas::fosfotransferasas::fosfotransferasas (grupo alcohol aceptor)::proteína cinasas::proteína-tirosina cinasas::receptores proteína-tirosina cinasas::proteínas protooncogénicas c-met; Otros calificadores::Otros calificadores::Otros calificadores::/antagonistas & inhibidores
Wiley
Cancer Science;111(2)
https://doi.org/10.1111/cas.14254
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
Articles científics - HVH [3440]
