Journal Article

Capmatinib is an effective treatment for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy

Budd, Kaitlin M., Roach, Jordan T., Twarog, Nathaniel, Li, Yong, Onar-Thomas, Arzu, Ernst, Kati J., Xie, Jia, Bagchi, Aditi, Freeman, Burgess B., Shelat, Anang A., Zhang, Junyuan, Rankovic, Zoran, Chiang, Jason, Hover, Laura, Li, Xiaoyu, Andrews, Jared, Dalton, James, McKinnon, Peter J., He, Chen, Ocasio, Jennifer K., Chan, Kenneth Chun-Ho, Jones, David T. W., Xu, Ke, Baker, Suzanne J., Pfister, Stefan M., Hofmann, Nina, Wang, Yingzhe, Chepyala, Divyabharathi, Yang, Lei, Sloan-Henry, Roketa, Zuckermann, Marc, Zhu, Xiaoyan, Bianski, Brandon, Tinkle, Christopher L.

2024

Overview

Background Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. Methods To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. Results Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. Conclusions We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Anilides - pharmacology / Animals / Benzamides - pharmacology / Benzamides - therapeutic use / Biomedical and Life Sciences / Biomedicine / Brain Neoplasms - drug therapy / Brain Neoplasms - genetics / Brain Neoplasms - pathology / Brain Neoplasms - radiotherapy / Brain tumors / Cancer Research / Capmatinib / Cell Line, Tumor / Child / Combination therapy / Crizotinib - pharmacology / Crizotinib - therapeutic use / Disease Models, Animal / Female / Glioma - drug therapy / Glioma - genetics / Glioma - pathology / Glioma - therapy / Gliomas / Humans / Imidazoles / MET inhibition / Mice / Neoplasm Grading / Oncogene Proteins, Fusion - genetics / Oncogene Proteins, Fusion - metabolism / Oncology / Pediatric-type diffuse high-grade glioma / Pediatrics / Preclinical trials / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Proto-Oncogene Proteins c-met - antagonists & inhibitors / Proto-Oncogene Proteins c-met - genetics / Proto-Oncogene Proteins c-met - metabolism / Pyridines - pharmacology / Pyridines - therapeutic use / Radiation / Radiosensitization / Radiotherapy / Triazines / Tyrosine / Xenograft Model Antitumor Assays