Capmatinib shows superior efficacy for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy [RNA-seq]

Pediatric 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 pHGGs, and are associated with devastating morbidity and mortality. 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 (RT). The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib. Strikingly, capmatinib treated mice displayed long-term progression-free survival (PFS) when combined with radiotherapy in two complementary mouse models. Molecular analysis of the treated tumors revealed impaired DNA repair after MET inhibition as a plausible mechanism of radiosensitization. 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 a plausible molecular mechanism. We thereby demonstrate the groundbreaking efficacy of capmatinib and radiation, as a highly promising concept for future clinical trials. RNA seq of tumors from a somatic TFG-MET driven high-grade glioma model, treated in 6 different treatment arms: capmatinib, crizotinib, vehicle +/- radiation. 4 Mice each were sacrificed after two days of treatment (PD cohort), the remainig mice were monitored until onset of symptoms (Survival cohort)