Abstract Radiation-induced gliomas (RIGs) can occur in regions of the central nervous system (CNS) previously irradiated for primary malignancies including leukemia, medulloblastoma, and ependymoma. Latency is variable, generally ranging from 5-40 years after initial exposure. Prognosis is uniformly poor despite treatment with standard of care therapy with radiation +/- alkylating chemotherapy. Recent studies have shown that a subset of patients have gene fusions in targetable receptor tyrosine kinases including MET, NTRK2, and RAF1. However, clinical response and outcomes with targeted therapy in this patient population has not been described. Here, we report two young adults (age 23, 25) with history of childhood medulloblastoma who developed RIGs harboring MET fusions (Case 1 = CAPZA2:MET, Case 2 = PTPRZ1:MET). Both patients were treated with re-irradiation followed by off-label capmatinib targeted therapy. Capmatinib is a highly specific MET inhibitor that is approved for the treatment of metastatic non-small cell lung cancer. Recent pre-clinical studies have shown that it has good CNS penetration and promising activity in pediatric high-grade glioma models (in-vitro and in-vivo). Drug treatment was well tolerated in both patients with the only notable side effect being peripheral edema (grade 2, CTCAE v5.0). MRI imaging showed significant radiographic response (partial response in both as assessed by RANO criteria (≥50% decrease)). Unfortunately, both tumors became resistant and progressed. Overall survival (OS) from diagnosis was 11 and 15 months, respectively, while median OS in historical cohorts was ∼ 9 months. Our two cases highlight the promising CNS penetration and on-target activity of capmatinib in MET-altered glioma; however, the development of rapid resistance emphasizes the pressing need to develop combination and/or new therapies for RIG.
Ford et al. (2025) studied this question.