TRK inhibitors in pediatric gliomas

The NTRK1, NTRK2, and NTRK3 genes encode the TRKA, TRKB, and TRKC receptors, critical for nervous system development. Gene fusions involving neurotrophic tyrosine receptor kinase (NTRK) are found in various cancers. In the pediatric population, NTRK gene fusions have been identified in up to 5.3% of high-grade gliomas (HGGs) and 2.5% of low-grade gliomas (LGGs). The prevalence is notably higher in young children, particularly in infantile hemispheric gliomas, where the fusion frequency is about 20%. Targeted therapies with TRK inhibitors (TRKi), including larotrectinib and entrectinib, have shown promising efficacy with rapid and durable responses for patients with LGGs and HGGs. TRKi are usually well tolerated, but on-target and off-target adverse events have been reported, such as increased AST/ALT, fatigue, decreased neutrophil, weight gain, and fractures with entrectinib. Resistance to TRKi arises from on-target mutations or new pathway activations, with second-generation inhibitors addressing some resistant cases. Despite efficacy, challenges remain in diagnosis, treatment access, and long-term safety, particularly regarding cognitive development and bone health. Overall, TRKi represent a significant advance for treating NTRK fusion-positive CNS tumors, especially in pediatric populations, offering new hope for patients with limited treatment options. Further studies are required to optimize their use and address unresolved challenges.