Biomarker-guided treatment strategies for patients with gliomas in clinical practice

Targeted therapy has made important contributions to improving outcomes for patients with many solid tumors, but has had only limited activity so far in patients with gliomas, notably glioblastoma. Failure of targeted therapy in glioblastoma is likely due to redundance of oncogenic pathway activation and so far the inability to identify suitable targets and apply biomarker-based enrichment strategies in clinical trial designs. In contrast, in non-glioblastoma tumors, there are promising developments which have already changed clinical practice: inhibition of mutant isocitrate dehydrogenase (IDH) exemplified by vorasidenib, the first approved drug specifically for IDH-mutant gliomas, has changed the landscape for targeted therapy of WHO grade 2 gliomas. Furthermore, dordaviprone, an antagonist of dopamine receptor D2/3 (DRD2/3) and an allosteric agonist of the mitochondrial protease caseinolytic mitochondrial matrix peptidase proteolytic subunit (ClpP), emerges as a potentially active agent in patients with recurrent K27M-mutant diffuse midline gliomas. Finally, BRAF mutations, neurotrophic tyrosine receptor kinase ( r fibroblast growth factor receptor (FGFR) gene fusions continue to raise interest as therapeutic targets at least for subsets of patients with gliomas. Almost no targeted therapy approaches for ependymomas have emerged. Improved clinical trial designs including shared control arms early on and using pharmacodynamic endpoints ideally in enriched patient populations are the path forward towards the identification of further active treatments for patients with gliomas.