Abstract
The integration of targeted therapies into neuro-oncology is revolutionizing the management of primary CNS malignancies. Advances in sequencing technologies and the incorporation of molecular alterations into CNS tumor classification have led to more precise tumor prognosis and enabled the identification of actionable oncogenic drivers. However, challenges such as drug delivery, tumor and microenvironment heterogeneity, and limitations of preclinical models complicate the selection of effective therapies. This review presents a comprehensive framework for optimizing drug selection in neuro-oncology. We discuss strategies to enhance drug development and improve clinical trial success, including window-of-opportunity trials and advanced imaging techniques. Additionally, we highlight recent advances in the treatment of isocitrate dehydrogenase-mutant gliomas, focusing on the INDIGO study and its role in the regulatory approval of vorasidenib. The review also examines the use of MAPK inhibitors, from BRAF inhibitors to PAN-RAF inhibitors, in both pediatric and adult patients, as well as novel investigational agents. Finally, we explore emerging targeted therapies for rarer oncogenic drivers, such as FGFR and NTRK alterations, emphasizing the need for CNS-specific drug development strategies.