Among pediatric CNS tumors, pediatric low-grade gliomas (pLGG) are the most common tumor type. Their biology and prognosis differ significantly from tumors occurring in adult patients, with a 20-year overall survival rate of 87% [8]. To evaluate the molecular background of these tumors, numerous systematic molecular studies have been performed, revealing a pathologic activation of the RAS/MAP kinase signaling pathway in the vast majority of cases [9,10,11]. Following these analyses, it is now known that the majority of pLGGs harbor a KIAA1549::BRAF fusion (35–60%), followed by a BRAF p.V600E point-mutation (10–15%) and alterations in the FGFR signaling pathway. It has been also shown that tumors with BRAF p.V600E mutations may be associated with a worse prognosis when treated with standard chemotherapy [10, 12]. These results translate directly into clinical treatment, since inhibitors of the RAS/MAP kinase pathway are available and have been approved for multiple indications in the adult population.

After a number of successful treatments in individual cases and subsequent phase I–III clinical trials, certain therapies have now been approved for the pediatric population to use in routine clinical practice.

Dabrafenib a serine/threonine inhibitor that selectively blocks the serine/threonine kinase BRAF can be administered for BRAF V600E, V600K and V600D variants. Based on better tolerability and efficacy, dabrafenib should be combined with trametinib, a MEK inhibitor [13]. In 2022, a phase II trial was published showing an improved response in 47% of cases compared to the standard arm (carboplatin + vincristine), with only 11% [12]. Hence, in March 2023, the combination therapy was approved as first-line therapy for pLGG with verified BRAF mutations by the US Food and Drug Administration (FDA) and in December 2023 by the European Medicines Agency (EMA). Selumetinib is an approved MEK inhibitor in Europe for treatment of neurofibromatosis patients with plexiform neurofibromas.

The pan-RAF inhibitor DAY-101 is currently being investigated within the FIREFLY‑1 phase 2 study including pediatric patients with recurrent or progressive low-grade glioma. This broadens the spectrum of possible therapeutics targeting the RAS/MAP-kinase signaling pathway. This development may also have a role in some rare entities, such as primary diffuse leptomeningeal melanomatosis [14].

High-grade tumors in the pediatric population have a more diverse molecular background, frequently lacking any targetable alteration. However, in some cases an oncogenic driver can be identified leading to significant survival improvement. A prime example are NTRK-fused tumors, in which treatment with TRK inhibitors such as entrectinib or larotrectinib led to continuous disease stabilization in selected high-grade cases [15, 16]. Similarly, tumors harboring FGFR alterations treated with a FGFR inhibitor, such as erdafitinib responded remarkably to targeted treatment [17, 18].

New approaches are also emerging for tumors lacking a specific druggable target but being characterized by other alterations such as a high mutational burden suggesting potential response to immunotherapy, for example, check-point inhibition by nivolumab, however, with limited response rates observed in CNS tumor patients so far [19]. However, they may have a particular role in patients suffering from constitutive mismatch repair deficiency (cMMRD) syndrome [20]. For diffuse midline gliomas with H3K27 alteration the DRD2 antagonist ONC201 has been investigated in several studies, without clear results at present [21]. A phase I/II trial is currently ongoing. An overview on targets, treatment options and open clinical trials is given in Table 1.

Interestingly, a broader approach summarized under the acronym MEMMAT, combining well established drugs given orally, augmented by intravenous bevacizumab and intrathecal administration of chemotherapy led to a significantly improved survival in recurrent medulloblastoma patients. Its efficacy in other entities is currently being investigated within a randomized, multicenter, phase II trial.

Concluding, there are many additional treatment options emerging for all types of CNS tumors also within the pediatric age group. While some are already well established, others still need to be investigated within well-planned clinical trials. Meanwhile, decisions for off-label therapies should be based on decisions within interdisciplinary tumor boards such as is implemented at the Brain Tumor Center for Children and Adolescents Vienna since 2020 for Pediatric CNS tumors and patients receiving off-label treatment. Importantly, these real-world evidence is captured in international efforts to inform therapy and trial concepts [22, 23].