Abstract BACKGROUND Although the BRAFV600E mutation and NRTK-fusion are rare entities in high-grade glioma (HGG) patients (Pts), these cases are significant because some Pts may respond well to BRAF/MEK and NTRK inhibitors. Given limited literature, this study aims to evaluate in real life cohort the efficacy of these target therapies (TT) in treating adult and pediatric Pts with HGG. MATERIAL AND METHODS We retrospectively analyzed a cohort of adult and pediatric Pts with recurrent HGG treated with TT across different Italian centers. Molecular analysis was obtained on tissue samples with next-generation sequencing or PCR. Dabrafenib-trametinib was given as part of compassionate use program or off-label, while larotrectinib and entrectinib have an agnostic approval. Response assessment followed RANO criteria. RESULTS Between 03-2020 and 03-2025, 25 Pts received TT: 15 adults with dabrafenib-trametinib, 6 adults with larotrectinib and 4 pediatric Pts with larotrectinib or entrectinib. Of the 25 Pts included, 16 died while 7 pts are currently undergoing treatment. Of the 21 adult Pts included (19 GBM and 2 grade 4 IDH mutant astrocytomas) the median age at diagnosis was 51.2years (range 17-68). All pediatric Pts included were HGG infant type with a median age at diagnosis of 1.2 years (range 0-13). The median line of therapy was 2 for both adult (range 1-4) and pediatric Pts (range 1-3). As of 03-2025, median follow-up was 34 months (ms). Median progression-free survival (PFS) after starting TT were 5.2ms (adult-BRAF), 5.3ms (adult-NTRK), 33.3 ms (pediatric-NTRK). A notable disease control rate (DCR) in all subgroups was observed: 66% (adult-BRAF), 75% (pediatric-NTRK) and 50% (adult-NTRK). In the pediatric cohort, there were 2 partial responses (PR) and 1 complete response (CR); in the adult cohort with BRAF alterations, 2 PR and 2 CR were observed, while in the adult cohort with NTRK alterations, only 1 PR was recorded. Median overall survival (OS) were 23.4 ms(adult-BRAF), 19 ms(adult-NTRK) and NR (pediatric-NTRK). The pediatric NRTK fusion subgroup showed the longest median PFS (33.3 m), with a significant difference in PFS compared to adult NTRK (p= 0.05). Regarding the BRAF cohort, no differences in PFS were shown between 2nd-line or later administration (mPFS2L: 5,16ms, mPFS2L: 5,14ms; p=0.69). No grade 3-4 adverse events were observed in either subgroup; no patient discontinued treatment due to toxicity. CONCLUSION Our findings support dabrafenib-trametinib for BRAF V600E mutant HGG adult patients. NTRKi is more active in pediatric Pts, but has also activity in adults, suggesting further research is needed to understand outcomes, molecular characteristics, prognostic factors and treatment timing in adults.
Cella et al. (Wed,) studied this question.