Williams, Andrew Evan

Abstract BACKGROUND Tovorafenib is a type II rapidly accelerated fibrosarcoma (RAF) kinase inhibitor approved by the FDA in 2024 for relapsing or chemotherapy-refractory pediatric low-grade gliomas with mutations or alterations in the gene BRAF. There is potential for the use of this drug outside the pediatric population. We present a single institution case series of adults with CNS tumors with mutations or alterations in BRAF treated (off-label) with tovorafenib. METHODS Chart review. RESULTS 8 adult (age >18) patients were treated with tovorafenib at our institution between March 2024 and June 2025. Age range was 21-66 years old (median age 42). The population included 5 males and 3 females. Indications for treatment were pilocytic astrocytoma (n = 2), high grade astrocytoma with piloid features (HGAP) (n = 2), Erdheim-Chester disease (n = 2), pleomorphic xanthoastrocytoma (n = 1), and otherwise unclassified low-grade glioma (n = 1). All patients had mutations or alterations in BRAF including KIAA1549 fusion (n = 4), V600E mutation (n = 3), or GAB2 fusion (n = 1). Radiographic response to therapy was seen in 5/8 patients with 3 cases of radiographic stability (though one patient later progressed) and 2 cases of decrease in tumor size (in a pilocytic astrocytoma and in an HGAP). Both cases of decreased tumor size after treatment were in tumors with KIAA1549 fusions. Adverse effects of tovorafenib included fatigue (n=2), headache, myalgias, diplopia, cytopenias, and transaminitis (n=1). 3/8 patients had to pause or stop treatment due to adverse effects (intolerable headache, cytopenias, and transaminitis respectively). CONCLUSION Tovorafenib is a promising new treatment for CNS tumors with BRAF mutations or alterations. Our single institution case series suggests the efficacy of this drug for multiple tumor types in adults. Certain tumor subtypes such as KIAA1549 fusions may be more likely to benefit from this treatment.

Abstract BACKGROUND Diffuse hemispheric glioma (DHG) is an uncommon infiltrating glioma, defined in the World Health Organization 2021 guidelines by a mutation in the H3F3A gene at codon 34 (H3.G34). DHG primarily affects children and young adults. Due to its rarity, there is paucity of knowledge regarding factors affecting overall survival (OS). We retrospectively assessed our institutional experience and present a review of the literature. METHODS We searched our institution’s pathology records to identify six cases of DHG. Demographic, clinical, diagnostic, treatment, and outcome data were recorded. We next searched for published articles regarding DHG cases via PubMed through May 2023. Four-hundred-fifty-four published individual cases of H3.G34 glioma were identified, 204 of which were hemispheric/supratentorial tumors with OS data reported, providing a combined 210 cases for analysis. 132 of these cases included MGMT promoter methylation status. 111 included extent of surgical resection. Kaplan-Meier and Cox regression survival analysis was performed. RESULTS Age range for DHG patients was 7-66 years (median 17). Median OS was 18.5 months (95% CI, 17-25). Greater extent of surgical resection and presence of MGMT promoter methylation were associated with better prognosis. Median OS for biopsy alone was 12 months (95% CI, 10-NA), subtotal resection was 16 months (95% CI, 14-23), and gross total resection was 27 months (95% CI 23-NA) – log-rank p< 0.001. OS for MGMT promoter unmethylated was 14 months (95% CI 12-22), MGMT promoter methylated was 24 months (95% CI, 17-30) – log-rank p=0.028. Contrary to previous reports, patient age was not found to impact prognosis (using 18, 21, and 40 years as cutoffs or as a continuous variable with Cox regression). CONCLUSION Extent of surgical resection and MGMT promoter methylation status are important prognostic factors for DHG. Unlike many primary brain tumors, survival does not appear to be significantly impacted by age.