PATH-77. Clinical and molecular predictors of survival and treatment response in AYA/adults with BRAF-V600 mutant high-grade glioma

BACKGROUND Despite promising advances in BRAF-targeted therapy for glioma, the clinical characteristics and predictors of treatment response and survival in BRAF V600E-mutant high-grade glioma (HGG) are unclear. METHODS We identified 98 BRAF-altered gliomas from a single-institution prospective cohort within an IRB-approved registry protocol. Inclusion criteria were histopathologic grade 3 or 4 with BRAF V600E mutation confirmed on any surgical pathology specimen and clinical follow-up through first-line therapy. RESULTS Forty-eight patients with HGG and BRAF-V600E mutation met inclusion criteria, of whom 54%(n=26) were female and 71%(n=34) were Caucasian. Median KPS was 90(Range50-100). Median age at HGG diagnosis was 35.5 years (IQR 27.12–55.15), and 26 patients were alive at the time of last follow-up. On pathologic analysis, 38%(n=18) were classified as GBM, 31%(n=15) as anaplastic PXA, and the remainder as HGG NOS. Nine tumors had progressed from prior low-grade glioma, including grade 2 PXA (n=5) and grade 1 ganglioglioma (n=4). MGMT promoter was unmethylated in 82% of specimens with known status (n=34). CDKN2A/B was lost in 48% of specimens in which it was evaluated (n=33). 45 patients received a radiation-based regimen following HGG diagnosis, 71%(n=34) with temozolomide (PFS: 15.5mo[IQR7.9–67.0], OS: 2.75yr[IQR1.1–7.6]). Six patients received BRAF inhibitor (BRAFi) as part of their first-line regimen (PFS: 18.1mo[IQR 7.2–25.9], OS: 2.5yr[IQR 2.1–2.8]). Overall, 22 patients received at least one line of BRAFi, with 7 receiving two or more lines (PFS:13.9mo[IQR 7.7–26.9]). Older age and grade 4 pathology were associated with inferior OS in the overall cohort. Prior diagnosis of LGG and younger age at HGG diagnosis showed a trend towards improved PFS following BRAFi(p=0.1). Further molecular characterization is ongoing. CONCLUSIONS Responses to BRAFi are non-uniform in patients with HGG, but some patient and tumor characteristics may be associated with response. These real-world data can inform prospective clinical trial designs.