Sheila S. McThenia ^1,2,3* Kartik Reddy ¹ Rachael Beer ¹ Ethan Castellino ¹ Eswar Damaraju ³ Franklin Chien ^1,2,3 Robert Craig Castellino ^1,2,3 Zhulin He ¹ Adam Goldman-Yassen ¹ Jason Fangusaro ^1,2,3 Tobey MacDonald ^1,2,3

• ¹ Emory University, Atlanta, United States
• ² Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, Colorado, United States
• ³ Children's Healthcare of Atlanta, Atlanta, Georgia, United States

BACKGROUND: Pediatric low-grade gliomas (pLGGs) have an overall survival of over 90%; however, patients harboring a BRAFV600E-alteration may have worse outcomes, particularly when treated with classic chemotherapy. Combined BRAF/MEK inhibition following incomplete resection demonstrated improved outcome in BRAFV600E-altered pLGG compared to combined carboplatin/vincristine chemotherapy and is now considered the standard FDA-approved treatment for these tumors. The aim herein was to investigate the efficacy and tolerability of single agent BRAF inhibitor (BRAFi) treatment in BRAFV600E-altered pLGG. METHODS: A single institution retrospective chart review analysis was performed on patients, 0 to 21-years-old with newly diagnosed and/or progressive BRAFV600E-mutated pLGGs at Children's Healthcare of Atlanta treated off-study with BRAFi monotherapy.. 2-year progression free survival (PFS) and objective tumor response was evaluated. All toxicities possibly associated with BRAFi therapy were evaluated and described according to Common Terminology Criteria for Adverse Events version 5 (CTCAEv5). MRI brain imaging data at baseline and best response was evaluated to identify patterns that may predict response to BRAFi monotherapy. RESULTS: Fifteen patients diagnosed with BRAFV600E-mutated pLGG, treated with monotherapy BRAFi, were identified. Median age of diagnosis: 3.8 years (0.2 -18.1). Histologic diagnosis: pilocytic astrocytoma (PA) (N=4); ganglioglioma (GGL) (N=3); GGL, atypical (N=3); pleomorphic xanthroastrocytoma (PXA) (N=2); low-grade neuroepithelial tumor (N=1); infiltrating glioma (N=1); and LGG (NOS) (N=1). Mean duration of BRAFi monotherapy: 38.41 months (range 3.9-83.7). Median follow-up: 32.6 months (16 -78.1). Two-year PFS for patients on BRAFi monotherapy for at least 10 months: 90% (95% CI: 73.2%-100%). Objective Response (OR) for 15 evaluable patients on BRAFi therapy: 73% (0/15 CR + 6/15 PR + 5/15 MR) with Overall Response Rate (ORR=CR+PR): 40%. Overall, patients tolerated treatment well with Grade 1 rash being the most common toxicity. Two of 15 patients (13%) discontinued therapy due to toxicities, and 2 other patients switched within drug class from vemurafenib to dabrafenib due to toxicities. DISCUSSION: In this small cohort of incompletely resected BRAF V600E mutated pLGGs, BRAFi monotherapy was effective and well tolerated with an ORR comparable to published prospective outcomes of dual MEK/BRAFi therapy. This promising monotherapy treatment should be considered when choosing treatment for incompletely resected BRAFV600E-altered pLGGs.