Dabrafenib in pediatric patients with BRAF V600–positive high-grade glioma (HGG).

10505 Background: The BRAF V600 mutation constitutively activates the MAPK/ERK pathway and is an oncogenic driver in many tumor types, including pediatric brain cancers. There are limited effective therapies for patients (pts) with HGG, ≈ 5% of whom have BRAF V600 alterations. The kinase inhibitor dabrafenib (which targets BRAF V600) demonstrated tolerability in pediatric pts across tumor types in a dose-escalation (ESC) cohort of a phase I/IIa study (Kieran et al, ASCO 2015; NCT01677741). Here we report preliminary analyses in this study of safety and clinical benefit with dabrafenib in pts with HGG across the ESC and disease-expansion (EXP) cohorts. Methods: Pts aged 1 to < 18 y with BRAF V600–positive HGG who had refractory or progressive disease after receiving ≥ 1 standard therapy were treated with dabrafenib (2 equal daily doses) either in the ESC cohort or with the recommended dose of 5.25 mg/kg/d (pts < 12 y) or 4.5 mg/kg/d (pts ≥ 12 y) in the EXP cohort. Measurable disease was not required. Primary objectives were safety and tolerability, and secondary objectives included tumor response and pharmacokinetics. Tumor response was reported by independent review (IR) and investigator assessment (INV) using RANO criteria. Exploratory analyses included independent histopathological review and tumor biology analysis (eg, mutation, methylation status). Results: Pts (n = 31) were treated with dabrafenib across the ESC (n = 8) and EXP (n = 23) cohorts. Median age was 14 y (range, 3 - < 18 y). Across both cohorts (n = 31), the most frequent AEs (any causality) were fatigue (48%), vomiting (42%), and headache (39%). Grade 3/4 AEs occurred in 12/31 pts (39%). No on-treatment deaths occurred. Median duration of exposure was 22 wk (range, 4-225 wk), and 10/31 pts (32%) had treatment ongoing. ORR by IR was 45% (14/31, with 3 CRs), and ORR by INV was 32% (10/31, with 4 CRs). By IR, median duration of response was 7.7 mo (95% CI, 3.0 mo-not estimable) and 13/19 pts with measurable lesions (68%) achieved a maximum tumor reduction of ≥ 50%. Tumor mutational and methylation analyses are ongoing. Conclusions: Dabrafenib was well tolerated in pediatric pts with BRAF V600–positive HGG, and a number of durable objective responses demonstrate the potential for clinical benefit. Clinical trial information: NCT01677741.