Abstract Background BRAF V600E mutations occur in many pediatric malignancies, including ~5% to 10% of pediatric high-grade gliomas (HGGs). Despite efforts over the decades, prognosis of pediatric HGG remains dismal, with low survival rates. Dabrafenib has shown efficacy in pediatric patients with BRAF V600 mutation–positive malignancies in a phase 1/2a study. This report combines data from all pediatric patients with HGG in both dose escalation (part 1) and tumor-specific dose expansion (part 2) parts of the study, including patients with HGG for the first time in phase 2a. Methods Patients aged 1 to 18 years with BRAF V600 mutation–positive HGG who had refractory or progressive disease after standard therapy received oral dabrafenib 3.0 to 5.25 mg/kg/day (part 1) or the recommended dose (part 2) of 5.25 mg/kg/day (age 12 years) or 4.5 mg/kg/day (age ≥12 years) as 2 equal doses twice daily. The primary objectives were safety and tolerability of dabrafenib (part 1; previously published) and clinical activity (part 2), defined as ORRs reported by investigator assessment and independent review using RANO 2010 criteria. Results Overall, 35 pediatric patients with HGG were treated. Histologic diagnosis included pleomorphic xanthoastrocytoma (n=8), glioblastoma (n=7), anaplastic astrocytoma (n=6), anaplastic ganglioglioma (n=4), and other gliomas (n=10). The ORRs were 29% (95% CI, 14.6, 46.3) and 46% (28.8, 63.4) by investigator assessment and independent review, respectively. The 24-month PFS rates were 30% and 40%, respectively. Most common treatment-related adverse events were dry skin (31%), fatigue (29%), and pyrexia (26%). No treatment-related deaths were reported. Conclusions In pediatric patients with relapsed/refractory BRAF V600–mutated HGG, dabrafenib exhibited sustained objective tumor responses and a manageable safety profile.
Geoerger et al. (Sat,) studied this question.
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