Dabrafenib Plus Trametinib in Relapsed or Refractory BRAF V600–Mutant Pediatric High-Grade Glioma

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In a phase II trial reported in the Journal of Clinical Oncology, Hargrave et al found that dabrafenib plus trametinib was highly active in pediatric patients with relapsed or refractory BRAF V600–mutant high-grade glioma.

Study Details

In the trial, 41 previously treated patients (median age, 13 years; range, 2–17 years) were enrolled from sites in 13 countries between December 2017 and August 2020. Patients received dabrafenib twice daily (5.25 mg/kg/d for age < 12 years, 4.5 mg/kg/d for age ≥ 12 years) and trametinib once daily (0.032 mg/kg/d for age < 6 years, 0.025 mg/kg/d for age ≥ 6 years). Treatment was continued until loss of clinical benefit or unacceptable toxicity. The primary outcome measure was objective response rate on independent review. The hypothesized response rate was 35%, based on previously reported findings with current standard-of-care agents in molecularly unselected patients.


Median follow-up was 25.1 months. Objective response was observed in 23 of 41 patients (56.1%, 95% CI = 39.7%–71.5%), including a complete response in 12 (29.3%). Stable disease was observed in an additional five patients (12.2%). Median duration of response was 22.2 months (95% CI = 7.6 months to not reached); 84.7% and 62.2% of responses were ongoing at 6 and 12 months, respectively.

Median progression-free survival was 9.0 months (95% CI = 5.3–24.0 months), with 6- and 12-month rates of 66.8% and 44.1%. Median overall survival was 32.8 months (95% CI = 19.2 months to not reached), with 12- and 24-month rates of 76.3% and 58.6%.

Adverse Events

The most common adverse events of any grade were pyrexia (51%), headache (34%), dry skin (32%), and vomiting (29%). Grade ≥ 3 adverse events occurred in 68% of patients, most commonly headache (10%) and vomiting (5%). Serious adverse events occurred in 61% of patients and were considered related to treatment in 17%. Adverse events led to discontinuation of treatment in two patients (5%). No treatment-related deaths were reported.

The investigators concluded: “In relapsed/refractory BRAF V600–mutant pediatric high-grade glioma, dabrafenib plus trametinib improved objective response rate vs previous trials of chemotherapy in molecularly unselected patients…and was associated with durable responses and encouraging survival. These findings suggest that dabrafenib plus trametinib is a promising targeted therapy option for children and adolescents with relapsed/refractory BRAF V600–mutant high-grade glioma.”

Darren R. Hargrave, MD, MBChB, MRCP, of UCL Great Ormond Street Institute of Child Health, Paediatric Oncology Unit, Great Ormond Street Hospital, London, is the corresponding author of the Journal of Clinical Oncology article.

Disclosure: The study was supported by Novartis Pharmaceuticals Corporation. For full disclosures of the study authors, visit

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