In a phase II trial reported in The New England Journal of Medicine, Eric Bouffet, MD, and colleagues found that the combination of dabrafenib and trametinib produced a higher objective response rate vs standard chemotherapy in the first-line treatment of pediatric patients with low-grade glioma and BRAF V600 mutations.

Eric Bouffet, MD

Study Details

In the open-label trial, 110 patients from sites in 20 countries were randomly assigned 2:1 between September 2018 and December 2020 to receive dabrafenib/trametinib (n = 73) or standard chemotherapy with carboplatin/vincristine (n = 37). Dabrafenib was given twice daily at total daily doses of 5.25 mg/kg for age < 12 years and 4.5 mg/kg for age ≥ 12 years; trametinib was given once daily at 0.032 mg/kg for age < 6 years and 0.025 mg/kg for age ≥ 6 years. Treatment was continued until loss of clinical benefit or unacceptable toxicity.

Median age was 10 years (range = 1–17 years) in the dabrafenib/trametinib group and 8 years (range = 1–17 years) in the chemotherapy group. The primary outcome measure was independently assessed objective response rate.

Responses

Median follow-up was 18.9 months (range = 7.9–35.4 months). Objective responses were observed in 34 (47%, 95% confidence interval [CI] = 35%–59%) of 73 patients in the dabrafenib/trametinib group vs 4 (11%, 95% CI = 3%–25%) of 37 in the standard chemotherapy group (risk ratio [RR] = 4.31, 95% CI = 1.7–11.2, P < .001); complete responses were observed in two patients (3%) and one patient (3%), respectively. Median duration of response was 20.3 months (95% CI = 12.0 months to not evaluable) vs not evaluable (95% CI = 6.6 months to not evaluable).

Clinical benefit (objective response plus stable disease for ≥ 24 weeks) was observed in 63 patients (86%, 95% CI = 76%–93%) in the dabrafenib/trametinib group vs 17 patients (46%, 95% CI = 30%–63%) in the chemotherapy group (RR = 1.88, 95% CI = 1.3–2.7, P < .001).

Median progression-free survival was 20.1 months (95% CI = 7.4 months to not evaluable) with dabrafenib/trametinib vs 7.4 months (95% CI= 3.6–11.8 months) with chemotherapy (hazard ratio = 0.31, 95% CI = 0.17–0.55, P < .001).

Adverse Events

Grade ≥ 3 adverse events occurred in 47% of patients in the dabrafenib/trametinib group and 94% of those in the chemotherapy group. The most common events in the dabrafenib/trametinib group included neutropenia (10%), pyrexia (8%), and increased weight (7%); the most common in the chemotherapy group included decreased neutrophil count (48%), neutropenia (30%), and anemia (24%). Serious adverse events occurred in 40% vs 39% of patients; adverse events led to discontinuation of treatment in 4% vs 18% of patients.

The investigators concluded. “Among pediatric patients with low-grade glioma with BRAF V600 mutations, dabrafenib plus trametinib resulted in significantly more responses, longer progression-free survival, and a better safety profile than standard chemotherapy as first-line therapy.”

Dr. Bouffet, of the Hospital for Sick Children, University of Toronto, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by Novartis. For full disclosures of the study authors, visit nejm.org.