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
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.
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).
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.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.