On March 16, 2023, the U.S. Food and Drug Administration (FDA) approved dabrafenib (Tafinlar) with trametinib (Mekinist) for pediatric patients aged 1 year and older with low-grade glioma with a BRAF V600E mutation who require systemic therapy. The FDA also approved new oral formulations of both drugs suitable for patients who cannot swallow pills.
This represents the first FDA approval of a systemic therapy for the first-line treatment of pediatric patients with low-grade glioma with a BRAF V600E mutation.
Study Details
Efficacy was evaluated in Study CDRB436G2201 (ClinicalTrials.gov identifier NCT02684058), a multicenter, open-label trial in patients with low-grade glioma (World Health Organization grades 1 and 2) who require first-line systemic therapy. Patients were randomly assigned 2:1 to receive dabrafenib plus trametinib or carboplatin plus vincristine. BRAF mutation status was identified prospectively by local or central laboratory tests. Retrospective testing of available tumor samples by the central laboratory was also performed to evaluate mutation status. Patients received age- and weight-based dosing of dabrafenib/trametinib until they were no longer deriving benefit or experienced unacceptable toxicity. Carboplatin and vincristine were dosed based on body surface area at 175 mg/m2 and 1.5 mg/m2 (0.05 mg/kg for patients < 12 kg), respectively, as one 10-week induction course, followed by eight 6-week cycles of maintenance therapy.
The major efficacy outcome measure was overall response rate by independent review based on RANO LGG (2017) criteria. Additional efficacy outcome measures were progression-free survival and overall survival. The primary analysis was performed when all patients had completed at least 32 weeks of therapy.
In the low-grade glioma cohort, 110 patients were randomly assigned to receive dabrafenib/trametinib (n = 73) or carboplatin/vincristine (n = 37). Overall response rate was 46.6% (95% confidence interval [CI] = 34.8%–58.6%) in the dabrafenib/trametinib arm and 10.8% (95% CI = 3.0%–25.4%) in those receiving carboplatin/vincristine (P ≤ .001). Duration of response was 23.7 months (95% CI = 14.5 months to not estimable) in the dabrafenib/trametinib arm and not estimable (95% CI = 6.6 months to not estimable) in the carboplatin/vincristine arm. Progression-free survival was 20.1 months (95% CI = 12.8 months to not estimable) and 7.4 months (95% CI = 3.6–11.8 months; hazard ratio [HR] = 0.31; 95% CI = 0.17–0.55; P ≤ .001) in the dabrafenib/trametinib and carboplatin/vincristine arms, respectively. At the time of the interim analysis of overall survival conducted when all patients had completed at least 32 weeks of treatment or had discontinued treatment earlier, there was one death on the carboplatin/vincristine arm. The overall survival results at the interim analysis did not reach statistical significance.
Safety
In the pooled safety population of pediatric patients receiving dabrafenib/trametinib (N = 166), the most common (> 20%) adverse reactions were pyrexia (66%), rash (54%), headache (40%), vomiting (38%), musculoskeletal pain (36%), fatigue (31%), dry skin (31%), diarrhea (30%), nausea (26%), epistaxis and other bleeding events (25%), abdominal pain (24%), and dermatitis acneiform (23%). The most common (> 2%) grade 3 or 4 laboratory abnormalities were decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and increased aspartate aminotransferase (3.1%).
The recommended doses for dabrafenib and trametinib in pediatric patients are based on body weight; dabrafenib is administered orally twice daily, and trametinib is administered orally once daily. Dabrafenib and trametinib are administered until disease progression or unacceptable toxicity.
