On March 16, 2023, dabrafenib with trametinib was approved for pediatric patients aged 1 year and older with low-grade glioma with a BRAF V600E mutation who require systemic therapy.1,2 The U.S. Food and Drug Administration also approved new oral formulations of both drugs suitable for patients who cannot swallow pills.
Approval was based on findings in the multicenter open-label Study CDRB436G2201 (ClinicalTrials.gov identifier NCT02684058), in which 110 patients (aged 1 to up to 18) were randomly assigned on a 2:1 basis to receive dabrafenib plus trametinib (n = 73), given in age- and weight-based dosing, or carboplatin plus vincristine (n = 37).
An objective response on independent review was observed in 34 patients (46.6%, 95% confidence interval [CI] = 34.8%–58.6%) in the dabrafenib/trametinib group vs 4 patients (10.8%, 95% CI = 3.0%–25.4%) in the carboplatin/vincristinegroup (P < .001). Median duration of response was 23.7 months (95% CI = 14.5 months to not estimable) vs not estimable (95% CI = 6.6 months to not estimable). Median progression-free survival was 20.1 months (95% CI = 12.8 months to not estimable) in the dabrafenib/trametinib group vs 7.4 months (95% CI = 3.6–11.8 months) in the carboplatin/vincristine group (hazard ratio = 0.31, 95% CI = 0.17–0.55, P < .001).
How It Is Used
The recommended doses for dabrafenib and trametinib in pediatric patients are based on body weight. For a body weight of 26 to ≥ 51 kg, dabrafenib doses range from 75 to 150 mg twice daily, and trametinib doses range from 1 to 2 mg once daily. Treatment is continued until disease progression or unacceptable toxicity.
Safety Profile
In Study CDRB436G2201, the most common adverse events of any grade in the dabrafenib/trametinib group were pyrexia (68% vs 18% in the carboplatin/vincristine group), rash (51% vs 18%), headache (47% vs 33%), vomiting (34% vs 48%), musculoskeletal pain (34% vs 30%), fatigue (33% vs 39%), diarrhea (29% vs 18%), dry skin (26% vs 3%), nausea (25% vs 45%), hemorrhage (25% vs 12%), and abdominal pain (25% vs 24%). The most common grade ≥ 3 adverse events in the dabrafenib/trametinib group included pyrexia (8%) and increased weight (7%). The most common grade 3 or 4 laboratory abnormalities were decreased neutrophils (17%), decreased magnesium (4%) and calcium (4%), and increased potassium (4%).
Serious adverse events occurred in 40% of the dabrafenib/trametinib group, most commonly pyrexia (14%) and vomiting (4%). Dabrafenib and trametinib were each discontinued because of adverse events in 4% of patients.
Dabrafenib has warnings/precautions for new primary malignancies, tumor promotion in BRAF wild-type tumors, hemorrhage, cardiomyopathy, uveitis, serious febrile reactions, serious skin toxicities, hyperglycemia, glucose-6-phosphate dehydrogenase deficiency, and embryofetal toxicity.
Trametinib has warnings/precautions for new primary malignancies, hemorrhage, colitis and gastrointestinal perforation, venous thromboembolism, cardiomyopathy, ocular toxicities, interstitial lung disease, serious febrile reactions, serious skin toxicities, hyperglycemia, and embryofetal toxicity.
REFERENCES
1. Tafinlar(dabrafenib) capsules prescribing information, Novartis, March 2023. Available at https://www.accessdata.fda.gov/drugsatfda_docs/-label/2023/202806s025lbl.pdf. Accessed March 27, 2023.
2. Mekinist(trametinib) tablets prescribing information, Novartis, March 2023. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/-204114s025lbl.pdf. Accessed March 27, 2023.
