On March 16, 2023, the FDA approved dabrafenib (Tafinlar; Novartis), a BRAF inhibitor, plus trametinib (Mekinist; Novartis), a MEK inhibitor, for pediatric patients aged ≥1 years with low-grade glioma and a BRAF V600E mutation who require systemic therapy. The agency also approved new liquid formulations of both drugs, providing an important option for patients who cannot swallow pills. This indication was granted priority review, breakthrough designation, and orphan drug designation.
This is the first systemic therapy that is FDA approved for the first-line treatment of pediatric patients with low-grade glioma and a BRAF V600E mutation.
Dabrafenib with trametinib was previously approved for patients with other BRAF mutation–positive cancers, including metastatic melanoma, metastatic non–small-cell lung cancer, locally advanced or metastatic anaplastic thyroid cancer, melanoma, and unresectable or metastatic solid tumors solid tumors.
This approval was based on the results of the phase 2/3 TADPOLE study (NCT02684058), a multicenter, open-label, clinical trial including 110 patients with low-grade glioma. Patients were randomly assigned 2:1 to first-line treatment with dabrafenib plus trametinib or to the chemotherapy regimen carboplatin plus vincristine. BRAF mutation status was identified prospectively by local or central laboratory tests and retrospectively via testing available tumor samples by the central laboratory.
In the dabrafenib plus trametinib arm, patients received age- and weight-based dosing until they no longer derived benefit or had unacceptable toxicity. In the carboplatin plus vincristine arm, patients received a 10-week induction course, followed by eight 6-week cycles of maintenance therapy, with dosing based on body surface area at 175 mg/m2 and 1.5 mg/m2 (0.05 mg/kg for patients <12 kg), respectively.
The primary end point was overall response rate (ORR); additional efficacy measures included progression-free survival (PFS) and overall survival (OS). The primary analysis was performed when all patients had completed at least 32 weeks of therapy.
In all, 73 of the 110 patients with low-grade glioma received dabrafenib plus trametinib, and 37 received carboplatin plus vincristine. The ORR was 46.6% (95% confidence interval [CI], 34.8-58.6) for patients receiving dabrafenib plus trametinib and 10.8% in the chemotherapy arm (95% CI, 3.0-25.4; P <.001). The dabrafenib plus trametinib arm had a 23.7-month DOR (95% CI, 14.5-not estimable), and the DOR was not estimable in the carboplatin plus vincristine arm (95% CI, 6.6-not estimable). The dabrafenib plus trametinib and chemotherapy arms had a PFS of 20.1 months (95% CI, 12.8-not estimable) and 7.4 months (95% CI, 3.6-11.8; hazard ratio, 0.31; 95% CI, 0.17-0.55; P <.001), respectively. OS was analyzed when all patients had completed at least 32 weeks of treatment, and 1 patient in the carboplatin plus vincristine arm had died. The OS results at this time did not reach statistical significance.
The most common (>20%) adverse events in the pooled safety population of 166 pediatric patients receiving dabrafenib plus trametinib included pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, dry skin, diarrhea, nausea, epistaxis and other bleeding events, abdominal pain, and dermatitis acneiform. The most common (>2%) grade 3 or 4 laboratory abnormalities included decreased neutrophil count, increased alanine aminotransferase, and increased aspartate aminotransferase.
“It is more important than ever to test for genetic mutations in patients living with low-grade glioma. This FDA approval may offer new hope to pediatric patients living with BRAF V600E low-grade glioma,” said Roger Packer, MD, Director, Brain Tumor Institute at Children’s National Hospital, Washington, DC. “This has the potential to change the way healthcare providers treat these pediatric patients, offering a significant advancement compared to chemotherapy.”
For pediatric patients, the recommended doses for dabrafenib and trametinib are based on body weight. Dabrafenib is administered orally twice daily and trametinib orally once daily, both until disease progression or unacceptable toxicity.