On March 16, 2023, the FDA approved dabrafenib (Tafinlar; Novartis) in combination with trametinib (Mekinist; Novartis) for the treatment of pediatric patients aged ≥1 year with low-grade glioma that harbors a BRAFV600E mutation and who require systemic therapy.
The FDA also approved new oral formulations of both drugs suitable for patients who cannot swallow pills, making this the first time a BRAF/MEK inhibitor has been developed in a formulation suitable for patients as young as 1 year of age.
With this latest approval, dabrafenib plus trametinib is now FDA-approved across 6 indications for multiple BRAFV600E solid tumors, including melanoma, thyroid cancer, and lung cancer.
The new approval was based on results of the TADPOLE study, an open-label, multicenter, clinical trial of patients with low-grade glioma requiring first systemic therapy. BRAF mutation status was identified prospectively by local or central laboratory tests, and retrospective testing of available tumor samples was also performed by central laboratory tests to evaluate mutation status.
Patients were randomized (2:1) to receive dabrafenib plus trametinib or carboplatin plus vincristine. Patients received age- and weight-based dosing of the dabrafenib plus trametinib combination until they were no longer deriving benefit or experienced unacceptable toxicity.
The major efficacy outcome measure was overall response rate (ORR) by independent review based on RANO LGG (2017) criteria. Additional efficacy outcome measures were progression-free survival (PFS) and overall survival (OS).
The ORR in patients treated with dabrafenib plus trametinib (N = 73) was 46.6% (95% confidence interval [CI], 34.8%-58.6%) compared with 10.8% (95% CI, 3.0%-25.4%) in those treated with carboplatin plus vincristine (N = 37; P ≤.001). The duration of response was 23.7 months (95% CI, 14.5-not estimable [NE]) in the dabrafenib plus trametinib arm and NE (95% CI, 6.6-NE) in the carboplatin plus vincristine arm. PFS was 20.1 months and 7.4 months, respectively.
At the time of the interim analysis of OS conducted when all patients had completed at least 32 weeks of treatment or had discontinued earlier, there was 1 death in the carboplatin plus vincristine arm. The OS results at the interim analysis did not reach statistical significance.
In the pooled safety population of pediatric patients treated with dabrafenib plus trametinib (N = 166), the most common (>20%) adverse reactions were 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 were neutrophil count, increased alanine aminotransferase, and increased aspartate aminotransferase.