FDA Approval Summary: Dabrafenib in combination with trametinib for BRAF V600E mutation-positive low-grade glioma.

On March 16, 2023, the U.S. Food and Drug Administration (FDA) approved dabrafenib in combination with trametinib (Tafinlar®, Mekinist®, Novartis Pharmaceuticals Corporation) for the treatment of pediatric patients with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. FDA also approved oral formulations of both drugs suitable for patients who cannot swallow pills. This approval was based on the LGG cohort from Study CDRB436G2201 (NCT02684058), a multicenter, open-label trial in which pediatric patients with LGG with a BRAF V600E mutation were randomized 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). The overall response rate (ORR) by independent review based on RANO LGG (2017) criteria was assessed in 110 patients randomized to D+T (n=73) or C+V (n=37). ORR was 47% (95% CI: 35, 59) in the D+T arm and 11% (95% CI: 3.0, 25) in the C+V arm. Duration of response (DOR) was 23.7 months (95% CI: 14.5, NE) in the D+T arm and not estimable (95% CI: 6.6, NE) in the C+V arm. Progression-free-survival (PFS) was 20.1 months (95% CI: 12.8, NE) and 7.4 months (95% CI: 3.6, 11.8) (HR=0.31 [95% CI: 0.17, 0.55]; p= <0.001) in the D+T and C+V arms, respectively. The most common (> 20%) adverse reactions were pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain and dermatitis acneiform. This represents the first FDA approval of a systemic therapy for the first-line treatment of pediatric patients with LGG with a BRAF V600E mutation.