FDA D.I.S.C.O. Burst Edition: FDA approval of Tafinlar (dabrafenib) with Mekinist (trametinib) for pediatric patients with low-grade glioma with a BRAF V600E mutation
Regulatory approval: On March 16, 2023, the FDA approved dabrafenib (Tafinlar) with trametinib (Mekinist) for pediatric patients aged ≥1 year with low-grade glioma harboring a BRAF V600E mutation who require systemic therapy. The FDA also approved new oral formulations of both agents for patients unable to swallow pills. Efficacy was evaluated in Study CDRB436G2201, an open-label randomized trial comparing dabrafenib+trametinib versus carboplatin+vincristine, with ORR by independent review as the major endpoint.
FDA approval (March 16, 2023)
The US FDA approved dabrafenib (Tafinlar) plus trametinib (Mekinist) for pediatric patients ≥1 year with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. The FDA also approved new oral formulations of both drugs intended for patients who cannot swallow pills.
The FDA described this as the first FDA approval of a systemic therapy for first-line treatment of pediatric patients with LGG with a BRAF V600E mutation.
Supporting evidence
Efficacy was evaluated in Study CDRB436G2201, a multicenter, open-label trial in patients with LGG requiring first systemic therapy. Patients were randomized 2:1 to dabrafenib+trametinib vs carboplatin+vincristine. BRAF mutation status was identified prospectively by local or central testing, with additional retrospective central testing of available samples.
The major efficacy endpoint was overall response rate (ORR) by independent review using RANO LGG (2017) criteria; additional endpoints included progression-free survival and overall survival. The primary analysis occurred after all patients completed ≥32 weeks of therapy.
Safety (pooled pediatric population)
Common adverse reactions (>20%) included pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, dry skin, diarrhea, nausea, epistaxis/other bleeding events, abdominal pain, and dermatitis acneiform. Common grade 3/4 lab abnormalities (>2%) included decreased neutrophils and increased ALT/AST.