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FDA Approves Dabrafenib with Trametinib for Paediatric Patients with Low-Grade Glioma with a BRAF V600E Mutation

Evidence for efficacy is based on the results from the Study CDRB436G2201
24 Mar 2023

On 16 March 2023, the US Food and Drug Administration (FDA) approved dabrafenib (Tafinlar, Novartis) with trametinib (Mekinist, Novartis) for paediatric patients 1 year of age and older with low-grade glioma with a BRAF V600E mutation who require systemic therapy. The FDA also approved new oral formulations of both drugs suitable for patients who cannot swallow pills.

This represents the first FDA approval of a systemic therapy for the first-line treatment of paediatric patients with low-grade glioma with a BRAF V600E mutation.

Full prescribing information for Tafinlar is available here and for Mekinst here.

Efficacy was evaluated in Study CDRB436G2201 (NCT02684058), a multicentre, open-label study in patients with low-grade glioma (WHO grades 1 and 2) requiring first systemic therapy. Patients were randomised 2:1 to dabrafenib plus trametinib or carboplatin plus vincristine. BRAF mutation status was identified prospectively by local or central laboratory tests. Retrospective testing of available tumour samples by the central laboratory was also performed to evaluate mutation status. Patients received age- and weight-based dosing of dabrafenib plus trametinib until they were no longer deriving benefit or experienced unacceptable toxicity. Carboplatin plus vincristine were dosed based on body surface area at 175 mg/m2 and 1.5 mg/m2 (0.05 mg/kg for patients < 12 kg), respectively, as one 10-week induction course, followed by eight 6-week cycles of maintenance therapy. 

The major efficacy outcome measure was overall response rate (ORR) by independent review based on RANO low-grade glioma (2017) criteria. Additional efficacy outcome measures were 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 the low-grade glioma cohort, 110 patients were randomised to dabrafenib plus trametinib (n = 73) or carboplatin plus vincristine (n = 37). ORR was 46.6% (95% confidence interval [CI] 34.8, 58.6) in the dabrafenib plus trametinib arm and 10.8% (95% CI 3.0, 25.4) for those receiving carboplatin plus vincristine (p < 0.001). Duration of response was 23.7 months (95% CI 14.5, not estimable) in the dabrafenib plus trametinib arm and not estimable (95% CI 6.6, not estimable) in the carboplatin plus vincristine arm. PFS was 20.1 months (95% CI 12.8, not estimable) and 7.4 months (95% CI 3.6, 11.8) with hazard ratio 0.31 (95% CI 0.17, 0.55; p < 0.001) in the dabrafenib plus trametinib and carboplatin plus vincristine arms, 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 one death on the carboplatin plus vincristine arm. The OS results at the interim analysis did not reach statistical significance.

In the pooled safety population of paediatric patients receiving dabrafenib plus trametinib (n = 166), the most common (>20%) adverse reactions were pyrexia (66%), rash (54%), headache (40%), vomiting (38%), musculoskeletal pain (36%), fatigue (31%), dry skin (31%), diarrhoea (30%), nausea (26%), epistaxis and other bleeding events (25%), abdominal pain (24%), and dermatitis acneiform (23%). The most common (>2%) grade 3 or 4 laboratory abnormalities were decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and aspartate aminotransferase increased (3.1%).

The recommended doses for dabrafenib and trametinib in paediatric patients are based on body weight; dabrafenib is administered orally twice daily and trametinib is administered orally once daily. Dabrafenib and trametinib are administered until disease progression or unacceptable toxicity.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review, breakthrough designation and orphan drug designation.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact FDA’s Oncology Center of Excellence Project Facilitate.

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