FDA approves first systemic therapy for children with BRAF V600E-mutated low-grade glioma
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The FDA approved dabrafenib with trametinib for children with previously untreated low-grade glioma who harbor BRAF V600E mutations and require systemic therapy.
The approval — which applies to children aged 1 year or older — is the first for a systemic therapy for first-line treatment of this patient population.
The agency also approved new liquid formulations of both agents appropriate for patients who cannot swallow pills.
“It is more important than ever to test for genetic mutations [among] patients living with low-grade glioma,” Roger J. Packer, MD, senior vice president of Center for Neurosciences and Behavioral Medicine at Children’s National Hospital, said in a Novartis-issued press release. “This FDA approval may offer new hope to pediatric patients living with BRAF V600E low-grade glioma. This has the potential to change the way health care providers treat these pediatric patients, offering a significant advancement compared [with] chemotherapy.”
Dabrafenib (Tafinlar, Novartis) is a BRAF inhibitor. Trametinib (Mekinist, Novartis) is a MEK1/2 inhibitor.
The combination is approved for five other indications in the United States, including treatment of BRAF V600-mutated lung cancer, melanoma or thyroid cancer.
The FDA based the new indication on results of the phase 2/phase 3 TADPOLE trial, which included 110 patients with low-grade glioma who required first systemic therapy.
Researchers randomly assigned 73 patients to dabrafenib plus trametinib via age- and weight-based dosing. Treatment continued until patients developed unacceptable toxicity or no longer derived benefit.
The other 37 patients received carboplatin 175 mg/m2 plus vincristine 1.5 mg/m2, with one 10-week induction course plus eight 6-week cycles of maintenance therapy.
Investigators determined BRAF mutation status prospectively by local or central laboratory tests.
Overall response rate per independent review served as the major efficacy outcome. Additional efficacy outcomes included PFS and OS.
Researchers performed the primary analysis after all patients completed at least 32 weeks of therapy.
Median follow-up was 18.9 months.
Results showed improved outcomes in the dabrafenib-trametinib arm, including a higher ORR (46.6% vs. 10.8%; P < .001) and longer median PFS (20.1 months vs. 7.4 months; HR = 0.31; 95%, 0.17-0.55).
An interim OS analysis — performed after all patients had completed at least 32 weeks of treatment or discontinued earlier — showed one death in the carboplatin-vincristine group. The difference in OS between groups had not reached statistical significance.
A pooled safety analysis of 166 children treated with dabrafenib-trametinib showed the most common adverse events included pyrexia (66%), rash (54%), headache (40%), vomiting (38%), musculoskeletal pain (36%), fatigue (31%), dry skin (31%), diarrhea (30%), nausea (26%), epistaxis and other bleeding events (25%), abdominal pain (24%), and dermatitis acneiform (23%).
The most common grade 3/grade 4 laboratory abnormalities included decreased neutrophil count (20%), increased alanine aminotransferase (3.1%) and increased aspartate aminotransferase (3.1%).
The FDA previously granted dabrafenib with trametinib priority review, breakthrough therapy designation and orphan drug designation for this indication.
References:
- FDA approves dabrafenib with trametinib for pediatric patients with low-grade glioma with BRAF V600E mutation (press release). Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-dabrafenib-trametinib-pediatric-patients-low-grade-glioma-braf-v600e-mutation. Published March 16, 2023. Accessed March 16, 2023.
- Novartis Tafinlar + Mekinist approved by FDA for pediatric patients with BRAF V600E low-grade glioma, the most common pediatric brain cancer (press release). Available at: https://www.novartis.com/news/media-releases/novartis-tafinlar-mekinist-approved-fda-pediatric-patients-braf-v600e-low-grade-glioma-most-common-pediatric-brain-cancer. Published2023. Accessed March 17, 2023.
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