The US Food and Drug Administration (FDA) has approved dabrafenib (Tafinlar) with trametinib (Mekinist) for children aged 1 year or older who need systemic treatment for low-grade gliomas that have a BRAF V600E mutation.
The FDA also approved new oral formulations of both drugs for young children and others who cannot swallow the pills, according to an agency press announcement.
Dabrafenib/trametinib is the first systemic therapy approved for frontline treatment of low-grade, BRAF-mutated pediatric gliomas, the FDA said.
The combination was approved in June 2022 for adult and pediatric patients with unresectable or metastatic BRAF V600E-mutated solid tumors, but only after previous treatments.
Approval for the new indication was based on an open-label trial that randomly assigned 73 children to receive dabrafenib/trametinib and 37 to receive carboplatin plus vincristine.
Dabrafenib was given orally twice daily, and trametinib was given orally once daily. Children in the chemotherapy arm received a 10-week induction course followed by eight 6-week maintenance cycles.
After at least 32 weeks of treatment, the overall response rate was 46.6% in the dabrafenib/trametinib arm compared with 10.8% in the chemotherapy arm. Progression-free survival was almost three times longer in the dabrafenib/trametinib arm: 20.1 months vs 7.4 months (hazard ratio, 0.31).
However, at the interim analysis, there was no statistically significant difference in overall survival between the two arms. One death occurred in the chemotherapy arm, and none occurred in the targeted therapy arm.
Low-grade gliomas are the most common pediatric brain tumor. BRAF V600 mutations are present in 15% to 20%. They are associated with less favorable responses to chemotherapy and poorer survival, according to a press release from Novartis, maker of both targeted therapies.
“This new indication for Tafinlar+Mekinist is a potential new standard of care” for young patients with low-grade glioma that have BRAF mutations, Reshema Kemps-Polanco, the company’s executive vice president of US Oncology, said in the press release.
The most common adverse events with dabrafenib/trametinib in the trial were 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 more common grade 3 or 4 laboratory abnormalities were decreased neutrophil count (20%) and increases in alanine aminotransferase (3.1%) and aspartate aminotransferase levels (3.1%).
The combination is administered until disease progression or unacceptable toxicity, FDA said.
M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected].
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