Dabrafenib-Trametinib Combination Receives FDA Approval for Childhood Brain Tumors

On March 16, 2023, the FDA (US Food and Drug Administration) approved dabrafenib (Tafinlar) plus trametinib (Mekinist) for children aged 1 and older with BRAF V600E-mutated low-grade glioma requiring systemic therapy.

The FDA also approved new oral formulations of both drugs for young children and other patients unable to swallow tablets.

Dabrafenib/trametinib became the first FDA-approved systemic first-line treatment for pediatric low-grade BRAF-mutated glioma.

The combination had been approved in June 2022 for adults and children with advanced or metastatic BRAF V600E-mutated solid tumors progressing despite previous treatment (see the related approval). BRAF thus became the 4th pan-cancer tumor biomarker to receive site-independent FDA approval, following MSI, TMB and NTRK as molecular targets approved in this way.

Approval in pediatric glioma was based on an open-label study randomly assigning 73 children to dabrafenib/trametinib and 37 to carboplatin plus vincristine.

Dabrafenib was given orally twice daily and trametinib orally once daily. Children receiving chemotherapy had a 10-week induction followed by eight 6-week maintenance courses.

Results

• After at least 32 weeks of treatment, overall response rates with dabrafenib/trametinib versus chemotherapy were 46.6% versus 10.8% .
• Disease-free survival with dabrafenib/trametinib was nearly 3 times longer : 20.1 versus 7.4 months (hazard ratio, 0.31).

However, the interim analysis found no statistically significant overall survival difference. One death occurred with chemotherapy and none with targeted treatment.

Low-grade glioma is the most common childhood brain tumor. BRAF V600 mutations occur in 15% to 20% and are associated with less favorable chemotherapy responses and poorer survival.

The most common adverse effects with dabrafenib/trametinib were fever (66%), rash (54%), headache (40%), vomiting (38%), musculoskeletal pain (36%), fatigue (31%), dry skin (31%), diarrhea (30%), nausea (26%), nosebleeds and other bleeding (25%), abdominal pain (24%) and acneiform dermatitis (23%).

The more common grade 3 or 4 laboratory abnormalities were decreased neutrophils (20%) and increased alanine aminotransferase (3.1%) and aspartate aminotransferase (3.1%).

The FDA stated that treatment is continued until disease progression or unacceptable toxicity.

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Gliomas are tumors arising from glial cells, the supporting cells of the central nervous system that nourish, support and protect neurons. Pediatric gliomas generally occur in structures such as the brain and spinal cord.

Pediatric gliomas can be classified by grade and growth rate:

1. Low-Grade Gliomas (Grades I and II): These generally grow slowly and have a better prognosis. Examples include pilocytic astrocytoma, diffuse astrocytoma and oligodendroglioma.

2. High-Grade Gliomas (Grades III and IV): These grow rapidly and are more aggressive. Examples include anaplastic astrocytoma, anaplastic oligodendroglioma and glioblastoma multiforme (GBM).

Gliomas account for approximately 50% of childhood brain tumors. Each year, brain tumors are diagnosed in approximately 3-5 of 100,000 children, and about half are gliomas. Pediatric gliomas are therefore relatively rare.

Incidence may vary with age, sex and geography. They are generally more common in boys and occur more frequently at ages 3-7, although they may arise at any stage of life.

Risk factors are incompletely understood, but genetic syndromes such as neurofibromatosis type 1 and Li-Fraumeni syndrome, family history and some environmental factors may contribute.

Symptoms depend on tumor size, type and location and may include:

• Headache
• Nausea and vomiting
• Seizures
• Vision, hearing or speech problems
• Balance and coordination problems
• Cognitive or behavioral changes