FDA Approves Dabrafenib Plus Trametinib for Pediatric BRAF V600E-Mutant Low-Grade Glioma


Findings from the phase 2 Study CDRB436G2201 trial have led the FDA to approve dabrafenib combined with trametinib for pediatric patients with BRAF V600E-mutated low-grade glioma who require systemic therapy.

The FDA has granted approval to dabrafenib (Tafinlar) in combination with trametinib (Mekinist) for the treatment of pediatric patients aged 1 year and older with low-grade glioma that harbor a BRAF V600E mutation and requires systemic therapy.1

The FDA has also approved new oral formulations of both drugs suitable for patients who cannot swallow pills. This marks the first FDA-approved systemic therapy for the first-line treatment of this patient population.

"Pediatric cancer research is vital to uncover new treatment methods for a population,” said Eric Bouffet, MD, FRCPC, principal investigator of the TADPOLE clinical trial (NCT02684058) and associate scientist emeritus at The Hospital for Sick Children. “Developing targeted therapies based on the unique genetic features of a patient’s tumor is the future of pediatric cancer care.”

Data from the phase 2 Study CDRB436G2201 trial2 supports this approval as patients enrolled in the study who were treated with dabrafenib plus trametinib (n = 73) had an overall response rate (ORR) of 46.6% (95% CI, 34.8%-58.6%) vs 10.8% (95% CI, 3.0%-25.4%) for patients treated with carboplatin plus vincristine (n = 37; P < .001).1

In the dabrafenib and trametinib arm, the median duration of response was 23.7 months (95% CI, 14.5–not estimable [NE]), compared with NE (95% CI, 6.6-NE) for patients administered carboplatin and vincristine. With the dabrafenib/trametinib combination, the median progression-free survival (PFS) was 20.1 months (95% CI, 12.8-NE) vs 7.4 months (95% CI, 3.6-11.8) with carboplatin/vincristine (HR, 0.31; 95% CI, 0.17-0.55; P < .001).

One death was reported in the control arm, which was at the time of the interim analysis and when all patients had completed at least 32 weeks of treatment or discontinued earlier. Further, the OS data at this time point did not reach statistical significance.

Pooled safety data from 166 patients showed that those who treated with dabrafenib and trametinib tolerated the treatment well. The most common adverse events observed in the study 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%). Grade 3 or 4 laboratory abnormalities occurred in >2% of patients with the most common being neutrophil count (20%), increased alanine aminotransferase (3.1%), and aspartate aminotransferase increased (3.1%).

The FDA recommends that the combination of dabrafenib and trametinib be based on the patient’s body weight with a dosing schedule of twice daily for dabrafenib and once daily for trametinib.

Prior to FDA approval, dabrafenib plus trametinib was granted priority review, breakthrough designation and orphan drug designation.

“It is more important than ever to test for genetic mutations in patients living with low-grade glioma. This FDA approval may offer new hope to pediatric patients living with BRAF V600E low-grade glioma,” said Roger Packer, MD, senior vice president of the Center for Neurosciences and Behavioral Medicine at Children’s National Hospital. “This has the potential to change the way healthcare providers treat these pediatric patients, offering a significant advancement compared to chemotherapy.”

  1. FDA approves dabrafenib with trametinib for pediatric patients with low-grade glioma with a BRAF V600E mutation. News release. FDA. March 16, 2023. Accessed March 16, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
  2. Phase II pediatric study with dabrafenib in combination with trametinib in patients with HGG and LGG. ClinicalTrials.gov. Updated January 30, 2023. Accessed March 16, 2023. https://clinicaltrials.gov/ct2/show/NCT02684058
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