FDA Approves Dabrafenib With Trametinib for Pediatric BRAF V600E–mutant Low-grade Glioma


FDA has approved the BRAF/MEK combination of dabrafenib plus trametinib for pediatric BRAF V600E–mutant low-grade glioma. The label comes with a warning for pyrexia.

The FDA has approved the combination of dabrafenib (Taflinar) and trametinib (Mekinist) for the treatment of pediatric patients older than 1 year with low-grade glioma whose disease harbors a BRAF V600E mutation. The approval comes in 2 regimens, an oral formulation for patients who may have difficulty swallowing and in capsules and tablets.1-3

The regulatory agency noted that this is the first systemic therapy approval for the front-line treatment of this patient population.1

The approval is based on data from the phase 2 trial (NCT02684058) in which 73 patients aged at least 1 year and not exceeding 18 years with low-grade glioma received the combination and had an overall response rate of 46.6% (95% CI, 34.8%-58.6%) compared with 10.8% (95% CI, 3.0%-25.4%) among patients in the carboplatin plus vincristine arm (n = 37; P < .001). Most responses were partial responses in both arms (44% and 8%, respectively) with 2 complete responses reported in the investigative arm and 1 reported in the control arm.

The median duration of response was 23.7 months (95% CI, 14.5-not estimable [NE]) with dabrafenib plus trametinib and NE with chemotherapy (95% CI, 6.6-NE). A majority of patients in both arms (56% and 50%, respectively) had a response lasting at least 12 months. More responders in the chemotherapy arm (25%) had a response lasting 2 years or longer compared with the investigative arm (15%).

The median progression-free survival was 20.1 months (95% CI, 12.8-NE) with the BRAF/MEK inhibitor combination compared with 7.4 months (95% CI, 3.6-11.8) on the chemotherapy arm (HR, 0.31; 95% CI, 0.17-0.55; P < .001).1,2

The overall survival results calculated at the interim analysis (32 weeks post treatment for all patients) were not significant.1,2

The label notes that patients must have confirmed presence of BRAF V600E mutations in a tumor specimen prior to administration and that there is not current FDA-approved test for this.

On study, patients received age- and weight-based doses of the agents. The recommended dosages range by body weight 8 kg through 51 kg or more. The median age of patients enrolled on the trial was 9.5 years (range, 1-17).1,2

When administering the agents formulated for oral suspension, it is recommended to prepare with approximately 5 mL of water for up to 4 tablets and approximately 10 mL for 5 to 15 tablets. It may take up to 3 minutes for tablets to dissolve and the mixture will be cloudy white. If the mixture is not administered within 30 minutes, it should be discarded. Agents should be administered until disease progression or unacceptable toxicity.1-3

In terms of safety, pyrexia was the most reported warning and precaution for the agent with 68% of pediatric patients having an event on the trial (8% grade 3). It is recommended to withhold both agents if a patient experiences a fever of 100.4 °F or higher and patients should be monitored for infection, serum creatinine levels, and other renal functions at the onset of pyrexia. When resuming the combination, administer antipyretics as secondary prophylaxis if severe febrile reaction or fever associated with complications occurred. Corticosteroids should be administered for at least 5 days for second or subsequent pyrexia if temperature does not return to baseline within 3 days of onset of pyrexia. Steroids can also be used to treat pyrexia that is associated with complications, such as dehydration, hypotension, renal failure, or severe chills/rigors, so long as there is no sign of infection.

Other common adverse effects on the study were rash (51%), headache (47%), musculoskeletal pain (34%), and vomiting (34%), which were mostly grade 1 or 2.2,3


  1. FDA approves dabrafenib with trametinib for pediatric patients with low-grade glioma with a BRAF V600E mutation. FDA. March 16, 2023. Accessed March 16, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-dabrafenib-trametinib-pediatric-patients-low-grade-glioma-braf-v600e-mutation
  2. Mekinist. Prescribing information. Novartis; 2023. Accessed March 16, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/204114s025lbl.pdf
  3. Tafinlar. Prescribing information. Novartis; 2023. Accessed March 16, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/202806s025lbl.pdf
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