TO THE EDITOR,
The combined use of dabrafenib and trametinib was approved by the U.S.
Food and Drug Administration (FDA) for use in BRAF V600E mutated
non-small cell lung cancer and melanoma in 2017 and 2018, respectively.
Use of targeted therapy regimens in pediatric low-grade glioma have been
under investigation.1 Dabrafenib is commercially
available as a 50 mg and 75 mg capsule. As per the FDA, it should not be
opened or crushed.2 Trametinib is distributed as 0.5
mg and 2 mg film-coated tablets to be swallowed
whole.3
Phase 1and 2 of a study on dabrafenib use in pediatric cancers offered
both the commercial capsule and an investigational suspension
formulation of the drug for patients unable to tolerate
capsules.1,4 Similarly, an oral suspension of
dabrafenib and crushed administration of trametinib were used
temporarily for patients unable to swallow.5Suspension had a faster absorption and higher peak serum concentration,
however similar exposure to the drug was seen when compared to capsular
administration of dabrafenib. In this study, the bioavailability of the
suspension was 85% of the capsule formulation.4
At our institution, we compounded a liquid suspension of trametinib and
dabrafenib for those unable to swallow pills. In November 2019, a
17-month-old presented with right esotropia and was found to have a
posterior fossa tumor with leptomeningeal extension into the brain stem
and abnormal T2 prolongation in the upper cervical spine (Fig. 1A). She
underwent a near total resection. Pathology demonstrated a high-grade
glioneuronal tumor, with a BRAF V600E mutation and H3K27m wild-type. To
avoid radiation, treatment was customized to target the BRAF V600E
mutation. She was started on a compounded liquid suspension of
dabrafenib (75 mg once daily, 4.5 mg/kg) and trametinib (0.5 mg once
daily, 0.03 mg/kg) in December 2019. The dose was adjusted for weight
gain during clinical course. Imaging after two months and six months of
treatment showed stable T2 prolongation and expansion in the upper
cervical spine and stable medullary leptomeningeal disease. In October
2020, she was intubated for acute respiratory failure. Subsequently, she
had a tracheostomy and gastrostomy tube was placed due to pharyngeal
swallowing dysfunction. Due to swallowing dysfunction, crushed
dabrafenib tablets and opened trametinib capsules were each administered
through the gastrostomy tube in 5 ml of water by the parents followed by
a 10 ml water flush. Follow-up imaging three months after showed
significant improvement in both the leptomeningeal disease and size of
expansile T2 prolongation in the cervical cord, consistent with
treatment response (Fig. 1B). The patient continues the crushed
dabrafenib and trametinib at this point.
In conclusion, a stable response with no tumor growth over 6 months
using crushed dabrafenib and trametinib was observed in a case of
pediatric glioneuronal tumor with BRAF V600E mutation. Although this is
not an approved administration route, this patient’s clear response to
therapy demonstrates adequate absorption using this method. This outcome
warrants further investigation into a broader study as crushing these
tablets would facilitate their use for many patients with BRAF V600E
mutated disease unable to swallow pills.