Best Management of a Patient With BRAF-Altered Recurrent or Refractory Pediatric Low-Grade Glioma

Matthew Cascio, MD, University of Florida, Gainesville, Florida, discusses the course of treatment he would take for a patient with BRAF V600E-mutated pediatric low-grade glioma. 

Transcript: 

Hello, my name is Matthew Cascio, the clinical director at the University of Florida. Thank you for taking part in this case. This is an interesting, but really a complicated case because of the age of this particular patient. Coming into a scenario of a patient of this age where we have progression of tumor, it becomes a little challenging to figure out what is going to be the best route for approaching this patient. We have a couple of different options based off the answer choices that we have, and 1 of those answer choices is a definite no whereas the other 3 can kind of come up as a possibility in our minds. 

In the first, we have dabrafenib and trametinib, which is a proven effective treatment for patients with low-grade gliomas with a BRAF V600E-mutated tumor. It is FDA-approved for patients with this mutation specifically in either upfront or recurrent refractory settings. However, the FDA approval is limited to children of 1 year of age or older and only to BRAF V600E-mutated tumors specifically. It is not FDA-indicated for other BRAF type alterations, so this is not really going to be one of the best options for this particular patient, largely because of the age. 

When we come down to the consideration of everolimus, this is a drug that is FDA-approved for certain types of astrocytoma, mainly associated with tuberous sclerosis, associated subependymal giant cell astrocytoma, otherwise known as SEGA. It is not FDA-approved for RAF-altered astrocytomas, in fact monotherapy with mTOR inhibitors like everolimus may paradoxically promote growth of tumors with RAF alterations due to compensatory pressures on the RAS pathway via the MAP kinase pathway. 

Tovorafenib is FDA-approved for children 6 months and older with recurrent or refractory low-grade gliomas harboring a BRAF fusion or rearrangement or BRAF V600E mutations. Whether patients have received front-line chemotherapy or targeted treatment with dabrafenib and trametinib, tovorafenib has been shown to be effective in treating progressive or recurrent disease as a second-line treatment, therefore this is a very good option potentially for this patient. 

While vinblastine has been commonly used as a treatment option for pediatric low-grade gliomas, in front-line and second-line settings, it is not FDA-approved for pediatric low-grade glioma, specifically. In a phase 2 study that included around 54 patients, 18 years and younger, with unresectable or progressive low-grade glioma an overall response rate with weekly vinblastine treatment was determined to be about 25.9% response while disease stabilization occurred in 87% of patients. Only 3 of 31 tumor samples tested in this study showed a BRAF V600E mutation, 1 of which progressed through the vinblastine treatment therefore, the low number of BRAF V600E cases in the study did not permit conclusive data on the effectiveness of vinblastine in this patient population. 

Of the treatment options that we have for this particular patient, who is less than 1 year of age, we come to the scenario of tovorafenib and vinblastine, tovorafenib which is FDA-approved specifically for this purpose and in this age group, so this can be the best treatment option.