Best Management Practices for a Patient With Pediatric Low-Grade Glioma

Lindsey Hoffman, DO, Phoenix Children’s Hospital, Phoenix, Arizona, discusses the course of treatment she would take for a patient with BRAF V600E-mutated pediatric ganglioglioma. 

According to Dr Hoffman, “there are a lot of effective treatment options, including targeted therapy and, for BRAF V600E-mutant low-grade gliomas, dabrafenib and trametinib should really be strongly considered for any patient who requires treatment as a first-line therapy.”

Transcript: 

Hi everyone, my name is Lindsay Hoffman, I am the section chief of neuro-oncology at Phoenix Children's Hospital. The case I'm presenting today is focused on pediatric low-grade glioma and the utility of molecularly targeted therapies for this patient population. I chose this case to highlight the fact that some targeted therapies are now FDA-approved for pediatric low-grade glioma. 

Low-grade gliomas represent about half of all central nervous system tumors that we see in children and adolescents and thankfully outcomes for these children are generally excellent. The therapeutic approach for pediatric low-grade glioma is defined largely based on the tumor location because, if the tumor can be completely resected in a safe manner, then that's generally the preferred first step for these patients. If the tumor is in a region of the brain or the spine for which there are more consequences to attempting a complete resection, then a biopsy or a subtotal resection is undertaken to make this diagnosis, and the child may need additional therapy thereafter.

In the case of the patient that I presented in the clinical vignette, her tumor is located in the medulla, a section of the brainstem that is sandwiched between the pons and the spinal cord. Surgery can be considered in this location of the brainstem, but it's often unlikely that a complete resection can be safely achieved because of all of the important nerves that run from the brain down to the rest of the body through this structure. In the case of our patient, she underwent a biopsy to make a diagnosis of ganglioglioma, which is a histologic subset of pediatric low-grade glioma that commonly harbors a BRAF V600E mutation. The percentage of gangliogliomas that harbor this specific point mutation in the BRAF gene depends on which paper you read, but the incidence of this mutation in ganglioglioma is around 30% to 50%. The BRAF V600E mutation is a common genetic driver in pediatric low-grade glioma, and it functions by turning on the MAP kinase pathway, so to speak. 

There are several medications that have been developed to specifically target or turn off the MAP kinase pathway and some of these are targeted or aimed specifically against the BRAF V600E mutation. Pediatric low-grade glioma in general is thought of as a single pathway disease, in that the MAP kinase pathway is turned on in every one of these tumors, so this pathway can be targeted therapeutically using several different medications. The main classes of medications include MEK inhibitors and RAF inhibitors. 

If you were to lay out the MAP kinase pathway on a piece of paper, you would note the following sequence: RAS, RAF, MEK, and ERC, so this is the order in which the molecules are activated. If you think about this sequence, you'll note that MEK is downstream of RAS and RAF. A MEK inhibitor, medication to turn off MEK, would potentially be useful for any tumor that has an activating mutation of RAS or RAF because MEK is downstream of those activating mutations. There are also RAF inhibitors, and these come in two different types, we talk about them as type 1 or type 2. Type 1 RAF inhibitors, like dabrafenib, are used against the BRAF V600E mutation, which is relevant in our case, and then type 2 BRAF inhibitors like tovorafenib, which was recently FDA-approved for relapsed pediatric low-grade glioma in April of 2024. Type 2 BRAF inhibitors are relevant in tumors that have both the BRAF V600E mutation as well as a BRAF fusion, another very common genetic alteration in pediatric low-grade glioma. 

For the patient in our vignette, she needs therapy because the tumor could not be completely resected or addressed with surgery. In her case, you would probably consider a chemotherapy, which is known to be effective against pediatric low-grade glioma in general, and you could also consider targeted therapy. 

Related to this treatment decision, I wanted to highlight a phase 2 clinical trial that was published in September of 2023 in the New England Journal of Medicine, and the first author was Dr Eric Bouffet. The results of this phase 2 study were ultimately what led to FDA approval of dabrafenib and trametinib in combination for the treatment of BRAF V600E-mutant glioma in children. Children or adolescents enrolled on this trial had a BRAF V600E-mutant tumor that required some type of systemic therapy, so they were exactly the same as the patient in our vignette. Patients on this trial were randomized to receive either dabrafenib and trametinib or carboplatin and vincristine, standard chemotherapy. There were 2 patients randomized to dabrafenib and trametinib for every 1 patient randomized to chemotherapy. In total, 110 pediatric patients were enrolled on this study, including 73 who received targeted therapy, dabrafenib and trametinib, and 37 who received chemotherapy. The primary end point of the study was focus on objective response, this was defined as either partial response, which was greater than a 50% reduction in the tumor size, or a complete response, which is complete resolution of the tumor. They also reported something called clinical benefit rate, which included tumor responses that I referred to before, as well as this also included patients who had prolonged stable disease, so stable disease for greater than 6 months.

Overall, the results of the study showed that dabrafenib and trametinib was a great success when it was compared to chemotherapy. The overall response rate for dabrafenib and trametinib in this population was 47% compared to just 11% for those who received chemotherapy. The clinical benefit rate, which I referenced before, including patients with prolonged stable disease, was 86% compared to 46% for those who received chemotherapy. For patients who did recur, time-to-recurrence was 20.1 months with dabrafenib and trametinib versus 7.4 months with chemotherapy. Another important point to mention is that adverse events, specifically grade 3 or higher adverse events, were lower with dabrafenib and trametinib compared to chemotherapy. Based on these results, as well as other data provided by the company, the FDA approved dabrafenib and trametinib for patients who have V600E-mutant glioma as long as they’re age greater than 1 year and they require some type of systemic therapy. If a patient undergoes a surgery and has a complete resection of a BRAF V600E-mutant glioma, you can still observe those patients, they don't require any treatment, but dabrafenib and trametinib can be used instead of chemotherapy for patients with BRAF V600E low-grade glioma that do require treatment. 

You may ask yourself; couldn't I also use a RAF inhibitor alone? Or a MEK inhibitor alone? And the answer is yes. There's presumed better efficacy of the combination of dabrafenib and trametinib together and interestingly, there are also fewer skin side effects specifically with the combination compared in particular to MEK inhibitors alone. The reason for this is that the combination prevents paradoxical activation of the MAP kinase pathway in some cells without the BRAF V600E mutation, including keratinocyte. Skin cells without the BRAF V600E mutation, if you're treating with a MEK inhibitor alone, they sort of get activated in a way that treating with the combination squashes that effect, so you get fewer skin side effects with the combination than you do with either agent alone.

There's still a lot to be learned and defined about how we use targeted therapy for pediatric low-grade glioma. The FDA recently provided a conditional approval for the use of tovorafenib, a type 2 RAF inhibitor for children with BRAF-altered pediatric low-grade glioma at the time of recurrence. This FDA approval would not be relevant for the patient we presented in the case vignette because she had not yet failed a first-line of therapy, but it's possible that with further study, medications like tovorafenib may be appropriate in the upfront setting as well. 

In summary, this is a really exciting time to be on the front lines of treating pediatric low-grade glioma. There are a lot of effective treatment options, including targeted therapy and for BRAF V600E-mutant low-grade gliomas. And dabrafenib and trametinib should really be strongly considered for any patient who requires treatment as a first-line therapy.

Reference:

Bouffet E, Hansford JR, Garrè ML, et al. Dabrafenib plus trametinib in pediatric glioma with BRAF V600 mutations. N Engl J Med. 2023;389(12):1108-1120. doi:10.1056/NEJMoa2303815