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

Ashley Margol, MD, Children’s Hospital of Los Angeles, California, discusses the course of treatment she would take for a patient with relapsed or refractory pediatric low-grade glioma. 

This patient was treated with tovorafenib. As stated by Dr Margol, "for a 7-year old who's going to be really active, most likely going to be in first grade, having to come to the clinic and get a traditional chemotherapy, such as vinblastine, is probably not the best option for the patient and she might have a much better quality of life taking a once weekly oral medication at home." 

Transcript: 

I'm Dr Ashley Margol, I am an associate professor of clinical pediatrics at the Keck School of Medicine at the University of Southern California and I am the director of the Brain Tumor Center at Children's Hospital of Los Angeles. 

Pediatric low-grade glioma is the most common type of pediatric brain tumor and we now know that these tumors are driven by alterations in the MAP kinase pathway. Those alterations typically occur at the level of BRAF but the vast majority of alterations being a KIAA1549-BRAF fusion and a minority of them being a BRAF-V600E mutation. Understanding the molecular phenotype of these tumors really helps us direct therapy.

When we think about front-line therapy for pediatric low-grade glioma we still use conventional chemotherapy as front-line therapy. We're currently doing clinical trials to compare the effectiveness of traditional chemotherapy with molecularly targeted therapy, but currently traditional chemotherapy, such as carboplatin and vincristine, remain the standard of care, so that's what the patient in the case got. About 50% of patients who have residual tumor will in fact have progressive disease, as was the case with this patient, so when we think about progressive or recurrent pediatric low-grade glioma we have a variety of treatment options to consider. We're just going to go through the options that were listed in the quiz and explain when one would be considered, and which one is the incorrect answer and should never be given to this patient.

When we consider options for children with recurrent or progressive low-grade glioma, we need to think about 2 potential buckets, we have traditional chemotherapy and then we have molecularly targeted agents. Vinblastine, which is the last option listed option D, as you all know, is a vinca alkaloid which will cause disruption of the microtubules and then prevent solid division. Most people nowadays with the discovery and development of molecularly targeted agents would preserve traditional chemotherapy for a patient who was multiply recurrent and was running out of options. 

When we think about molecularly targeted agents, we can target the MAP kinase pathway at 2 levels, we can target it at the level of BRAF or we can go downstream 1 to the level of MEK. The first option here would be the first choice for our patients with progressive, recurrent, or even refractory pediatric low-grade glioma and that is tovorafenib. The reason that it would be the first choice is that it's actually FDA-approved for this indication. Tovorafenib is an interesting drug because it's what we call a pan-RAF inhibitor,  it's going to inhibit the MAP kinase activation actually at the level of BRAF and the fact that it's a pan-RAF inhibitor allows it to be used for tumors that harbor either the KIAA1549-BRAF fusion or tumors that harbor BRAF-V600E mutation, so any tumor that is BRAF-altered can be targeted by tovorafenib. 

The second drug that's listed here is the wrong choice. This drug is dabrafenib and this is simply just a BRAF inhibitor in contrast to tovorafenib which is a pan-RAF inhibitor. These drugs work well for tumors that are BRAF-V600E–mutated however, you cannot use them for tumors that harbor the KIAA1549 BRAF fusion. If you do use this drug in that setting, you will actually cause what is called paradoxical activation, and the tumor will grow, so that is why dabrafenib is the wrong choice for this patient. 

Option C is selumetinib, a MEK inhibitor. This could be considered because there are data, there are clinical trials, that have demonstrated the efficacy of selumetinib in patients with recurrent or refractory pediatric low-grade glioma. However, this drug is not currently FDA approved for this indication.

For this patient, she's a 7 year old who now has radiographic progression of her disease as well as clinical progression with new symptoms, that is really the reason why we would re-initiate therapy at this time. When we think about our potential options, tovorafenib makes a lot of sense for this patient because, as I mentioned, it's FDA approved for this particular indication. Also it's an oral medication that's given once a week. For a 7-year old who's going to be really active, most likely going to be in first grade, having to come to the clinic and get a traditional chemotherapy, such as vinblastine, is probably not the best option for the patient and she might have a much better quality of life taking a once weekly oral medication at home.