Novartis has recently announced the primary results of dabrafenib plus trametinib combination therapy in children suffering from a glioma containing BRAF V600 mutation. Based on these preliminary results, dabrafenib and trametinib are being hailed as the potential first-line systemic treatment for pediatric low-grade gliomas. This blog is centered around understanding the significance of this preliminary result and what it means for low-grade glioma patients. It will dig deeper into the efficacy and safety of dabrafenib and trametinib and compare them with the current standard of care systemic mediations in low-grade gliomas.
First, let’s recall what cerebellar astrocytoma is
As the name indicates, cerebellar astrocytoma is a type of glioma found in the cerebellum part of the brain. Gliomas are a broad class of brain tumors that arise from glial or helper cells in the brain. Most cerebellar astrocytomas are low-grade gliomas, called pilocytic astrocytomas, that mostly affect children. They are slow-growing tumors with favorable outcomes following standard-of-care treatment. Other types, such as low-grade fibrillary astrocytoma or diffuse astrocytoma (DA), anaplastic astrocytoma, and glioblastoma multiforme, are more malignant but less common.
The slow-growing pilocytic astrocytoma blocks the flow of cerebrospinal flow in the brain and causes it to accumulate in its cavities. The raised pressure from the accumulation of fluid in the brain causes headaches, lethargy, and clumsiness among other non-specific symptoms . It is diagnosed when the brain is examined via magnetic resonance imaging and computed tomography.
How are cerebellar astrocytoma being treated?
Their management consists of surgical removal of as much tumor mass as possible. In most cases, complete removal of the tumor through brain surgery is curative but in some, additional treatment is required . This additional treatment is chemotherapy and not radiation therapy because the latter causes neurological complications in children. The chemotherapy drugs currently used for systemic therapy of pediatric low-grade gliomas are carboplatin and vincristine .
Description of the clinical trial
The trial evaluating this new combination therapy recruited low-grade glioma patients who:
Were under 18 years old
Had BRAF V600 mutation
Had a Karnofsky/Lansky performance score of ≥50%
Required systemic therapy
A total of 110 patients were randomly assigned to receive either dabrafenib and trametinib or the standard carboplatin and vincristine in a 2-to-1 ratio . Of them, 61 were in the dabrafenib plus trametinib group at the end of the study whereas, 8 participants were given the standard carboplatin plus vincristine treatment. Dabrafenib was given twice a day whereas trametinib was given once per day and the doses of these drugs were adjusted to the age and body weight of the patients. The primary endpoint of this study was the overall response rate and the secondary endpoint was the clinical benefit rate. The investigators also looked into progression-free survival. The results were significantly in the favor of the new drugs i.e., dabrafenib and trametinib .
The independently assessed overall response rate of the participants was found to be 47% in the dabrafenib plus trametinib group versus 11% in the carboplatin plus vincristine group.
Patients in the dabrafenib plus trametinib group showed a clinical benefit rate of 85% as compared to only 11% of the carboplatin plus vincristine group.
And the progression-free survival was 13.7 months greater in patients given dabrafenib plus trametinib as compared to the patients given the standard chemotherapy drugs.
In terms of safety, dabrafenib plus trametinib had no deaths and fewer instances of adverse effects as compared to 1 death and more instances of adverse effects such as fever, headache, and vomiting.
So, what do these results mean?
The presented results of this clinical trial clearly show that dabrafenib plus trametinib are efficacious and safe as compared to the standard carboplatin plus vincristine regimen. This indicates a potential role of dabrafenib plus trametinib in systemic therapy for low-grade pediatric gliomas having BRAG V600 mutation. However, to prefer dabrafenib plus trametinib over carboplatin plus vincristine as the first-line systemic therapy in this population, a phase 3 clinical trial with a larger sample size is required.
C. M. Bonfield and P. Steinbok, “Pediatric cerebellar astrocytoma: a review,” Childs Nerv Syst, vol. 31, no. 10, pp. 1677–1685, Oct. 2015, DOI: 10.1007/s00381-015-2719-1.
P. de Blank, P. Bandopadhayay, D. Haas-Kogan, M. Fouladi, and J. Fangusaro, “Management of Pediatric Low-Grade Glioma,” Curr Opin Pediatr, vol. 31, no. 1, pp. 21–27, Feb. 2019, DOI: 10.1097/MOP.0000000000000717.
Novartis Pharmaceuticals, “Phase II Open-label Global Study to Evaluate the Effect of Dabrafenib in Combination With Trametinib in Children and Adolescent Patients With BRAF V600 Mutation Positive Low Grade Glioma (LGG) or Relapsed or Refractory High Grade Glioma (HGG),” clinicaltrials.gov, Clinical trial registration NCT02684058, Sep. 2022. Accessed: Oct. 20, 2022. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT02684058
E. Bouffet et al., “Primary analysis of a phase II trial of dabrafenib plus trametinib (dab + tram) in BRAF V600–mutant pediatric low-grade glioma (pLGG).,” JCO, vol. 40, no. 17_suppl, pp. LBA2002–LBA2002, Jun. 2022, doi: 10.1200/JCO.2022.40.17_suppl.LBA2002.