The FDA has granted approval to dabrafenib (Tafinlar®, Novartis) with trametinib (Mekinist®, Novartis) for treatment of pediatric patients with BRAF V600E–mutated low-grade glioma (LGG) who require systemic therapy. In addition, the FDA approved new oral formulations of dabrafenib and trametinib for patients who cannot swallow pills. This is notable as it is the first approval of a systemic therapy in a first-line setting for pediatric patients with BRAF V600E–mutated LGG.
"LGG is the most common pediatric brain cancer, and BRAF V600 mutation has been detected in ≈17% of cases," wrote Dr. Eric Bouffet, a Professor of Pediatrics at the University of Toronto, Canada, and colleagues, in their published results of the CDRB436G2201 study (NCT02684058), on which approval was based. "Most patients with pediatric LGG (pLGG) have disease progression and require post-surgical therapy. The standard of care is chemotherapy, such as carboplatin + vincristine, which may be less effective in BRAF V600–mutant disease; thus, alternative treatment options are needed."
Safety and efficacy were evaluated in the phase 2, multicenter, open-label trial in which pediatric patients between the ages of 1 and <18, with a confirmed BRAF V600–mutant LGG diagnosis requiring first systemic therapy, were randomized 2:1 to receive either dabrafenib plus trametinib or carboplatin plus vincristine. Patients' BRAF mutation status was identified by local or central laboratory tests. Each patient receiving dabrafenib plus trametinib had their dosage based on age and weight, and they received treatment until unacceptable toxicity or disease progression. For those receiving carboplatin plus vincristine, dosing was based on body surface area at 175 mg/m2 for carboplatin and 1.5 mg/m2 (0.05 mg/kg for patients less than 12 kg) for vincristine. Treatment was conducted over a 10-week induction course, followed by maintenance therapy over eight six-week cycles.
The primary end point measured was overall response rate measured by independent review based on Response Assessment in Neuro-Oncology (RANO) LGG (2017) criteria. Secondary end points measured were progression-free survival and overall survival. Primary analysis was measured once a patient had completed 32 weeks of therapy. Overall response rate was 46.6% in those receiving dabrafenib with trametinib compared with 10.8% in those receiving carboplatin plus vincristine. Progression-free survival was 20.1 months in the dabrafenib plus trametinib arm compared with 7.4 months in the carboplatin plus vincristine arm. Overall survival did not reach statistical significance.
The most common adverse events in >20% of the pooled pediatric patients receiving dabrafenib with trametinib were pyrexia (66%), rash (54%), headache (40%), vomiting (38%), musculoskeletal pain (36%), fatigue (31%), dry skin (31%), diarrhea (30%), nausea (26%), epistaxis and other bleeding events (25%), abdominal pain (24%), and dermatitis acneiform (23%). The most common grade 3 or 4 laboratory abnormalities in >2% of patients were decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and increased aspartate aminotransferase (3.1%).
"Dabrafenib plus trametinib significantly increased overall response rate and clinical benefit rate and prolonged progression-free survival compared with carboplatin plus vincristine in patients with BRAF V600 mutation–positive pLGG," concluded Dr. Bouffet and colleagues. "These encouraging results and the tolerable safety profile suggest that dabrafenib plus trametinib may be a promising first-line systemic treatment option for this patient population."
The recommended dosage in pediatric patients for both dabrafenib and trametinib are quantified based on body weight. Dabrafenib is administered orally twice daily and trametinib is administered orally once daily, until disease progression or unacceptable toxicity.
For More Information
Bouffet E, Hansford J, Garré M, et al (2022). Primary analysis of a phase II trial of dabrafenib plus trametinib (dab + tram) in BRAF V600–mutant pediatric low-grade glioma (pLGG). J Clin Oncol, 40(suppl_17). DOI:10.1200/JCO.2022.40.17_suppl.LBA2002
Clinicaltrials.gov (2023). Phase II pediatric study with dabrafenib in combination with trametinib in patients with HGG and LGG. NLM identifier: NCT02684058.
Tafinlar® (dabrafenib) prescribing information (2023). Novartis. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/202806s025lbl.pdf
Makinist® (trametinib) prescribing information (2023). Novartis. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/204114s025lbl.pdf
US Food and Drug Administration (2023). FDA approves dabrafenib with trametinib for pediatric patients with low-grade glioma with a BRAF V600E mutation. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-dabrafenib-trametinib-pediatric-patients-low-grade-glioma-braf-v600e-mutation
Image Credit: Blondis. Licensed under Public Domain.
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