Dabrafenib Plus Trametinib Improve Overall Response Rates vs Standard-of-Care Chemotherapy in Pediatric Patients With Low-Grade Gliomas

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The combination of two targeted therapies, the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, significantly increased the overall response rate compared to the standard-of-care chemotherapy combination of carboplatin plus vincristine in pediatric patients with BRAF V600 mutation–positive low-grade gliomas. Secondary findings showed an improved clinical benefit rate and prolonged progression-free survival for dabrafenib plus trametinib compared to carboplatin plus vincristine, according to new research presented by Bouffet et al at the 2022 ASCO Annual Meeting (Abstract LBA2002).

Dabrafenib targets the V600-mutant form of BRAF, which is found at varying prevalence in many types of cancer, while trametinib targets the kinase MEK within the same signaling pathway. When combined, both medicines can inhibit the effect of the BRAF V600 mutation and thereby inhibit the growth of cancer cells with this mutation. Patients assigned to the comparison arm received the chemotherapy drugs carboplatin and vincristine, two standard-of-care agents that have been used for decades.

“For pediatric patients with BRAF V600–mutant low-grade glioma, dabrafenib plus trametinib may offer an improved standard of care. This represents an important advance for the youngest patients with brain cancer, as this is the first combination of targeted therapies developed for patients as young as [age 1 year],” said lead author Eric Bouffet, MD, FRCPC, Director of the Pediatric Neuro-Oncology Program at The Hospital for Sick Children in Toronto.  

Central nervous system tumors are the most common solid tumors in children. An estimated 4,170 new cases of childhood brain tumors are expected to be diagnosed in the United States in 2022, with gliomas accounting for up to 50% of those cases. Depending on their location, pediatric low-grade gliomas may not be able to be completely removed surgically, and patients with residual, progressive, or recurrent disease frequently require systemic therapy. With current approaches to treatment, 5-year survival rates are approximately 95%. However, there is a continued risk of tumor progression, and most patients require multiple lines of treatment.

The BRAF V600 mutation has been detected in about 15% to 20% of low-grade glioma cases and may be associated with an increased risk of progression to high-grade glioma. At the time this study was initiated, it was also noted, but not confirmed, that patients with BRAF V600–mutant disease may have worse outcomes than patients with nonmutated disease treated with the current standard of care.

About the Study

Dabrafenib was shown to be clinically meaningful as a stand-alone therapy in a phase I/II trial in patients with previously treated BRAF V600–mutant low-grade glioma. Data from the first pediatric study of dabrafenib plus trametinib demonstrated tolerability and preliminary clinical activity of the combination in those patients.   

The study was a double-blind clinical trial conducted at 57 investigative centers in 20 countries. The trial randomly assigned 110 patients from the age of 1 to 17 years who had BRAF V600 mutation–positive low-grade gliomas to either dabrafenib twice daily plus trametinib once daily or to standard-of-care doses of carboplatin plus vincristine. The primary endpoint was the overall response rate. Secondary endpoints included the clinical benefit rate, duration of response, time to response, progression-free survival, overall survival, and safety.

Key Findings

The primary trial endpoint was met, with an overall response rate of 47% for dabrafenib plus trametinib compared to 11% for carboplatin plus vincristine. For secondary endpoints, the clinical benefit rate was 86% for dabrafenib plus trametinib vs 46% for carboplatin plus vincristine, and the median progression-free survival was 20.1 vs 7.4 months, respectively. The findings were assessed independently by a central medical imaging vendor.

Patients in the dabrafenib plus trametinib arm had fewer high-grade adverse events (47% vs 94%) and fewer discontinuations of treatment due to adverse events (4% vs 18%) than patients in the carboplatin plus vincristine group. The most frequent adverse events in the dabrafenib plus trametinib vs carboplatin plus vincristine groups were fever (68% vs 18%), headache (47% vs 27%), and vomiting (34% vs 48%).

Next Steps

This study is ongoing and is still collecting long-term safety data. Safety data will also be collected in a companion study. Researchers hope to learn more about the optimal duration of treatment.   

The researchers hope to determine if this treatment fits into the World Health Organization (WHO) global initiative for childhood cancer. Pediatric low-grade glioma is one of six diseases that comprise the WHO initiative, and targeted therapies may have a potential impact as part of this initiative.

ASCO Perspective

Melissa M. Hudson, MD, FASCO

Melissa M. Hudson, MD, FASCO

“This study shows that a new, oral targeted therapy combination can significantly improve outcomes for the most common type of brain tumor in children over standard-of-care chemotherapy that often requires frequent visits to the hospital or clinic and can result in health problems later in life. It is exciting to see success in developing targeted treatments based on the unique genetic features of a tumor in a young patient,” said Melissa M. Hudson, MD, FASCO, ASCO expert in pediatric cancers.

Disclosure: This trial was funded by Novartis Pharmaceuticals Corp. For full disclosures of the study authors, visit

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