Dual-Targeted Therapy Improves Outcomes vs Chemotherapy for Some Pediatric Patients With Low-Grade Glioma

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The all-oral combination of dabrafenib plus trametinib—two targeted therapies—significantly improved the overall response rate vs standard-of-care chemotherapy with carboplatin plus vincristine in pediatric patients with BRAF V600 mutation–positive low-grade gliomas. The clinical benefit rate (response rate plus stable disease for 6 months or more) and progression-free survival were also improved with the targeted combination vs carboplatin plus vincristine. These phase II trial findings were featured at the 2022 ASCO Annual Meeting.1

The overall response rate was 47% with the combination vs 11% with standard chemotherapy (P < .001). The clinical benefit rate was 86% vs 46%, respectively. Median progression-free survival was 20.1 months vs 7.4 months, respectively (P < .001).

“This is the first-ever randomized clinical trial in pediatric patients with low-grade glioma and BRAF V600 mutations. These findings support the use of dabrafenib plus trametinib as a new potential standard of care in pediatric patients with low-grade glioma with BRAF V600 mutations. These results highlight the importance of early molecular testing in pediatric low-grade glioma to determine whether patients may benefit from targeted therapy,” said lead author Eric Bouffet, MD, FRCPC, Director of the Pediatric Neuro-Oncology Program at The Hospital for Sick Children, Toronto.

Eric Bouffet, MD, FRCPC

Eric Bouffet, MD, FRCPC

“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 children as young as 1 year of age,” he stated.

ASCO expert in pediatric cancers Melissa M. Hudson, MD, FASCO, of St. Jude Children’s Research Hospital, Memphis, shared her thoughts about these findings. “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, which 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,” she said. “We will need further follow-up to characterize long-term adverse events. These new data will allow us to personalize treatment for these children.”

It is exciting to see success in developing targeted treatments based on the unique genetic features of a tumor in a young patient.
— Melissa M. Hudson, MD, FASCO

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The most common type of solid tumor in children occurs in the central nervous system. In 2022, an estimated 4,170 new cases of childhood brain cancers will be diagnosed in the United States, and gliomas comprise up to 50% of these new cancers. Pediatric low-grade gliomas are not always completely resectable, depending on where they are situated in the brain, and systemic therapy is often needed for patients with residual, progressive, or recurrent disease. With modern approaches to treatment, the 5-year survival rate is about 95%, but most patients have disease progression and require multiple lines of postoperative systemic therapy.

Gliomas are characterized as high-grade or low-grade. About 15% to 20% of low-grade glioma cases are characterized by BRAF V600 mutations. Tumors with these mutations are associated with an increased risk for disease progression to high-grade glioma and a less favorable response to standard chemotherapy.

Dabrafenib is a BRAF inhibitor targeting the V600-mutant form of BRAF, and trametinib is a MEK inhibitor targeting the same pathway as BRAF. The combination of both drugs inhibits the growth of cancer cells characterized by the BRAF V600 mutation. 

Study Details

Based on previous studies, the combination therapy was found to be tolerable and active in pediatric patients with low-grade glioma. The double-blind clinical trial reported at the ASCO meeting was conducted at 57 centers in 20 countries. Patients (n = 110) from the age of 1 to 17 had BRAF V600 mutation–positive low-grade gliomas and progressive disease after surgery or were nonsurgical candidates who required systemic treatment. They were randomly assigned 2:1 to receive either dabrafenib twice daily plus trametinib once daily or standard doses of carboplatin plus vincristine. Dabrafenib was dosed at 5.25 mg/kg/d for patients younger than age 12 and at 4.5 mg/kg/d for those aged 12 and older. Trametinib was dosed at 0.032 mg/kg/d for those younger than age 6 and at 0.025 mg/kg/d for those aged 6 and older. Crossover was allowed for progressive disease.

The primary endpoint was overall response rate. Secondary endpoints included clinical benefit rate, duration of response, time to response, progression-free survival, overall survival, and safety. Baseline characteristics were well balanced between the two arms.

Key Findings

As previously mentioned, the study met its primary endpoint, and all secondary endpoints favored the combination over standard chemotherapy. At a median follow-up of 18.9 months, 84% of the dabrafenib/trametinib arm and 22% of the standard chemotherapy arm remained on treatment.

The rate of high-grade adverse events was lower with dabrafenib/trametinib: 47% vs 94%. The rate of treatment discontinuations due to adverse events was also lower with the combination therapy: 4% vs 18%, respectively. The frequency of adverse events was higher with dabrafenib/trametinib vs standard chemotherapy, with fever (68% vs 18%) and headache (47% vs 27%) noted. The rate of vomiting was 34% vs 48%, respectively. No deaths due to low-grade glioma were reported in the arm given combination targeted therapy, and one death occurred in the arm given standard chemotherapy.

The study is ongoing, and longer-term data will be collected to determine the safety and optimal duration of treatment.

Weight-Based Dosing and Quality of Life

During a press conference where these data were presented, Dr. Bouffet noted that both liquid and oral formulations of dabrafenib and trametinib are available, which may help with weight-based dosing the pediatric population.

When asked about whether the 47% of children with grade 3 or higher adverse events in the experimental arm had a good quality of life, Dr. Bouffet commented: “We found the children in the experimental arm had stable quality of life, whereas quality of life steadily deteriorated in the chemotherapy arm. Children treated with the targeted therapy combination were able to carry on their normal activities and were eager to return to school during clinic visits.”

Additional Commentary

The need for early molecular testing is relevant for this patient population [children with low-grade glioma and BRAF V600 mutation].
— Julie R. Gralow, MD, FACP, FASCO

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“Low-grade gliomas comprise up to 17% of the pediatric population, which is relatively small to start with,” stated Julie R. Gralow, MD, FACP, FASCO, Chief Medical Officer and Executive Vice President of ASCO, during a press conference. “Tumors with the BRAF V600 mutation represent a small percentage of the pediatric population with low-grade glioma. The response rates, clinical benefit rate, and progression-free survival are all higher with the combination therapy, and the median progression-free survival of 20.1 months vs 7.4 months for chemotherapy is impressive. There are actually fewer high-grade adverse events in the combination arm and fewer treatment discontinuations. This combination looks promising for a narrow percentage of patients with low-grade pediatric glioma.” 

Dr. Gralow added: “The theme of the need for early molecular testing is prevalent at this meeting and is relevant for this patient population. This study demonstrates that we should no longer use a ‘one-size-fits-all’ approach in this [and other] patient populations.” 

DISCLOSURE: The study was funded by Novartis. Dr. Bouffet has served as a consultant or advisor to Novartis and has received institutional research funding from Roche. Dr. Hudson has served as a consultant or advisor to Oncology Research Information Exchange Network, Princess Maxima Center, and SurvivorLink. Dr. Gralow has served as a consultant or advisor to Genentech, AstraZeneca, Roche, Novartis, and Seagen.


1. Bouffet E, Hansford J, Garré ML, et al: Primary analysis of a phase II trial of dabrafenib plus trametinib in BRAF V600–mutant pediatric low-grade glioma. 2022 ASCO Annual Meeting. Abstract LBA2002. Presented June 6, 2022.