Targeted therapy provides ‘phenomenal’ benefit for certain children with glioma
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CHICAGO — A combination of two targeted therapies significantly improved outcomes compared with standard care for children with BRAF V600 mutation-positive low-grade glioma, according to study results presented at ASCO Annual Meeting.
Dabrafenib (Tafinlar, Novartis) and trametinib (Mekinist, Novartis) increased response rate, extended PFS and improved clinical benefit rate compared with carboplatin plus vincristine, results of the phase 2/phase 3 study showed.
“We were expecting to see a difference, but the magnitude is phenomenal,” researcher Eric Bouffet, MD, FRCPC, director of the pediatric neuro-oncology program at The Hospital for Sick Children in Toronto, told Healio. “When you see these results, you say, ‘There’s no reason why I would continue to treat these kids with chemotherapy.”
Background and methods
BRAF V600E mutations are present in 15% to 20% of pediatric low-grade gliomas.
These tumors often respond less favorably to standard chemotherapy, and they are associated with increased risk for progression to secondary high-grade glioma.
Location influences whether pediatric low-grade gliomas can be completely removed via surgery. Patients with residual disease after surgery — or those who develop disease progression or recurrence — often require systemic therapy.
A study initiated in 2014 showed the combination of dabrafenib — a BRAF inhibitor — and trametinib — a MEK inhibitor — had clinical activity for children with pretreated BRAF V600-mutant pediatric low-grade glioma.
Bouffet and colleagues conducted an international, double-blind trial to compare the combination with chemotherapy as first systemic therapy.
The trial — conducted at 57 sites in 20 countries — included 110 children aged 1 to 17 years with BRAF V600-mutant low-grade glioma. Study participants either had progressive disease after surgical excision or were not candidates for surgery and needed to begin first systemic treatment because of risk for neurological impairment.
Researchers randomly assigned 73 children to dabrafenib twice daily plus trametinib once daily. The other 37 received standard doses of carboplatin plus vincristine. Children assigned chemotherapy could cross over to dabrafenib-trametinib upon disease progression.
Overall response rate served as the primary endpoint. Secondary endpoints included clinical benefit rate, duration of response, time to response, PFS, OS and safety.
Bouffet presented results of a preplanned primary analysis, performed after a median follow-up of 18.9 months.
Results
The dabrafenib-trametinib regimen appeared associated with a higher ORR (47% vs. 11%; OR = 7.2; 95% CI, 2.3-22.4) and a higher clinical benefit rate (86% vs. 46%), defined as patients who had complete response, partial response or stable disease for 6 months or longer.
Patients assigned the experimental regimen also achieved significantly longer PFS (20.1 months vs. 7.4 months; HR = 0.31; 95% CI, 0.17-0.55).
OS data remained immature. At data cutoff, one patient assigned chemotherapy had died of glioma, and none assigned dabrafenib-trametinib had died of their disease.
A higher percentage of patients assigned chemotherapy experienced grade 3 or grade 4 adverse events (94% vs. 47%) and discontinued treatment due to adverse events (18% vs. 4%).
The most common adverse events among patients assigned dabrafenib-trametinib included fever (68% for the combination vs. 18% for chemotherapy), headache (47% vs. 27%), vomiting (34% vs. 48%), fatigue (32% vs. 30%), diarrhea (29% vs. 18%), dry skin (26% vs. 3%) and nausea (25% vs. 45%).
Next steps
The study will continue so researchers can collect long-term safety data.
Liquid formulations of dabrafenib and trametinib have been developed that may help with weight-based dosing for these younger patients, Bouffet said.
The findings highlight the importance of early molecular testing for pediatric patients with low-grade glioma to determine whether they might benefit from targeted therapy, Bouffet added.
“At my institution, we do it systematically, but I’m pretty sure a significant proportion of institutions still do not consider testing upfront,” Bouffet told Healio. “We are trying to convince people to [test for] this molecular marker as early as possible, and compelling results like this certainly should help influence practice.”
Perspective
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Melissa M. Hudson, MD
The results of this study are impressive and exciting for several reasons.
These cancers — which represent almost 50% of pediatric brain tumors — often occur in areas that are unresectable. They are prone to recurrence or progression, requiring multiple lines of therapy.
Current standard therapy involves cytotoxic agents that cause the need for follow-up in the clinic and are associated with health problems later in life.
Having a targeted therapy that can be delivered orally, with an excellent safety profile and impressive early outcomes, is quite exciting.
Our hope is that continuing to monitor these children long term will enable us to document that there actually is less long-term adverse outcomes in this population.
This type of targeted therapy will enable us to personalize treatment for these children and hopefully improve the quality of their survival.
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Bouffet E, et al. Abstract LBA2002. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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