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Dabrafenib Plus Trametinib Improves Efficacy in Children and Adolescents with Relapsed/Refractory BRAF V600-mutated High-Grade Glioma

Findings from a phase II study
19 Sep 2023
Targeted Therapy;  Cancer in Adolescents and Young Adults (AYA)
Central Nervous System Malignancies

In a cohort of 41 children and adolescents with relapsed/refractory BRAF V600-mutated paediatric high-grade glioma included in a phase II study, treatment with dabrafenib plus trametinib was associated with an independently assessed overall response rate (ORR) of 56% and a median duration of response (DoR) of 22.2 months. Although historical data in the BRAF V600-mutated population are limited, these results compare favourably with current approaches to relapsed/refractory paediatric high-grade gliomas.

Safety was consistent with the established profile of dabrafenib plus trametinib in adult patients. The findings are published by Dr. Darren R. Hargrave of the Paediatric Oncology Unit, Great Ormond Street Hospital in London, UK, and colleagues on 29 August 2023 in the JCO.

The authors wrote in the background that gliomas are the most common primary brain and CNS tumours, accounting for almost half of these tumours in children and adolescents. Paediatric high-grade gliomas account for approximately 10% of childhood CNS tumours and are a leading cause of childhood cancer-related death.

Maximal surgical resection followed by focal radiotherapy in patients who are aged 3 years and older and chemotherapy is the current standard for newly diagnosed paediatric high-grade gliomas. Despite efforts to expand and improve treatment options, ORRs are <20%, and 2-year survival rates remain ≤35%. Most patients develop recurrent disease, and limited data available in the relapsed/refractory setting show response rates of ≤12%. There is no accepted standard of care for recurrent paediatric high-grade gliomas. Multiagent chemotherapy regimens currently used are associated with burdensome toxicity and limited benefit.

It has been estimated that 5-10% of paediatric high-grade gliomas harbour the BRAF V600E mutation. The prognostic role of this mutation is unproven, but the mutation is seen predominantly in favourable histologic subtypes of paediatric high-grade gliomas. Dabrafenib has demonstrated clinically meaningful activity as monotherapy in a phase I/II study in relapsed/refractory BRAF V600-mutated paediatric high-grade gliomas. A combination of dabrafenib with trametinib was also approved for the tumour-agnostic treatment of patients aged 6 years and older with BRAF V600E-mutated solid tumours that progressed after previous treatment, and patients aged 1 year and older with BRAF V600E-mutated low-grade glioma who require systemic therapy.

This phase II study combined two paediatric cohorts of high-grade glioma single-arm in the relapsed/refractory setting and low-grade glioma randomised comparison in the first-line setting to evaluate the efficacy and safety of dabrafenib plus trametinib in paediatric patients with BRAF V600E-mutated gliomas. In the latest article published in the JCO, the study team reports the results from the paediatric high-grade gliomas cohort.

The primary objective was ORR by independent review by Response Assessment in Neuro-Oncology criteria. Secondary objectives included ORR by investigator determination, DoR, progression-free survival, overall survival (OS), and safety.

From 28 December 2017 to 17 August 2020, a total of 41 patients with previously treated BRAF-mutated paediatric high-grade gliomas were enroled from 28 sites in 13 countries. Median age was 13 years (range, 2-17 years), median time since diagnosis was 17.4 months, all patients had previous therapy, and 48.8% had grade 4 disease by World Health Organization (WHO) 2016 criteria at initial diagnosis per investigator assessment.

Central histological determinations were reported by investigators following WHO 2016 criteria, which were the criteria available at the time of diagnosis; most common histologies were glioblastoma multiforme in 13 patients, anaplastic pleomorphic xanthoastrocytoma in 6 patients, high-grade glioma not otherwise specified in 4 patients, pleomorphic xanthoastrocytoma in 4 patients, and anaplastic astrocytoma in 3 patients. Of the 35 patients with available molecular data, 23 patients (65.7%) had tumour with homozygous deletion of CDKN2A/B, 3 (8.6%) had histone H3K27M mutations, and 6 (17.1%) had TP53 alterations.

At primary analysis, median follow-up was 25.1 months, and 51% of patients remained on treatment. A total, 16 of 20 discontinuations were due to progressive disease in this relapsed/refractory population of paediatric high-grade gliomas. Independently assessed ORR was 56% (95% confidence interval [CI] 40 to 72). Median DoR was 22.2 months (95% CI 7.6 months to not reached [NR]). Fourteen deaths were reported. Median OS was 32.8 months (95% CI 19.2 months to NR).

The most common all-cause adverse events were pyrexia (51%), headache (34%), and dry skin (32%). Two patients (5%) had adverse events (both rash) leading to discontinuation. Although the safety profiles of historical comparator cytotoxic regimens in paediatric high-grade gliomas vary, toxicity is generally considered a barrier to the high-dose chemotherapies typically used for relapsed/refractory disease. Thus, targeted therapy may offer improved tolerability, at least in the short term, although potential long-term effects are not addressed by this study.

The authors concluded that treatment with dabrafenib plus trametinib in relapsed or refractory BRAF V600-mutated paediatric high-grade gliomas resulted in improved efficacy, with a higher ORR and prolonged survival, and a manageable safety profile relative to historical expectations based on molecularly unselected cohorts.

Results from the ongoing Children's Oncology Group non-randomised phase II, ACNS1723 study evaluating the efficacy of dabrafenib plus trametinib after radiotherapy for treatment of paediatric patients with newly diagnosed BRAF V600-mutated paediatric high-grade gliomas are awaited.

The findings were previously presented in part at the ASCO 2022 Annual Meeting (3-7 June 2022, Chicago, IL, US).

The study was supported by Novartis Pharmaceuticals Corporation.


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