The combination of dabrafenib and trametinib has previously demonstrated efficacy in recurrent low-grade glioma with BRAF V600 mutations. A recent study published in The New England Journal of Medicine explored the benefits of this combination as a first-line treatment option. The results were highly promising, with dabrafenib plus trametinib showing improved response rates, a longer progression-free survival, and a more favourable safety profile compared to standard chemotherapy.
Certain paediatric low-grade gliomas are known to harbour BRAF V600 mutations, rendering them less responsive to conventional chemotherapy. Dabrafenib, a BRAF inhibitor designed to specifically target this mutation, has shown promising antitumour activity as monotherapy and in combination with trametinib in children with previously treated low-grade glioma with BRAF V600 mutations. However, data concerning the effectiveness of this combination as a first-line therapy are lacking. This study aims to bridge that knowledge gap by comparing first-line dabrafenib and trametinib with chemotherapy in children with low-grade gliomas harbouring BRAF V600 mutations.
This phase 2 trial included patients under 18 with paediatric low-grade glioma and a BRAF V600 mutation who were scheduled to receive first-line therapy. In total, 110 patients were randomly assigned (2:1) to receive dabrafenib plus trametinib (n=73) or standard chemotherapy (carboplatin plus vincristine, n=37). The primary outcome was the independently assessed overall response rate (ORR, complete or partial response) according to the Response Assessment in Neuro-Oncology criteria. In addition, also the clinical benefit rate (CBR, complete or partial response or stable disease for ≥24 weeks) and the progression-free survival (PFS) were assessed.
After a median follow-up of 18.9 months, the ORR was four times higher with dabrafenib plus trametinib than with chemotherapy (47% vs. 11%, respectively; risk ratio, 4.31; 95%CI: 1.7-11.2; p<0.001). Also the results for PFS favoured dabrafenib plus trametinib over chemotherapy, with a median PFS of 20.1 vs. 7.4 months, respectively (HR[95%CI]: 0.31[0.17-0.55]; p<0.001). Similarly, the CBR was superior in the combination arm than with chemotherapy (86% vs. 46%; risk ratio, 1.88; 95% CI: 1.3-2.7). Regarding safety, the proportion of patients with grade 3 or higher adverse events was lower in the dabrafenib plus trametinib group (47% vs. 94% in the chemotherapy arm).
In conclusion, among paediatric patients with low-grade glioma with BRAF V600 mutations, first-line dabrafenib plus trametinib resulted in significantly more responses, a longer PFS, and a better safety profile than standard chemotherapy.
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