Real-life efficacy and tolerance of trametinib in BRAF-rearranged low-grade gliomas: A multicenter study.
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BACKGROUND: MEK inhibition has demonstrated activity in pediatric low-grade gliomas (pLGGs) driven by BRAF rearrangements, but data on trametinib remain limited, regarding efficacy, short and long-term toxicities. METHODS: We conducted a retrospective multicenter study of patients with BRAF-rearranged non NF1 pLGGs receiving trametinib across three French pediatric oncology centers. Plasma concentrations were monitored. RESULTS: Between 2015 and 2023, 46 patients had a median age of 8.7 years (range 1.2-18.6). Trametinib achieved a radiological disease control rate of 78% (36/46), including 65% partial or minor responses and 13% stable disease, with activity even in heavily pretreated (up to 6 lines) and chemotherapy-refractory tumors. Clinical improvement occurred in 72% of patients. Median treatment duration was 14.2 months (range, 1.0-55.1). Among 35 patients who discontinued treatment, 37% remained treatment-free after a median follow-up of 16.1 months (4.3-44.2). Grade 3 treatment-related adverse events occurred in one-third of patients. Common toxicities included cutaneous events (69%), paronychia (64%), gastrointestinal symptoms (51%), elevated creatine kinase (54%) and transaminases (31%). Ophthalmologic (16%) toxicities and epistaxis (17%) of which 35% were grade 2 and required intervention, were observed. Body mass index Z-score increased during treatment but was clinically significant (≥1 SD) and related to trametinib in only 17% of patients. Pharmacokinetics showed high interpatient variability, with no correlation between plasma concentrations and efficacy or toxicity. CONCLUSION: Trametinib demonstrates sustained activity in BRAF-rearranged pLGGs, including in heavily pretreated patients. This study represents the largest reported cohort of BRAF-rearranged pLGGs, expanding prior evidence and supporting a class effect of MEK inhibitors.