Growth recovery in patients with BRAF -altered pediatric low-grade glioma following treatment with tovorafenib

Abstract Background The type II RAF inhibitor tovorafenib is US FDA-approved for patients ≥6 months of age with BRAF-altered, relapsed/refractory, pediatric low-grade glioma (pLGG). It is hypothesized that tovorafenib may inhibit CRAF within growth plate chondrocytes, slowing growth plate maturation and linear growth. This analysis investigated growth recovery after treatment with tovorafenib and factors that may impact growth recovery trajectories. Methods This was a retrospective pooled analysis of on- and off-treatment growth in children with BRAF-altered relapsed/refractory pLGG treated with tovorafenib for ≥6 months in two clinical trials and an expanded access program. Patients had to have at least one height measurement recorded 90 days post-treatment as of December 16, 2024. Growth suppression, recovery, and catch-up growth were derived from annualized growth velocity on and off treatment. Exposure–growth models explored growth patterns on and off treatment. Results Sixty-eight patients were included with median (range) baseline age of nine (2-16) years and median follow up 10 months post-treatment. Ninety percent of patients exhibited growth suppression during treatment, of whom 93% showed early post-treatment growth recovery and 77% showed catch-up growth. Reversible growth suppression was observed in both sexes across ages. Of 26 patients with on-treatment bone age, there was no abnormal advancement of bone age on or off treatment. Exposure–growth models suggest that younger baseline age may be associated with faster growth recovery off treatment. Conclusions Growth suppression observed with tovorafenib was reversible, with evidence of post-treatment growth recovery and catch-up growth in most patients. Clinical trials NCT04775485 (FIREFLY-1); NCT03429803 (PNOC014); NCT05760586 (Expanded Access Program).