Clinical stability after tovorafenib treatment in patients with relapsed/refractory pediatric low-grade glioma: Updated results from the phase 2 FIREFLY-1 trial

Abstract Background In the phase 2 FIREFLY-1 study, tovorafenib monotherapy achieved clinically meaningful, rapid, durable tumor responses in patients with BRAF-altered relapsed/refractory pediatric low-grade glioma (pLGG), supporting regulatory approval in the United States. This updated analysis provides longer follow-up and is based on a data cutoff of June 6, 2025. Methods Efficacy was assessed in patients with BRAF-altered pLGG (arm 1, n=77). Safety was assessed in a combined population that included an extension cohort (arm 2, n=60). Tovorafenib was administered at 420 mg/m2 (not to exceed 600 mg), once weekly, in 28-day cycles. After 26 cycles of treatment, patients could continue tovorafenib or enter a post-treatment observation period with an option of retreatment at progression. Results Median follow-up of patients in arm 1 was 40.6 months. Per Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO-LGG) criteria, overall response rate was 53%, median duration of response was 19.4 months, and median progression-free survival was 16.6 months. However, median time to next treatment was 42.6 months, tracking more closely with time to clinical progression than radiographic progression. For 39 patients who entered post-treatment observation (median follow-up of 16.0 months), median treatment-free interval was not reached; 31 patients remained off therapy with 30 (77%) treatment free for ≥12 months. No new safety signals were identified. Conclusions This updated analysis, with a median of 40.6 months of follow-up, confirmed the clinically meaningful activity of tovorafenib in the treatment of relapsed/refractory BRAF-altered pLGG and demonstrated prolonged clinical stability following completion of tovorafenib treatment. ClinicalTrials.gov ID: NCT04775485.