What question did this study set out to answer?

This analysis investigates the long-term efficacy and safety of tovorafenib in treating pediatric low-grade glioma with BRAF alterations. It aims to determine the impact of prior therapy on its activity and clinical outcomes.

June 26, 2026Open Access

ID #832 FIREFLY-1 3-Year Results: Impact of Prior Therapy on Tovorafenib Activity in BRAF-Altered Pediatric Low-Grade Glioma

Key Points

This analysis investigates the long-term efficacy and safety of tovorafenib in treating pediatric low-grade glioma with BRAF alterations. It aims to determine the impact of prior therapy on its activity and clinical outcomes.
Ongoing phase 2 study (NCT04775485) involving 77 patients aged 2-21 years with BRAF-altered pLGG
Patients received ≥26 28-day cycles of tovorafenib and could enter a post-treatment observation period
Subgroup analyses on treatment-naïve patients exploring treatment duration and response.
Overall response rate was 53% with a median duration of response of 19.4 months (95% CI 13.8–27.2)
77% of patients in post-treatment remained free of treatment for ≥12 months
Median time to next treatment was 42.6 months, surpassing median progression-free survival of 16.6 months.

Abstract

Abstract Tovorafenib is a selective, CNS-penetrant, type II RAF inhibitor that is FDA approved for patients aged ≥6 months with relapsed/refractory BRAF-altered pLGG, based on results from the ongoing FIREFLY-1 phase 2 study (NCT04775485). This updated analysis presents 3-year efficacy and safety data. After ≥26 28-day cycles in FIREFLY-1, patients could opt to stop tovorafenib and enter a post-treatment observation period. Tovorafenib could be reinitiated if disease progressed. As of June 6, 2025, 77 patients (aged 2–21 years) enrolled in the registrational arm. Median study duration was 40.6 months. Overall response rate per RAPNO criteria (n = 76 evaluable patients) was 53% (n = 40); median duration of response (DOR) was 19.4 months (95% CI 13.8–27.2); median time to response was 5.4 months (range 1.6–17.5). Median PFS by RAPNO was 16.6 months; however, median time to next treatment (TTNT) was 42.6 months. 44 patients (58%) remained on treatment for ≥26 cycles. 39 patients entered post-treatment observation; 77% (n = 30) remained treatment free for ≥12 months (median treatment free interval TFI not reached). 8/39 (21%) patients in the observation cohort were retreated with tovorafenib and remained on retreatment at data cutoff. Median change in tumor size during retreatment was 38%. Subgroup analyses demonstrated directionally longer TTNT and DOR in MAPK inhibitor naïve patients. Safety cohort data (N = 137) showed a favorable benefit-risk profile. Most patients in the observation period cohort were treatment free for ≥12 months after tovorafenib cessation. Median TTNT exceeded RAPNO PFS, suggesting that TTNT may be more clinically relevant than RAPNO PFS in guiding treatment decisions. Tumor rebound off treatment was minimal, and there was early evidence of retreatment activity. These results suggest prolonged clinical stability and durability beyond planned tovorafenib treatment.

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