Abstract
Abstract BACKGROUND Tovorafenib, a selective, CNS-penetrant, type II RAF inhibitor, received US FDA accelerated approval for r/r BRAF-altered pLGG. Results from the ongoing FIREFLY-1 (NCT04775485) phase 2 study (Kilburn LK, et al. Nat Med. 2023) in this population showed clinically meaningful tumor responses and a manageable safety profile. METHODS Patients in FIREFLY-1 treated for ≥26 cycles (~24 months) who entered a DH period were routinely assessed every 3 cycles; once-weekly tovorafenib 420 mg/m2 (not to exceed 600 mg) could be restarted if there was radiographic and/or clinical evidence of new disease progression. RESULTS As of the April 19, 2024 data cutoff, 26 patients (BRAF fusion: 22; BRAF V600E mutation: 4) (33.8%) of 77 patients in arm 1 (pLGG registrational) had completed 2 years of treatment and started a DH. No patients on a DH withdrew. Twenty-four patients (92.3%) remain on a DH, of which 22 were evaluable for response (duration range: 0.6-10.9 months); duration of response off-treatment ranged from 0.0-8.5 months. (Ranges exclude 2 non-evaluable patients treated beyond radiographic progression who remained on treatment in first 26 cycles due to ongoing clinical benefit; both remain on DH without clinical progression.) Two patients had tumor progression while on a DH and restarted treatment; 1 patient with a BRAF V600E mutation progressed (≥25% in tumor size) after 1 month (rebound growth per O’Hare P., et al. Neuro-Oncol. 2024: ≥25% increase [per RANO-LGG] w/in 6 months of stopping treatment) and has been on retreatment for 4 months; 1 patient with a BRAF fusion progressed after 9 months and has been on retreatment for 3 months. Treatment-related adverse events of any grade experienced by patients on retreatment were alopecia and rash (1 each). Independent radiographic analysis for response during retreatment is ongoing. CONCLUSIONS Tovorafenib provided durable tumor responses off-treatment in patients with r/r pLGG on a DH in FIREFLY-1.
Published Version
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