Type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma (pLGG): Reversible decreases in growth velocity in the phase 2 FIREFLY-1 trial.
Authors: Kline Cassie , Waanders Angela Jae , Ziegler David Simon , Kilburn Lindsay Baker , Nysom Karsten , van der Lugt Jasper , Hassall Timothy E. , Gerber Nicolas U. , Segal Devorah , Larouche Valérie , Mueller Sabine , Walter Ashley , Manley Peter , McLeod Lisa , Landi Daniel B 
Published: June 2024

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Background: Tovorafenib is an investigational, selective, CNS-penetrant, type II RAF inhibitor. Results from the ongoing FIREFLY-1 (NCT04775485) phase 2 study (1) in BRAF-altered pLGG showed clinically meaningful tumor responses and a manageable safety profile with tovorafenib monotherapy. Decreased growth velocity (GV) was observed; this is an update on changes in GV in skeletally immature children receiving tovorafenib. Methods: A planned safety analysis was completed on August 8, 2023 and included 137 patients (Arm 1: 77 & Arm 2: 60) treated with ≥1 dose of tovorafenib in FIREFLY-1. This report provides additional follow-up on all cases of decreased growth velocity (GV), an adverse event of special interest (AESI), reported to the Sponsor’s global safety database (GSDB) as of January 19, 2024. Results: Decreased GV was reported in 40 (29.2%) of 137 patients; 26 (19%) had GV reduction ≥50% from baseline (BL). Of those with decreased GV, 30 (75.0%) had pre-existing neuromuscular or endocrine comorbidities that may affect normal growth, including 6 (15%) with precocious puberty being treated with a gonadotropin-releasing hormone analogue, and 9 (22.5%) with BL heights 2 standard deviations above or below average for age and sex. Nineteen of the 40 patients with this AESI had on-treatment bone age assessments; none showed advancement of bone age from BL or premature closure of growth plates. No osteopenia or abnormal fractures were reported. Of the 35 patients with growth hormone (GH) testing, only 2 had signs of GH deficiency (both had optic pathway tumors; 1 had GH deficiency at BL, the other, a new tumor-associated GH deficiency). Post-treatment heights ≥3 months off treatment were reported for 10 of 40 patients who had interrupted or discontinued treatment for any reason (mean follow up: 5.8 months), including 2 (1.5%) permanent discontinuations and 3 (2.2%) interruptions due to decreased GV. All 10 showed post-treatment recovery in annualized GV (AGV) (average on-treatment AGV 1.1 cm/y vs. average post-treatment AGV 8 cm/y), in some cases exceeding expected average AGV for age. One additional 4-year-old boy with on-treatment AGV of 1.2 cm/y had an off-treatment AGV of 12.3 cm/y after 2 months of off-treatment follow-up. Decreased GV was reported to the GSDB for 5 (11.4%) of 44 patients who received above the maximum dose of tovorafenib used in FIREFLY-1 in an ongoing investigator-initiated study. Four of the 5 patients from this study had ≥3 months of off-treatment follow-up reported; all 4 showed evidence of GV recovery. Conclusions: Decreased GV has been observed in patients treated with tovorafenib. Early follow-up data from patients whose treatment was interrupted show consistent evidence for GV recovery and preservation of growth potential on bone age studies. 1. Kilburn LK, et al. Nat Med.2023. Clinical trial information: NCT04775485 .