LGG-40. 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

Cassie Kline,Cassie Kline,Patricia A Baxter,Olaf Witt,David S Ziegler,Valérie Larouche,Peter Manley,Samuel C Blackman,Jiaheng Qiu,Devorah Segal,Enrica E K Tan,Helen Toledano,Nicholas G Gottardo,Nicholas G Gottardo,Andrea T Franson,Susan N Chi,Daniel B Landi,Olaf Witt,Helen Toledano,Jordan R Hansford,Michal Yalon Oren,Timothy E Hassall,Simon Bailey,Angela J Waanders,Daniel Da Costa,Nicolas U Gerber,Ashley Walter,Lisa Mcleod,Jasper Van Der Lugt,Sabine Mueller,Sarah E S Leary,Karsten Nysom,David S Ziegler,Nada Jabado,Sébastien Perreault,Angela J Waanders,Jung Woo Han,Karen D Wright,Geoffrey Mccowage,Darren Hargrave,Jordan R Hansford,Liat Oren,Dolores Podesta,Nicholas S Whipple,Mohamed S Abdelbaki,Pablo Hernáiz Driever,Hyoung Jin Kang,Dong-Anh Khuong-Quang,Lindsay B Kilburn

doi:10.1093/neuonc/noae064.431

Abstract

Abstract BACKGROUND: Tovorafenib is an investigational, selective, CNS-penetrant, type II RAF inhibitor. The ongoing FIREFLY-1 (NCT04775485) phase 2 study (Kilburn LK, et al. Nat Med. 2023) of tovorafenib in BRAF-altered pLGG resulted in antitumor activity and manageable safety. Decreased growth velocity (GV) was observed; this is an update on GV changes in skeletally immature children receiving tovorafenib. Methods A planned safety analysis was completed on August 8, 2023 on 137 patients (Arm 1: 77 & Arm 2: 60). Additional follow-up on all cases of decreased GV (an AESI) reported to the global safety database (GSDB) as of January 19, 2024 is provided. Results Overall, 29% had decreased GV from baseline (BL); 19% had ≥50% decrease. Of the 40 with this AESI, 75% had pre-existing neuromuscular or endocrine comorbidities potentially affecting normal growth, including 6 on GnRH-analogues for precocious puberty and 9 with BL heights 2 SDs above/below average for age and sex. Nineteen had on-treatment bone age assessments; none showed bone age advancement from BL or premature growth plate closure. No osteopenia or abnormal fractures reported. All 10 who discontinued or interrupted tovorafenib for ≥3 months for any reason (mean follow-up: 5.8 months), with off-treatment growth measurements available, showed post-treatment annualized GV (AGV) recovery (average AGV: on-treatment, 1.1 cm/y; off-treatment, 8 cm/y), with some exceeding expected average AGV for age. A 4-year-old boy with 1.2 cm/y AGV on-treatment had 12.3 cm/y AGV off-treatment (follow-up: 2 months). Five additional events of decreased GV in patients not on study FIREFLY-1 were reported to the GSDB; 4 of 5 had ≥3 months of off-treatment follow-up, all 4 recovered GV. Conclusions Decreased GV has been observed in patients on tovorafenib. Preliminary follow-up data in those who interrupted treatment show consistent evidence of GV recovery and preservation of growth potential on bone age studies.

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