The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial

Lindsay B Kilburn*, Dong-Anh Khuong-Quang, Jordan R Hansford, Daniel Landi, Jasper van der Lugt, Sarah E S Leary, Pablo Hernáiz Driever, Simon Bailey, Sébastien Perreault, Geoffrey McCowage, Angela J Waanders, David S Ziegler, Olaf Witt, Patricia A Baxter, Hyoung Jin Kang, Timothy E Hassall, Jung Woo Han, Darren Hargrave, Andrea T Franson, Michal Yalon OrenHelen Toledano, Valérie Larouche, Cassie Kline, Mohamed S Abdelbaki, Nada Jabado, Nicholas G Gottardo, Nicolas U Gerber, Nicholas S Whipple, Devorah Segal, Susan N Chi, Liat Oren, Enrica E K Tan, Sabine Mueller, Izzy Cornelio, Lisa McLeod, Xin Zhao, Ashley Walter, Daniel Da Costa, Peter Manley, Samuel C Blackman, Roger J Packer, Karsten Nysom

*Corresponding author af dette arbejde
10 Citationer (Scopus)


BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system-penetrant, type II RAF inhibitor tovorafenib (420 mg m-2 once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. registration: NCT04775485 .

TidsskriftNature Medicine
Udgave nummer1
Sider (fra-til)207-217
Antal sider11
StatusUdgivet - jan. 2024


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