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

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16 Scopus citations


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 m2 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 .

Original languageEnglish
Pages (from-to)207-217
Number of pages11
JournalNature medicine
Issue number1
StatePublished - Jan 2024


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