Journal Article

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

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

2024

Overview

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. ClinicalTrials.gov registration: NCT04775485 . In a phase 2 trial, the oral type II RAF inhibitor tovorafenib exhibited an overall response rate of 67% in patients with BRAF -altered relapsed/refractory pediatric low-grade glioma.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 692/308/153 / 692/308/2779/109/1941 / 692/308/2779/777 / 692/699/67/1059/602 / 692/699/67/2332 / Anemia / Animals / Biomedical and Life Sciences / Biomedicine / Cancer Research / Central nervous system / Child / Creatine / Creatine kinase / Criteria / Fireflies / Glioma / Glioma - drug therapy / Glioma - genetics / Humans / Infectious Diseases / Inhibitors / Metabolic Diseases / Molecular Medicine / Neurosciences / Oncology / Patients / Pediatrics / Proto-Oncogene Proteins B-raf - genetics / Response rates