The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial
Lindsay Kilburn, Dong-Anh Khuong-Quang, Jordan R. Hansford, Daniel Landi, Jasper van der Lugt, Sarah Leary, Pablo Hernáiz Driever, Simon Bailey, Sébastien Perreault, Geoffrey McCowage, Angela J. Waanders, David S. Ziegler, Olaf Witt, Patricia Baxter, Hyoung Jin Kang, Tim Hassall, Jung Woo Han, Darren Hargrave, Andrea Franson, Michal Oren, Helen Toledano, Valérie Larouche, Cassie Kline, Mohamed S Abdelbaki, Nada Jabado, Nicholas G. Gottardo, Nicolas U. Gerber, Nicholas Whipple, Devorah Segal, Susan Chi, Liat Oren, Enrica E. K. Tan, Sabine Mueller, Izzy Cornelio, Lisa McLeod, Xin Zhao, Ashley A. Walter, Daniel Da Costa, Peter Manley, Samuel C. Blackman, Roger J. Packer, Karsten Nysom
Abstract
Abstract 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 .