TY - JOUR
T1 - The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma
T2 - the phase 2 FIREFLY-1 trial
AU - Kilburn, Lindsay B.
AU - Khuong-Quang, Dong Anh
AU - Hansford, Jordan R.
AU - Landi, Daniel
AU - van der Lugt, Jasper
AU - Leary, Sarah E.S.
AU - Driever, Pablo Hernáiz
AU - Bailey, Simon
AU - Perreault, Sébastien
AU - McCowage, Geoffrey
AU - Waanders, Angela J.
AU - Ziegler, David S.
AU - Witt, Olaf
AU - Baxter, Patricia A.
AU - Kang, Hyoung Jin
AU - Hassall, Timothy E.
AU - Han, Jung Woo
AU - Hargrave, Darren
AU - Franson, Andrea T.
AU - Yalon Oren, Michal
AU - Toledano, Helen
AU - Larouche, Valérie
AU - Kline, Cassie
AU - Abdelbaki, Mohamed S.
AU - Jabado, Nada
AU - Gottardo, Nicholas G.
AU - Gerber, Nicolas U.
AU - Whipple, Nicholas S.
AU - Segal, Devorah
AU - Chi, Susan N.
AU - Oren, Liat
AU - Tan, Enrica E.K.
AU - Mueller, Sabine
AU - Cornelio, Izzy
AU - McLeod, Lisa
AU - Zhao, Xin
AU - Walter, Ashley
AU - Da Costa, Daniel
AU - Manley, Peter
AU - Blackman, Samuel C.
AU - Packer, Roger J.
AU - Nysom, Karsten
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2024/1
Y1 - 2024/1
N2 - 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 .
AB - 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 .
UR - http://www.scopus.com/inward/record.url?scp=85176783862&partnerID=8YFLogxK
U2 - 10.1038/s41591-023-02668-y
DO - 10.1038/s41591-023-02668-y
M3 - Article
C2 - 37978284
AN - SCOPUS:85176783862
SN - 1078-8956
VL - 30
SP - 207
EP - 217
JO - Nature medicine
JF - Nature medicine
IS - 1
ER -