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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023, The Author(s). 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 .
Author(s): Kilburn LB, Khuong-Quang D-A, Hansford JR, Landi D, van der Lugt J, Leary SES, Driever PH, Bailey S, Perreault S, McCowage G, Waanders AJ, Ziegler DS, Witt O, Baxter PA, Kang HJ, Hassall TE, Han JW, Hargrave D, Franson AT, Yalon Oren M, Toledano H, Larouche V, Kline C, Abdelbaki MS, Jabado N, Gottardo NG, Gerber NU, Whipple NS, Segal D, Chi SN, Oren L, Tan EEK, Mueller S, Cornelio I, McLeod L, Zhao X, Walter A, Da Costa D, Manley P, Blackman SC, Packer RJ, Nysom K
Publication type: Article
Publication status: Published
Journal: Nature Medicine
Year: 2024
Volume: 30
Pages: 207-217
Print publication date: 01/01/2024
Online publication date: 17/11/2023
Acceptance date: 25/10/2023
Date deposited: 28/11/2023
ISSN (print): 1078-8956
ISSN (electronic): 1546-170X
Publisher: Nature Research
URL: https://doi.org/10.1038/s41591-023-02668-y
DOI: 10.1038/s41591-023-02668-y
Data Access Statement: The trial protocol (confidential information redacted) is provided in the Supplementary Information. The authors declare that all data supporting the findings of this trial are available within the article and the Supplementary Information. Requests for full datasets will be considered after completion of the trial and analysis of the data, which is anticipated to be in December 2024. To request individual participant data associated with any Day One Biopharmaceuticals clinical trial, email clinical@dayonebio.com. All requests will be evaluated within 8 weeks.
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