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

"Competing interests L.B.K. has received consulting fees from Blueprint Medicine as DSMB Chair and has contracted institutional research with Novartis, Regeneron Pharmaceuticals, Day One Biopharmaceuticals, Spring Works Therapeutics, Bristol Myers Squibb and SonALAsense. L.B.K. also owns stock in Onconova Therapeutics. J.R.H. has received honoraria for consultation from Bayer, Alexion Pharma and Boxer Capital. P.H.D. is on an advisory board with Alexion and is part of the Alexion ICI Sprinkle Study. S.P. is on advisory boards with Bayer, Alexion and Esai and has received research support from Novartis, Bayer and Roche. D.S.Z. has received consulting/advisory board fees from Bayer, AstraZeneca, Accendatech, Novartis, Day One Biopharmaceuticals, FivePhusion, Amgen, Alexion and Norgine and has received research support from Accendatech. O.W. is on advisory boards with Novartis, Janssen, Roche, Bristol Myers Squibb and AstraZeneca and has received research grants from Day One Biopharmaceuticals, Biomed Valley Discovery, Bristol Myers Squibb, Syndax and PreComb. H.J.K. is on advisory boards with Novartis, Jazz Pharmaceuticals, Takeda, Cartexell and GPCR. D.H. is on advisory boards with Alexion/AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Day One Biopharmaceuticals, Janssen, Novartis and Roche and has received research grants from Alexion/AstraZeneca and Roche. V.L. is on an advisory board with Alexion. C.K. is a study chair of an investigator-sponsored trial for which Day One Biopharmaceuticals provides drug and research support; she also has research relationships with other industry partners. D.S. is on an advisory board with Alexion. L.M., X.Z., A.W., D.D., P.M., I.C. and S.C.B. are employees of Day One Biopharmaceuticals and have received Day One Biopharmaceuticals stock and stock options. K.N. has received advisory board or consulting fees from Y-mAbs, EUSA Pharma, Bayer and Eli Lilly. All remaining authors declare no competing interests."

"This trial was funded by Day One Biopharmaceuticals. We thank the patients, families, caregivers and clinical investigators for their participation in the FIREFLY-1 trial. We are deeply grateful for the site coordinators and trial staff who are instrumental in making this work possible. The authors would like to thank the Pacific Pediatric Neuro-Oncology Consortium (PNOC) for their partnership in the conduct of this trial. We also would like to acknowledge and thank the PNOC014 investigators and trial team (principal investigator: K. Wright) for generating the initial observation of the activity of tovorafenib in pLGG in their phase 1 trial. We also thank M. C. Cox for his contribution to protocol development and trial management. Medical writing support was provided by M. Hoke and S. Govinda Raju of Day One Biopharmaceuticals and J. Heighway and A. Cleasby of Cancer Communications and Consultancy Ltd., funded by Day One Biopharmaceuticals. D.S.Z. is supported by grants from the National Health and Medical Research Council (Synergy Grant 2019056 and Leadership Grant APP2017898) and Cancer Institute New South Wales Program Grant TPG2037. D.H. is supported by funding from the National Institute for Health and Care Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR or the Department of Health and Social Care."

"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."