Clinical Trial

. 2025 Jun 21;27(5):1341-1355.

doi: 10.1093/neuonc/noae274.

Radiographic and visual response to the type II RAF inhibitor tovorafenib in children with relapsed/refractory optic pathway glioma in the FIREFLY-1 trial

Karsten Nysom¹, Lindsay B Kilburn², Sarah E S Leary³, Daniel B Landi⁴, Evelien de Vos-Kerkhof⁵, Sébastien Perreault⁶, Olaf Witt^{7

8

9

10

11}, David S Ziegler^{12

13

14}, Pablo Hernáiz Driever¹⁵, Andrea T Franson¹⁶, Patricia A Baxter¹⁷, Nicholas S Whipple¹⁸, Cassie Kline¹⁹, Devorah Segal²⁰, Nada Jabado²¹, Simon Bailey²², Geoffrey McCowage²³, Jordan R Hansford^{24

25

26}, Dong-Anh Khuong-Quang²⁷, Nicholas G Gottardo^{28

29}, Timothy Hassall³⁰, Jung Woo Han³¹, Michal Yalon Oren³², Susan N Chi³³, Jiaheng Qiu³⁴, Daniel Da Costa³⁴, Sandya Govinda Raju³⁴, Peter Manley³⁴, Darren Hargrave³⁵

Affiliations

¹ Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Capital Region of Denmark, Denmark.
² Children's National Hospital, Washington, District of Columbia, USA.
³ Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, Washington, USA.
⁴ Department of Pediatrics, Duke University, Durham, North Carolina, USA.
⁵ Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
⁶ CHU Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada.
⁷ National Center for Tumor Diseases (NCT), Heidelberg, Germany.
⁸ German Cancer Consortium (DKTK), Heidelberg, Germany.
⁹ Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.
¹⁰ Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹¹ Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
¹² School of Clinical Medicine, University of New South Wales, Sydney, New South Wales, Australia.
¹³ Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia.
¹⁴ Kids Cancer Centre, Sydney Children's Hospital, Randwick, New South Wales, Australia.
¹⁵ Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Berlin, German HIT-LOGGIC-Registry for LGG in Children and Adolescents, Pediatric Neurooncology Program, Berlin, Germany.
¹⁶ Department of Pediatrics, C.S. Mott Children's Hospital, University of Michigan Medical School, Ann Arbor, Michigan, USA.
¹⁷ Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
¹⁸ Primary Children's Hospital and University of Utah, Salt Lake City, Utah, USA.
¹⁹ Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
²⁰ NYU Langone Health, New York, New York, USA.
²¹ Department of Pediatrics, McGill University Health Centre (MUHC), The Montreal Children's Hospital (MCH), Montréal, Quebec, Canada.
²² Great North Children's Hospital and Newcastle University Centre for Cancer, Newcastle-upon-Tyne, UK.
²³ Sydney Children's Hospitals Network, Westmead, New South Wales, Australia.
²⁴ South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, Australia.
²⁵ South Australia Health and Medical Research Institute, Adelaide, South Australia, Australia.
²⁶ Michael Rice Centre for Hematology and Oncology, Women's and Children's Hospital, Adelaide, South Australia, Australia.
²⁷ Children's Cancer Centre, The Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia.
²⁸ Brain Tumor Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Washington, Australia.
²⁹ Department of Pediatric and Adolescent Oncology and Hematology, Perth Children's Hospital, Perth, Western Australia, Australia.
³⁰ Children's Health Queensland Hospital and Health Service, South Brisbane, Australia.
³¹ Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea.
³² Pediatric Hemato-Oncology Department, Sheba Medical Center, Ramat Gan, Tel Aviv District, Israel.
³³ Pediatric Neuro-Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, USA.
³⁴ Day One Biopharmaceuticals, Brisbane, California, USA.
³⁵ UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children, London, UK.

PMID: 39700439
PMCID: PMC12187376
DOI: 10.1093/neuonc/noae274

Clinical Trial

Radiographic and visual response to the type II RAF inhibitor tovorafenib in children with relapsed/refractory optic pathway glioma in the FIREFLY-1 trial

Karsten Nysom et al. Neuro Oncol. 2025.

. 2025 Jun 21;27(5):1341-1355.

doi: 10.1093/neuonc/noae274.

Authors

Affiliations

¹ Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Capital Region of Denmark, Denmark.
² Children's National Hospital, Washington, District of Columbia, USA.
³ Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, Washington, USA.
⁴ Department of Pediatrics, Duke University, Durham, North Carolina, USA.
⁵ Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
⁶ CHU Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada.
⁷ National Center for Tumor Diseases (NCT), Heidelberg, Germany.
⁸ German Cancer Consortium (DKTK), Heidelberg, Germany.
⁹ Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.
¹⁰ Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹¹ Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
¹² School of Clinical Medicine, University of New South Wales, Sydney, New South Wales, Australia.
¹³ Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia.
¹⁴ Kids Cancer Centre, Sydney Children's Hospital, Randwick, New South Wales, Australia.
¹⁵ Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Berlin, German HIT-LOGGIC-Registry for LGG in Children and Adolescents, Pediatric Neurooncology Program, Berlin, Germany.
¹⁶ Department of Pediatrics, C.S. Mott Children's Hospital, University of Michigan Medical School, Ann Arbor, Michigan, USA.
¹⁷ Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
¹⁸ Primary Children's Hospital and University of Utah, Salt Lake City, Utah, USA.
¹⁹ Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
²⁰ NYU Langone Health, New York, New York, USA.
²¹ Department of Pediatrics, McGill University Health Centre (MUHC), The Montreal Children's Hospital (MCH), Montréal, Quebec, Canada.
²² Great North Children's Hospital and Newcastle University Centre for Cancer, Newcastle-upon-Tyne, UK.
²³ Sydney Children's Hospitals Network, Westmead, New South Wales, Australia.
²⁴ South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, Australia.
²⁵ South Australia Health and Medical Research Institute, Adelaide, South Australia, Australia.
²⁶ Michael Rice Centre for Hematology and Oncology, Women's and Children's Hospital, Adelaide, South Australia, Australia.
²⁷ Children's Cancer Centre, The Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia.
²⁸ Brain Tumor Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Washington, Australia.
²⁹ Department of Pediatric and Adolescent Oncology and Hematology, Perth Children's Hospital, Perth, Western Australia, Australia.
³⁰ Children's Health Queensland Hospital and Health Service, South Brisbane, Australia.
³¹ Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea.
³² Pediatric Hemato-Oncology Department, Sheba Medical Center, Ramat Gan, Tel Aviv District, Israel.
³³ Pediatric Neuro-Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, USA.
³⁴ Day One Biopharmaceuticals, Brisbane, California, USA.
³⁵ UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children, London, UK.

PMID: 39700439
PMCID: PMC12187376
DOI: 10.1093/neuonc/noae274

Abstract

Background: Due to their anatomical locations, optic pathway gliomas (OPGs) can rarely be cured by resection. Given the importance of preserving visual function, we analyzed radiological and visual acuity (VA) outcomes for the type II RAF inhibitor tovorafenib in the OPG subgroup of the phase 2 FIREFLY-1 trial.

Methods: FIREFLY-1 investigated the efficacy (arm 1, n = 77), safety, and tolerability (arms 1/2) of tovorafenib (420 mg/m2 once weekly; 600 mg maximum) in patients with BRAF-altered relapsed/refractory pediatric low-grade glioma (pLGG). In this post hoc analysis, anti-tumor activity and VA were analyzed in arm 1 patients with OPG. Anti-tumor activity was independently assessed per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG), Response Assessment in Pediatric Neuro-Oncology-LGG (RAPNO), and RANO-LGG criteria. The data cutoff was June 5, 2023.

Results: Forty-two of 77 patients had OPGs; 35 of 42 had ≥2 VA assessments. The overall response rate in the OPG subgroup according to RANO-HGG, RAPNO, and RANO-LGG criteria were 64%, 50%, and 55%, with clinical benefit rates of 95%, 88%, and 90%, respectively. VA per patient was preserved for 80% of patients; 31% demonstrated improved VA; VA per eye was preserved in 87%, with 27% improving. The safety profile in the arm 1 OPG subgroup was similar to the overall FIREFLY-1 safety analysis set.

Conclusions: Tovorafenib demonstrated anti-tumor activity in relapsed/refractory BRAF-altered OPG across radiological assessment criteria and was generally well tolerated. Importantly, vision remained stable or improved in most patients.

Keywords: BRAF; FIREFLY-1; optic pathway glioma; tovorafenib; visual acuity.

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Conflict of interest statement

K.N. reports scientific writing support paid for by Day One, contracts between his employer and Amgen, Astra Zeneca, Daiichi-Sankyo, Lilly, Merck/MSD, Novartis, Pfizer, Roche, Turning Point, Y-mAbs in relation to conducting clinical trials where he is the national principal investigator, personal payment from Bayer, support for meeting attendance from Day One, personal payments in relation to service on the data monitoring committee of a clinical trial sponsored by Lilly, and non-compensated roles as a member of the Executive Committee of the Innovative Therapies for Children with Cancer (ITCC), chair of the Novel Therapy working group of the Nordic Society for Pediatric Hematology & Oncology (NOPHO), and chair of the multidisciplinary working group on central nervous system tumors of children in Denmark. L.B.K. reports contracted institutional research from Day One Biopharmaceuticals, support from Day One Biopharmaceuticals in relation to providing resources to complete the post hoc analysis, manage the manuscript development, and fund the medical writing, contracted institutional research from Novartis, Regeneron Pharmaceuticals, SpringWorks Therapeutics, Bristol Myers Squibb, SonALAsense, Recursion, and Chimerix, consulting fees from Blueprint Medicines as DSMB Chair, and Onconova Therapeutics stock ownership. S.E.S.L. reports support in relation to this manuscript (preparation, writing, journal charges) from Day One, and a clinical trial agreement with Day One supporting the conduct of the trial at the site, including provision of drug and research costs (no personal payment as an investigator). O.W. reports research grants to his institution from Day One Biopharmaceuticals and Biomede Valley Discovery, personal consulting fees from Novartis and Roche, a leadership role with SIOPE BTG in relation to the LOGGIC consortium, and a co-leadership role of the pLGG study group of the GPOH. D.S.Z. reports personal consulting fees from Novartis, FivePhusion, Amgen, and Accendatech, and participation in data safety monitoring or advisory boards for Day One, Alexion, and Norgine. P.H.D. reports a grant/contract from IPSEN, personal consulting fees from IPSEN and consulting fees paid to his institution from ALEXION and Bayer, and participation on a data safety monitoring board/advisory board for Biomede. A.T.F. reports participation on an advisory board for Day One Biopharmaceuticals. C.K. reports grants from Cannonball Kids’ Cancer Foundation, Kortney Rose Foundation, and Bristol-Myers Squibb Co, contracts related to clinical trials from Curis Inc, Regeneron Pharmaceuticals, Day One Biotherapeutics, Midatech, Ipsen, Chimerix, Kazia, and Bristol-Myers Squibb Co, and participation on scientific advisory boards for Cannonball Kids’ Cancer Foundation, Raymond A. Wood Foundation, and Children’s Brain Tumor Network. D.S. reports payment for participation on an advisory board from Alexion. G.M. reports that Day One Biopharmaceuticals funded the FIREFLY-1 trial and provided resources to complete the post hoc analysis, manage the manuscript development, and fund the medical writing. J.R.H. reports receiving personal consulting fees from Bayer Pharmaceuticals and Alexion Pharmaceuticals, institutional honoraria for scientific advisory boards from Servier International, and support for attending meetings and/or travel from Alexion Pharmaceuticals. N.G.G. has received payment/honoraria from Bayer and is the Board Chair of ANZCHOG (Australian and New Zealand Children’s Haematology and Oncology Group). T.H. reports that Day One Biopharmaceuticals funded the FIREFLY-1 trial and provided resources to complete the post hoc analysis, manage the manuscript development, and fund the medical writing. J.Q., D.D.C., S.G.R., and P.M. are employees of Day One Biopharmaceuticals and have received Day One Biopharmaceuticals stock/stock options. D.H. reports clinical trial funding for selumetinib (institutional) from AstraZeneca/Alexion, personal consulting fees from AstraZeneca/Alexion, Novartis, and Day One Biotherapeutics, personal payment/honoraria from Alexion, support for attending meetings and/or travel from AstraZeneca/Alexion and Novartis, and participation on a data safety monitoring board or advisory board from AstraZeneca, Novartis, and Day One Biotherapeutics. D.B.L., E.dV.K., S.P., P.A.B., N.S.W., N.J., S.B., D.A.K.Q., J.W.H., M.Y.O., S.N.C., have declared no conflict of interest.

Figures

**Figure 1.**
Best change in tumor size in patients with an OPG who were deemed evaluable for response by the independent radiology review committee according to RANO-HGG, RAPNO, and RANO-LGG criteria. Data for 1 patient was not included (RANO-HGG and RAPNO assessments) as they had no post-baseline contrast image. CR, complete response; HGG, high-grade glioma; LGG, low-grade glioma; MR, minor response; OPG, optic pathway glioma; PD, progressive disease; PR, partial response; RANO, Response Assessment in Neuro-Oncology; RAPNO, Response Assessment in Pediatric Neuro-Oncology; SD, stable disease.

**Figure 2.**
Swimlane plots of time to response and duration of therapy according to RAPNO and RANO-LGG criteria. In patients with confirmed responses, symbols indicate the start of response (MR or PR). If initial responses improved with continued treatment (from MR to confirmed PR), both the timepoint of the initial response and the timepoint that the response initially improved are marked accordingly. BRAFi, BRAF inhibitor; LGG, low-grade glioma; MEKi, MEK inhibitor; PR, partial response; MR, minor response; RANO, Response Assessment in Neuro-Oncology; RAPNO, Response Assessment in Pediatric Neuro-Oncology.

**Figure 3.**
(A) Waterfall plot of best visual acuity change from baseline per eye (n = 52). Visual acuity progression was defined as an increase of ≥0.2 logMAR from baseline and visual acuity response as a decrease of ≥0.2 logMAR from baseline. (B) Visual morbidity per patient at the start and end of treatment/data cutoff (n = 35). EOT, end of treatment; logMAR, logarithm of the minimum angle of resolution; VA visual acuity.

See this image and copyright information in PMC

References

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1. Samples DC, Mulcahy Levy JM, Hankinson TC.. Neurosurgery for optic pathway glioma: optimizing multidisciplinary management. Front Surg. 2022;9:884250. - PMC - PubMed
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Radiographic and visual response to the type II RAF inhibitor tovorafenib in children with relapsed/refractory optic pathway glioma in the FIREFLY-1 trial

Affiliations

Radiographic and visual response to the type II RAF inhibitor tovorafenib in children with relapsed/refractory optic pathway glioma in the FIREFLY-1 trial

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous