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; Lindsay B Kilburn; Sarah E S Leary; Daniel B Landi; Evelien de Vos-Kerkhof; Sébastien Perreault; Olaf Witt; David S Ziegler; Pablo Hernáiz Driever; Andrea T Franson; Patricia A Baxter; Nicholas S Whipple; Cassie Kline; Devorah Segal; Nada Jabado; Simon Bailey; Geoffrey McCowage; Jordan R Hansford; Dong-Anh Khuong-Quang; Nicholas G Gottardo; Timothy Hassall; Jung Woo Han; Michal Yalon Oren; Susan N Chi; Jiaheng Qiu; Daniel Da Costa; Sandya Govinda Raju; Peter Manley; Darren Hargrave

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

Neuro Oncol. 2024 Dec 19:noae274. doi: 10.1093/neuonc/noae274. Online ahead of print.

Authors

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}, Dong-Anh Khuong-Quang²⁶, Nicholas G Gottardo²⁷, Timothy Hassall²⁸, Jung Woo Han²⁹, Michal Yalon Oren³⁰, Susan N Chi³¹, Jiaheng Qiu³², Daniel Da Costa³², Sandya Govinda Raju³², Peter Manley³², Darren Hargrave³³

Affiliations

¹ Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
² Children's National Hospital, Washington, DC, USA.
³ Cancer and Blood Disorders Center, Seattle Children's, Seattle, WA, USA.
⁴ Duke University, Durham, NC, USA.
⁵ Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
⁶ CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada.
⁷ Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
⁸ Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁹ Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.
¹⁰ German Cancer Consortium (DKTK), Heidelberg, Germany.
¹¹ National Center for Tumor Diseases (NCT), Heidelberg, Germany.
¹² Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia.
¹³ Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
¹⁴ School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia.
¹⁵ 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, Department of Pediatric Oncology/Hematology, Berlin, Germany.
¹⁶ CS 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, TX, USA.
¹⁸ Primary Children's Hospital and University of Utah, Salt Lake City, UT, USA.
¹⁹ Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
²⁰ NYU Langone Health, New York, NY, USA.
²¹ McGill University Health Centre (MUHC) - The Montreal Children's Hospital (MCH), Montréal, QC, Canada.
²² Great North Children's Hospital and Newcastle University Centre for Cancer, Newcastle-upon-Tyne, UK.
²³ Sydney Children's Hospitals Network, Westmead, NSW, Australia.
²⁴ Michael Rice Centre for Hematology and Oncology, Women's and Children's Hospital, Adelaide, SA, Australia.
²⁵ South Australia Health and Medical Research Institute, Adelaide, Australia; South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, Australia.
²⁶ Children's Cancer Centre, The Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia.
²⁷ Department of Pediatric and Adolescent Oncology and Hematology, Perth Children's Hospital, Perth, Australia and Brain Tumor Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, WA, Australia.
²⁸ Children's Health Queensland Hospital and Health Service, South Brisbane, Australia.
²⁹ Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea.
³⁰ Pediatric Hemato-Oncology Department, Sheba Medical Center, Ramat Gan, Israel.
³¹ Pediatric Neuro-Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
³² Day One Biopharmaceuticals, Brisbane, CA, USA.
³³ UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children, London, UK.

PMID: 39700439
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 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.