Clinical stability after tovorafenib treatment in patients with relapsed/refractory pediatric low-grade glioma: Updated results from the phase 2 FIREFLY-1 trial

Abstract Background In the phase 2 FIREFLY-1 study, tovorafenib monotherapy achieved clinically meaningful, rapid, durable tumor responses in patients with BRAF-altered relapsed/refractory pediatric low-grade glioma (pLGG), supporting regulatory approval in the United States. This updated analysis provides longer follow-up and is based on a data cutoff of June 6, 2025. Methods Efficacy was assessed in patients with BRAF-altered pLGG (arm 1, n=77). Safety was assessed in a combined population that included an extension cohort (arm 2, n=60). Tovorafenib was administered at 420 mg/m2 (not to exceed 600 mg), once weekly, in 28-day cycles. After 26 cycles of treatment, patients could continue tovorafenib or enter a post-treatment observation period with an option of retreatment at progression. Results Median follow-up of patients in arm 1 was 40.6 months. Per Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO-LGG) criteria, overall response rate was 53%, median duration of response was 19.4 months, and median progression-free survival was 16.6 months. However, median time to next treatment was 42.6 months, tracking more closely with time to clinical progression than radiographic progression. For 39 patients who entered post-treatment observation (median follow-up of 16.0 months), median treatment-free interval was not reached; 31 patients remained off therapy with 30 (77%) treatment free for ≥12 months. No new safety signals were identified. Conclusions This updated analysis, with a median of 40.6 months of follow-up, confirmed the clinically meaningful activity of tovorafenib in the treatment of relapsed/refractory BRAF-altered pLGG and demonstrated prolonged clinical stability following completion of tovorafenib treatment. ClinicalTrials.gov ID: NCT04775485.

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Journal
Neuro-Oncology Pediatrics
Published
2026-04-22
DOI
https://doi.org/10.1093/neuped/wuag022
Primary Topic
Glioma Diagnosis and Treatment
Type
article
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article

Clinical stability after tovorafenib treatment in patients with relapsed/refractory pediatric low-grade glioma: Updated results from the phase 2 FIREFLY-1 trial

Daniel Landi, Angela J. Waanders, Nicholas G. Gottardo, Jordan R. Hansford et al.
Neuro-Oncology Pediatrics
Glioma Diagnosis and Treatment
article

Clinical stability after tovorafenib treatment in patients with relapsed/refractory pediatric low-grade glioma: Updated results from the phase 2 FIREFLY-1 trial

Daniel Landi, Angela J. Waanders, Nicholas G. Gottardo, Jordan R. Hansford, Pablo Hernáiz Driever, Peter Manley, Devorah Segal, Elly Barry, Lindsey Ott, Lindsay Kilburn, David S. Ziegler, Nicholas Whipple, Tim Hassall, Cassie Kline, Jasper van der Lugt, Johnathan C. Maher, Karsten Nysom, Hyoung Jin Kang, Mohamed Shebl Abdelbaki, Sébastien Perreault, Liat Oren, Katherine Pehlivan, Sarah E S Leary, Helen Toledano, Michal Yalon Oren, Samuele Renzi, Jung Woo Han, Dong-Anh Khuong-Quang, Andrea T Franson, Simon Bailey, Patricia A Baxter, Sabine Mueller, Susan N Chi, Nicolas U Gerber, Geoffrey McCowage, Nada Jabado, Olaf Witt, Darren Hargrave, Jingyang Zhang, Enrica E K Tan
article en

Abstract

Abstract Background In the phase 2 FIREFLY-1 study, tovorafenib monotherapy achieved clinically meaningful, rapid, durable tumor responses in patients with BRAF-altered relapsed/refractory pediatric low-grade glioma (pLGG), supporting regulatory approval in the United States. This updated analysis provides longer follow-up and is based on a data cutoff of June 6, 2025. Methods Efficacy was assessed in patients with BRAF-altered pLGG (arm 1, n=77). Safety was assessed in a combined population that included an extension cohort (arm 2, n=60). Tovorafenib was administered at 420 mg/m2 (not to exceed 600 mg), once weekly, in 28-day cycles. After 26 cycles of treatment, patients could continue tovorafenib or enter a post-treatment observation period with an option of retreatment at progression. Results Median follow-up of patients in arm 1 was 40.6 months. Per Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO-LGG) criteria, overall response rate was 53%, median duration of response was 19.4 months, and median progression-free survival was 16.6 months. However, median time to next treatment was 42.6 months, tracking more closely with time to clinical progression than radiographic progression. For 39 patients who entered post-treatment observation (median follow-up of 16.0 months), median treatment-free interval was not reached; 31 patients remained off therapy with 30 (77%) treatment free for ≥12 months. No new safety signals were identified. Conclusions This updated analysis, with a median of 40.6 months of follow-up, confirmed the clinically meaningful activity of tovorafenib in the treatment of relapsed/refractory BRAF-altered pLGG and demonstrated prolonged clinical stability following completion of tovorafenib treatment. ClinicalTrials.gov ID: NCT04775485.

Neuro-Oncology Pediatrics
South Australia Pathology (AU), Royal Children's Hospital (AU), Primary Children's Hospital (US), Children's Hospital of Philadelphia (US), Children's National (US), Duke University (US), The Kids Research Institute Australia (AU), German Cancer Research Center (DE), University of California, San Francisco (US), Washington University in St. Louis (US), Heidelberg University (DE), Sheba Medical Center (IL), Montreal Children's Hospital (CA), Great Ormond Street Hospital (GB), University Health System (US), Rambam Health Care Campus (IL), Women's and Children's Hospital (AU), McGill University Health Centre (CA), Cancer Institute of New South Wales (AU), University Hospital Heidelberg (DE), Centre Hospitalier Universitaire Sainte-Justine (CA), Copenhagen University Hospital (DK), Rigshospitalet (DK), UNSW Sydney (AU), Humboldt-Universität zu Berlin (DE), NYU Langone Health (US), Children’s Health Queensland Hospital and Health Service (AU), Seoul National University Children's Hospital (KR), Schneider Children's Medical Center (IL), Center for Cancer and Blood Disorders (US), University of California San Francisco Medical Center (US), National Center for Tumor Diseases (DE), KK Women's and Children's Hospital (SG), Rappaport Family Institute for Research in the Medical Sciences (IL), Hopp Children's Cancer Center Heidelberg (DE), SA Health (AU), NGM Biopharmaceuticals (United States) (US), Sydney Children's Hospital (AU), Lurie Children's Hospital (US), Princess Máxima Center (NL), University Children's Hospital Zurich (CH), South Australian Health and Medical Research Institute (AU), Great North Children's Hospital (GB), Centre for Cancer Biology (AU), Texas Children's Hospital (US), Sydney Children’s Hospitals Network (AU), Children's Cancer Center (US), C. S. Mott Children's Hospital (US), Yonsei University Health System (KR), Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US), Université Laval (CA), Deutsches Konsortium für Translationale Krebsforschung (DE), University College London (GB), Université de Montréal (CA)
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Glioma Diagnosis and Treatment
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