CTNI-09. TYPE II RAF INHIBITOR TOVORAFENIB IN RELAPSED/REFRACTORY (R/R) PEDIATRIC LOW-GRADE GLIOMA (PLGG): RESULTS FROM PATIENTS ON A DRUG HOLIDAY (DH) IN THE PHASE 2 FIREFLY-1 TRIAL

Abstract BACKGROUND Tovorafenib, a selective, CNS-penetrant, type II RAF inhibitor, received US FDA accelerated approval for r/r BRAF-altered pLGG. Results from the ongoing FIREFLY-1 (NCT04775485) phase 2 study (Kilburn LK, et al. Nat Med. 2023) in this population showed clinically meaningful tumor responses and a manageable safety profile. METHODS Patients in FIREFLY-1 treated for ≥26 cycles (~24 months) who entered a DH period were routinely assessed every 3 cycles; once-weekly tovorafenib 420 mg/m2 (not to exceed 600 mg) could be restarted if there was radiographic and/or clinical evidence of new disease progression. RESULTS As of the April 19, 2024 data cutoff, 26 patients (BRAF fusion: 22; BRAF V600E mutation: 4) (33.8%) of 77 patients in arm 1 (pLGG registrational) had completed 2 years of treatment and started a DH. No patients on a DH withdrew. Twenty-four patients (92.3%) remain on a DH, of which 22 were evaluable for response (duration range: 0.6-10.9 months); duration of response off-treatment ranged from 0.0-8.5 months. (Ranges exclude 2 non-evaluable patients treated beyond radiographic progression who remained on treatment in first 26 cycles due to ongoing clinical benefit; both remain on DH without clinical progression.) Two patients had tumor progression while on a DH and restarted treatment; 1 patient with a BRAF V600E mutation progressed (≥25% in tumor size) after 1 month (rebound growth per O’Hare P., et al. Neuro-Oncol. 2024: ≥25% increase [per RANO-LGG] w/in 6 months of stopping treatment) and has been on retreatment for 4 months; 1 patient with a BRAF fusion progressed after 9 months and has been on retreatment for 3 months. Treatment-related adverse events of any grade experienced by patients on retreatment were alopecia and rash (1 each). Independent radiographic analysis for response during retreatment is ongoing. CONCLUSIONS Tovorafenib provided durable tumor responses off-treatment in patients with r/r pLGG on a DH in FIREFLY-1.

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Journal
Neuro-Oncology
Published
2024-11-01
DOI
https://doi.org/10.1093/neuonc/noae165.0377
Primary Topic
Glioma Diagnosis and Treatment
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article
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article

CTNI-09. TYPE II RAF INHIBITOR TOVORAFENIB IN RELAPSED/REFRACTORY (R/R) PEDIATRIC LOW-GRADE GLIOMA (PLGG): RESULTS FROM PATIENTS ON A DRUG HOLIDAY (DH) IN THE PHASE 2 FIREFLY-1 TRIAL

Geoffrey McCowage, Daniel Landi, Darren Hargrave, Angela J. Waanders et al.
Neuro-Oncology
Glioma Diagnosis and Treatment
article

CTNI-09. TYPE II RAF INHIBITOR TOVORAFENIB IN RELAPSED/REFRACTORY (R/R) PEDIATRIC LOW-GRADE GLIOMA (PLGG): RESULTS FROM PATIENTS ON A DRUG HOLIDAY (DH) IN THE PHASE 2 FIREFLY-1 TRIAL

Geoffrey McCowage, Daniel Landi, Darren Hargrave, Angela J. Waanders, Nicholas G. Gottardo, Molly E. Hoke, Jordan R. Hansford, Pablo Hernáiz Driever, Peter Manley, Devorah Segal, Nicolas U. Gerber, Jung Woo Han, Sarah Leary, Lindsay Kilburn, David S. Ziegler, Nicholas Whipple, Valérie Larouche, Tim Hassall, Daniel Da Costa, Dong-Anh Khuong-Quang, Andrea Franson, Cassie Kline, Nada Jabado, Jasper van der Lugt, Michal Oren, Helen Toledano, Karsten Nysom, Hyoung Jin Kang, Mohamed Shebl Abdelbaki, Sébastien Perreault, Susan N. Chi, Patricia Baxter, Simon Bailey, Sabine Mueller, Ashley A. Walter, Liat Oren, Yeonhee Kim, Olaf Witt, Enrica E. K. Tan
article en

Abstract

Abstract BACKGROUND Tovorafenib, a selective, CNS-penetrant, type II RAF inhibitor, received US FDA accelerated approval for r/r BRAF-altered pLGG. Results from the ongoing FIREFLY-1 (NCT04775485) phase 2 study (Kilburn LK, et al. Nat Med. 2023) in this population showed clinically meaningful tumor responses and a manageable safety profile. METHODS Patients in FIREFLY-1 treated for ≥26 cycles (~24 months) who entered a DH period were routinely assessed every 3 cycles; once-weekly tovorafenib 420 mg/m2 (not to exceed 600 mg) could be restarted if there was radiographic and/or clinical evidence of new disease progression. RESULTS As of the April 19, 2024 data cutoff, 26 patients (BRAF fusion: 22; BRAF V600E mutation: 4) (33.8%) of 77 patients in arm 1 (pLGG registrational) had completed 2 years of treatment and started a DH. No patients on a DH withdrew. Twenty-four patients (92.3%) remain on a DH, of which 22 were evaluable for response (duration range: 0.6-10.9 months); duration of response off-treatment ranged from 0.0-8.5 months. (Ranges exclude 2 non-evaluable patients treated beyond radiographic progression who remained on treatment in first 26 cycles due to ongoing clinical benefit; both remain on DH without clinical progression.) Two patients had tumor progression while on a DH and restarted treatment; 1 patient with a BRAF V600E mutation progressed (≥25% in tumor size) after 1 month (rebound growth per O’Hare P., et al. Neuro-Oncol. 2024: ≥25% increase [per RANO-LGG] w/in 6 months of stopping treatment) and has been on retreatment for 4 months; 1 patient with a BRAF fusion progressed after 9 months and has been on retreatment for 3 months. Treatment-related adverse events of any grade experienced by patients on retreatment were alopecia and rash (1 each). Independent radiographic analysis for response during retreatment is ongoing. CONCLUSIONS Tovorafenib provided durable tumor responses off-treatment in patients with r/r pLGG on a DH in FIREFLY-1.

Neuro-OncologyVol. 26(Supplement_8)
Lurie Children's Hospital (US), Royal Children's Hospital (AU), St. Louis Children's Hospital (US), Primary Children's Hospital (US), Children's Hospital of Philadelphia (US), Children's National (US), Tel Aviv University (IL), Duke University (US), The Kids Research Institute Australia (AU), The University of Western Australia (AU), German Cancer Research Center (DE), University of California, San Francisco (US), Baylor College of Medicine (US), University of Utah (US), Heidelberg University (DE), University of Michigan (US), Sheba Medical Center (IL), Montreal Children's Hospital (CA), Severance Hospital (KR), Great Ormond Street Hospital (GB), Princess Margaret Hospital for Children (AU), Rambam Health Care Campus (IL), Women's and Children's Hospital (AU), McGill University Health Centre (CA), Cancer Institute of New South Wales (AU), 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), KK Women's and Children's Hospital (SG), Hopp Children's Cancer Center Heidelberg (DE), NGM Biopharmaceuticals (United States) (US), Sydney Children's Hospital (AU), Princess Máxima Center (NL), University Children's Hospital Zurich (CH), South Australian Health and Medical Research Institute (AU), Great North Children's Hospital (GB), 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), Perth Children's Hospital, University College London (GB), The University of Adelaide (AU), Université de Montréal (CA), Freie Universität Berlin (DE), Charité - Universitätsmedizin Berlin (DE), University of Pennsylvania (US), Newcastle University (GB), Philadelphia University (US)
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