LOGGIC/FIREFLY-2: a phase 3, randomized trial of tovorafenib vs. chemotherapy in pediatric and young adult patients with newly diagnosed low-grade glioma harboring an activating RAF alteration
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Published:2024-01-30
Issue:1
Volume:24
Page:
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ISSN:1471-2407
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Container-title:BMC Cancer
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language:en
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Short-container-title:BMC Cancer
Author:
van Tilburg Cornelis M.,Kilburn Lindsay B.,Perreault Sébastien,Schmidt Rene,Azizi Amedeo A.,Cruz-Martínez Ofelia,Zápotocký Michal,Scheinemann Katrin,Meeteren Antoinette Y. N. Schouten-van,Sehested Astrid,Opocher Enrico,Driever Pablo Hernáiz,Avula Shivaram,Ziegler David S.,Capper David,Koch Arend,Sahm Felix,Qiu Jiaheng,Tsao Li-Pen,Blackman Samuel C.,Manley Peter,Milde Till,Witt Ruth,Jones David T. W.,Hargrave Darren,Witt Olaf
Abstract
Abstract
Background
Pediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG. However, this combination is not approved for the treatment of patients with tumors harboring BRAF fusions as type I RAF inhibitors are ineffective in this setting and may paradoxically enhance tumor growth. The type II RAF inhibitor, tovorafenib (formerly DAY101, TAK-580, MLN2480), has shown promising activity and good tolerability in patients with BRAF-altered pLGG in the phase 2 FIREFLY-1 study, with an objective response rate (ORR) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria of 67%. Tumor response was independent of histologic subtype, BRAF alteration type (fusion vs. mutation), number of prior lines of therapy, and prior MAPK-pathway inhibitor use.
Methods
LOGGIC/FIREFLY-2 is a two-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. current standard of care (SoC) chemotherapy in patients < 25 years of age with pLGG harboring an activating RAF alteration who require first-line systemic therapy. Patients are randomized 1:1 to either tovorafenib, administered once weekly at 420 mg/m2 (not to exceed 600 mg), or investigator’s choice of prespecified SoC chemotherapy regimens. The primary objective is to compare ORR between the two treatment arms, as assessed by independent review per RANO-LGG criteria. Secondary objectives include comparisons of progression-free survival, duration of response, safety, neurologic function, and clinical benefit rate.
Discussion
The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG.
Trial registration
ClinicalTrials.gov: NCT05566795. Registered on October 4, 2022.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Genetics,Oncology
Reference47 articles.
1. Ostrom QT, Price M, Ryan K, Edelson J, Neff C, Cioffi G, et al. CBTRUS Statistical Report: Pediatric Brain Tumor Foundation Childhood and Adolescent Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014–2018. Neuro Oncol. 2022;24(Suppl 3):iii1–38. 2. Gnekow AK, Falkenstein F, von Hornstein S, Zwiener I, Berkefeld S, Bison B, et al. Long-term follow-up of the multicenter, multidisciplinary treatment study HIT-LGG-1996 for low-grade glioma in children and adolescents of the German Speaking Society of Pediatric Oncology and Hematology. Neuro Oncol. 2012;14(10):1265–84. 3. Gnekow AK, Kandels D, Tilburg CV, Azizi AA, Opocher E, Stokland T, et al. SIOP-E-BTG and GPOH guidelines for diagnosis and treatment of children and adolescents with low grade glioma. Klin Padiatr. 2019;231(3):107–35. 4. Goebel AM, Gnekow AK, Kandels D, Witt O, Schmidt R, Hernaiz Driever P. Natural history of pediatric low-grade glioma disease - first multi-state model analysis. J Cancer. 2019;10(25):6314–26. 5. Alemany M, Velasco R, Simo M, Bruna J. Late effects of cancer treatment: consequences for long-term brain cancer survivors. Neurooncol Pract. 2021;8(1):18–30.
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