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.

Children's National Hospital Washington DC USA

CHU Sainte Justine Université de Montréal Montréal QC Canada

Clinical Cooperation Unit Pediatric Oncology German Cancer Research Center Heidelberg Germany

Day One Biopharmaceuticals Brisbane CA USA

Department of Neuro oncology Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

Department of Neuropathology Charité Universitätsmedizin Berlin Berlin Germany

Department of Neuropathology German Cancer Research Center Heidelberg Germany

Department of Paediatric Haematology and Oncology Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Pediatric Oncology Hematology Immunology and Pulmonology Heidelberg University Hospital Heidelberg Germany

Department of Pediatrics and Adolescent Medicine Comprehensive Center for Pediatrics and Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Pediatrics and Adolescent Medicine Rigshospitalet Copenhagen Denmark

Department of Pediatrics McMaster Children's Hospital and McMaster University Hamilton Canada

Department of Radiology Alder Hey Children's Hospital NHS Foundation Trust Liverpool UK

Division of Oncology Hematology Children's Hospital of Eastern Switzerland St Gallen Switzerland

Division of Pediatric Glioma Research German Cancer Research Center Heidelberg Germany

DKTK Partner Site Berlin Germany

Faculty of Health Sciences and Medicine University of Lucerne Lucerne Switzerland

German Cancer Consortium Heidelberg Germany

German HIT LOGGIC Registry for LGG in Children and Adolescents Charité Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin Berlin Germany

Hopp Children's Cancer Center Heidelberg Heidelberg Germany

Institute of Biostatistics and Clinical Research Münster Germany

Kids Cancer Centre Sydney Children's Hospital Randwick NSW Australia

Lowy Cancer Research Centre Children's Cancer Institute University of New South Wales Sydney NSW Australia

National Center for Tumor Diseases Heidelberg Germany

Neuro oncology Unit Pediatric Cancer Center Hospital Sant Joan de Déu Barcelona Spain

Pediatric Hematology Oncology and Stem Cell Transplant Division Padua University Hospital Padua Italy

School of Clinical Medicine University of New South Wales Sydney NSW Australia

UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children London UK

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ClinicalTrials.gov
NCT05566795