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
Por:
van Tilburg CM, Kilburn LB, Perreault S, Schmidt R, Azizi AA, Cruz-Martínez O, Zápotocký M, Scheinemann K, Meeteren AYNS, Sehested A, Opocher E, Driever PH, Avula S, Ziegler DS, Capper D, Koch A, Sahm F, Qiu J, Tsao LP, Blackman SC, Manley P, Milde T, Witt R, Jones DTW, Hargrave D and Witt O
Publicada:
30 ene 2024
Ahead of Print:
30 ene 2024
Resumen:
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.
Filiaciones:
van Tilburg CM:
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
German Cancer Consortium (DKTK), Heidelberg, Germany
National Center for Tumor Diseases (NCT), Heidelberg, Germany
Kilburn LB:
Children's National Hospital, Washington, DC, USA
Perreault S:
CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada
Schmidt R:
Institute of Biostatistics and Clinical Research, Münster, Germany
Azizi AA:
Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
Cruz-Martínez O:
Neuro-Oncology Unit, Pediatric Cancer Center, Hospital Sant Joan de Deu, Barcelona, Spain
Zápotocký M:
Department of Paediatric Haematology and Oncology, Charles University, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
Scheinemann K:
Division of Oncology-Hematology, Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland
Faculty of Health Sciences and Medicine, University of Lucerne, Lucerne, Switzerland
Department of Pediatrics, McMaster Children's Hospital and McMaster University, Hamilton, Canada
Meeteren AYNS:
Department of Neuro-oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Sehested A:
Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark
Opocher E:
Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, Padua, Italy
Driever PH:
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
Avula S:
Department of Radiology, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK
Ziegler DS:
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
School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia
Capper D:
Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
DKTK Partner Site, Berlin, Germany
Koch A:
Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
Sahm F:
Department of Neuropathology, German Cancer Research Center (DKFZ), University Hospital Heidelberg and CCU Neuropathology, German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Qiu J:
Day One Biopharmaceuticals, Brisbane, CA, USA
Tsao LP:
Day One Biopharmaceuticals, Brisbane, CA, USA
Blackman SC:
Day One Biopharmaceuticals, Brisbane, CA, USA
Manley P:
Day One Biopharmaceuticals, Brisbane, CA, USA
Milde T:
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
German Cancer Consortium (DKTK), Heidelberg, Germany
National Center for Tumor Diseases (NCT), Heidelberg, Germany
Witt R:
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
German Cancer Consortium (DKTK), Heidelberg, Germany
National Center for Tumor Diseases (NCT), Heidelberg, Germany
Jones DTW:
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
German Cancer Consortium (DKTK), Heidelberg, Germany
Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
Hargrave D:
UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children, London, UK
Witt O:
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. o.witt@kitz-heidelberg.de
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. o.witt@kitz-heidelberg.de
Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany. o.witt@kitz-heidelberg.de
German Cancer Consortium (DKTK), Heidelberg, Germany. o.witt@kitz-heidelberg.de
National Center for Tumor Diseases (NCT), Heidelberg, Germany. o.witt@kitz-heidelberg.de
Princess Maxima Ctr Pediat Oncol, Dept Neurooncol, Utrecht, Netherlands
Princess Maxima Ctr Pediat Oncol, Dept Neurooncol, Utrecht, Netherlands
Green Submitted, gold
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