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.

person Cornelis Martinus van Tilburg Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg University Hospital and German Cancer Research Center (DKFZ), Heidelberg, Germany info_outline Cornelis Martinus van Tilburg, Lindsay Baker Kilburn, Erin Crotty, Amy Amundson Smith, Sébastien Perreault, Andrea Flynn Franson, Nada Jabado, Lindsey M. Hoffman, Rene Schmidt, Antoinette Y.N. Schouten-van Meeteren, Astrid Sehestedt, Enrico Opocher, Pablo Hernáiz Driever, Shivaram Avula, David Simon Ziegler, Jiaheng Qiu, Li-Pen Tsao, Peter Manley, Darren R. Hargrave, Olaf Witt

Authors person Cornelis Martinus van Tilburg Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg University Hospital and German Cancer Research Center (DKFZ), Heidelberg, Germany info_outline Cornelis Martinus van Tilburg, Lindsay Baker Kilburn, Erin Crotty, Amy Amundson Smith, Sébastien Perreault, Andrea Flynn Franson, Nada Jabado, Lindsey M. Hoffman, Rene Schmidt, Antoinette Y.N. Schouten-van Meeteren, Astrid Sehestedt, Enrico Opocher, Pablo Hernáiz Driever, Shivaram Avula, David Simon Ziegler, Jiaheng Qiu, Li-Pen Tsao, Peter Manley, Darren R. Hargrave, Olaf Witt Organizations Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg University Hospital and German Cancer Research Center (DKFZ), Heidelberg, Germany, Children's National Hospital, Washington, DC, Seattle Children’s Hospital, Seattle, WA, Orlando Health Arnold Palmer Hospital for Children, Orlando, FL, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada, C. S. Mott Children's Hospital, Ann Arbor, MI, McGill University Health Centre, Montreal, QC, Canada, Phoenix Children's Hospital, Phoenix, AZ, Institute of Biostatistics and Clinical Research, Münster, Germany, Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands, Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark, Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, Padua, Italy, 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, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, United Kingdom, Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia, Day One Biopharmaceuticals, Brisbane, CA, UCL Great Ormond Street Institute of Child Health, London, United Kingdom, Hopp Children’s Cancer Center (KiTZ), University Hospital Heidelberg, German Cancer Research Center and National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Day One Biopharmaceuticals Background: Pediatric low-grade gliomas (pLGGs) are the most common CNS tumors of childhood. Genomic alterations of BRAF are oncogenic drivers in almost all pLGGs. Approximately 50%‒60% of pLGGs harbor a KIAA1549-BRAF fusion and 5%‒15% a BRAF V600E mutation. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan-RAF inhibitor. The registrational, phase 2 FIREFLY-1 (NCT04775485) study of tovorafenib in pediatric patients with recurrent/progressive LGG is ongoing and interim analysis has shown encouraging anticancer activity. Methods: LOGGIC/FIREFLY-2 (NCT05566795) is a registrational, 2-arm, randomized, multicenter, global (~100 sites across Australia, Canada, Europe, New Zealand, Singapore, South Korea, and USA), phase 3 trial being conducted in collaboration with the SIOPe Brain Tumor Group LOGGIC Consortium. The study is evaluating the efficacy, safety, and tolerability of tovorafenib vs. standard of care (SoC) chemotherapy in patients < 25 years old with pLGG harboring an activating RAF -alteration and requiring first-line systemic therapy. Approximately 400 patients will be randomized 1:1 to receive oral tovorafenib, 420 mg/m 2 (≤600 mg) once weekly (tablet or liquid suspension), or an investigator’s choice of SoC chemotherapy: COG-V/C regimen (60 weeks), SIOPe-LGG-V/C regimen (81 weeks), or single-agent vinblastine (70 weeks). Tovorafenib will be continued until the occurrence of radiographic progression (based on Response Assessment in Neuro-Oncology [RANO] criteria as determined by the investigator and confirmed by independent review) or unacceptable toxicity; patients with radiographic progression may be allowed to continue tovorafenib if, in the opinion of the treating investigator, they are deriving clinical benefit from study treatment. Patients who progress in the SoC arm during or after completion of chemotherapy are eligible to cross-over to receive tovorafenib. The primary endpoint is the objective response rate based on RANO criteria, as determined by independent review. Key secondary endpoints are progression-free survival and duration of response per RANO criteria by independent review and overall survival. Other secondary endpoints include efficacy assessments per Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria, changes in neurological and visual function, and safety and tolerability. Exploratory endpoints include efficacy assessments per investigator, tumor volume, adaptive behavior and quality of life. Prognostic and predictive molecular biomarkers, including senescence profiles for treatment outcome, response prediction, and treatment resistance, will be explored in parallel studies. Clinical trial information: NCT05566795.

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