TARGET: A phase I/II open-label multicenter study to assess safety and efficacy of fexagratinib in patients with relapsed/refractory FGFR fusion-positive glioma.

Autor:	Picca A; Service de Neuro-Oncologie, Institut de Neurologie, DMU Neurosciences, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France.; Sorbonne Université, Inserm, CNRS, UMR S 1127, Paris Brain Institute (ICM), Paris, France., Di Stefano AL; Department of Neurology, Foch Hospital, Suresnes, France.; Division of Neurosurgery, Spedali Riuniti di Livorno-USL Toscana Nord-Ovest, Livorno, Italy.; Sorbonne Université, Inserm, CNRS, UMR S 1127, Paris Brain Institute (ICM), Paris, France., Savatovsky J; Department of Radiology, Hôpital Fondation A. de Rothschild, Paris, France., Ducray F; Department of Neuro-Oncology, East Group Hospital, Hospices Civils de Lyon, Lyon, France., Chinot O; Department of Neuro-Oncology, AP-HM, University Hospital Timone, Marseille, France., Moyal EC; Department of Radiotherapy, Claudius Regaud Institute, Cancer University Institute of Toulouse, Oncopole 1, Paul Sabatier University, Toulouse III, Toulouse, France., Augereau P; Department of Medical Oncology, Institut de Cancérologie de L'ouest- Paul Papin, Angers, France., Le Rhun E; Department of Neurosurgery, Lille University Hospital, Lille, France., Schmitt Y; Sorbonne Université, Inserm, CNRS, UMR S 1127, Paris Brain Institute (ICM), Paris, France., Rousseaux N; Service de Neuro-Oncologie, Institut de Neurologie, DMU Neurosciences, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France., Yepnang AMM; AP-HP, Hôpital Pitié Salpêtrière, Unité de Recherche Clinique PSL-CFX, Paris, France., Estellat C; Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique-IPLESP, AP-HP, Hôpital Pitié Salpêtrière, Département de Santé Publique, Unité de Recherche Clinique PSL-CFX, Paris, France., Charbonneau F; Department of Radiology, Hôpital Fondation A. de Rothschild, Paris, France., Letourneur Q; Sorbonne Université, INSERM, UMR S 938 and SIRIC CURAMUS, Centre de Recherche Saint-Antoine (CRSA), Paris, France., Branger DF; Department of Pathology and Neuropathology, La Timone Hospital, Aix Marseille University, Marseille, France., Meyronet D; Department of Neuropathology, Hospices Civils de Lyon, Lyon, France., Fardeau C; Department of Ophthalmology, Hôpital de la Pitié-Salpêtrière, Paris, France., Mokhtari K; Sorbonne Université, Inserm, CNRS, UMR S 1127, Paris Brain Institute (ICM), Paris, France.; Department of Neuropathology, Hôpital de la Pitié-Salpêtrière, Paris, France., Bielle F; Sorbonne Université, Inserm, CNRS, UMR S 1127, Paris Brain Institute (ICM), Paris, France.; Department of Neuropathology, Hôpital de la Pitié-Salpêtrière, Paris, France., Iavarone A; Institute for Cancer Genetics, Columbia University Medical Center, New York, New York, USA.; Department of Neurological Surgery, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida, USA., Sanson M; Service de Neuro-Oncologie, Institut de Neurologie, DMU Neurosciences, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France.; Sorbonne Université, Inserm, CNRS, UMR S 1127, Paris Brain Institute (ICM), Paris, France.
Jazyk:	angličtina
Zdroj:	Neuro-oncology advances [Neurooncol Adv] 2024 May 20; Vol. 6 (1), pp. vdae068. Date of Electronic Publication: 2024 May 20 (Print Publication: 2024).
DOI:	10.1093/noajnl/vdae068
Abstrakt:	Background: Oncogenic FGFR-TACC fusions are present in 3-5% of high-grade gliomas (HGGs). Fexagratinib (AZD4547) is an oral FGFR1-3 inhibitor with preclinical activity in FGFR-TACC+ gliomas. We tested its safety and efficacy in patients with recurrent FGFR-TACC + HGGs. Patients and Methods: TARGET (NCT02824133) is a phase I/II open-label multicenter study that included adult patients with FGFR-TACC + HGGs relapsing after ≥1 line of standard chemoradiation. Patients received fexagratinib 80 mg bd on a continuous schedule until disease progression or unacceptable toxicity. The primary endpoint was the 6-month progression-free survival rate (PFS6). Results: Twelve patients with recurrent IDH wildtype FGFR-TACC + HGGs (all FGFR3-TACC3+) were included in the efficacy cohort (male/female ratio = 1.4, median age = 61.5 years). Most patients (67%) were included at the first relapse. The PFS6 was 25% (95% confidence interval 5-57%), with a median PFS of 1.4 months. All patients without progression at 6 months ( n  = 3) were treated at first recurrence (versus 56% of those in progression) and remained progression-free for 14-23 months. The best response was RANO partial response in 1 patient (8%), stable disease in 5 (42%), and progressive disease in 6 (50%). Median survival was 17.5 months from inclusion. Grade 3 toxicities included lymphopenia, hyperglycaemia, stomatitis, nail changes, and alanine aminotransferase increase ( n  = 1 each). No grade 4-5 toxicities were seen. A 32-gene signature was associated with the benefit of FGFR inhibition in FGFR3-TACC3 + HGGs. Conclusions: Fexagratinib exhibited acceptable toxicity but limited efficacy in recurrent FGFR3-TACC3 + HGGs. Patients treated at first recurrence appeared more likely to benefit, yet additional evidence is required. Competing Interests: A.P. and M.S. declare having received travel support from Astra Zeneca. The other authors have declared no conflict of interest relevant to this paper. (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
Databáze:	MEDLINE
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