Infigratinib in Patients with Recurrent Gliomas and FGFR Alterations: A Multicenter Phase II Study
Lassman, Andrew B; Sepúlveda-Sánchez, Juan Manuel; Cloughesy, Timothy; Gil-Gil, Miguel J; Puduvalli, Vinay K; Raizer, Jeffrey; De Vos, Filip Y F; Wen, Patrick Y; Butowski, Nicholas; Clement, Paul M J; Groves, Morris D; Belda-Iniesta, Cristobal; Giglio, Pierre; Soifer, Harris S; Rowsey, Steven; Xu, Cindy; Avogadri, Francesca; Wei, Ge; Moran, Susan; Roth, Patrick
(2022) Clinical cancer research : an official journal of the American Association for Cancer Research, volume 28, issue 11, pp. 2270 - 2277
(Article)
Abstract
Purpose: FGFR genomic alterations (amplification, mutations, and/or fusions) occur in ~8% of gliomas, particularly FGFR1 and FGFR3. We conducted a multicenter open-label, single-arm, phase II study of a selective FGFR1–3 inhibitor, infigratinib (BGJ398), in patients with FGFR-altered recurrent gliomas. Patients and Methods: Adults with recurrent/progressive gliomas harboring FGFR alterations received
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oral infigratinib 125 mg on days 1 to 21 of 28-day cycles. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate by Response Assessment in Neuro-Oncology criteria. Comprehensive genomic profiling was performed on available pretreatment archival tissue to explore additional molecular correlations with efficacy. Results: Among 26 patients, the 6-month PFS rate was 16.0% [95% confidence interval (CI), 5.0–32.5], median PFS was 1.7 months (95% CI, 1.1–2.8), and objective response rate was 3.8%. However, 4 patients had durable disease control lasting longer than 1 year. Among these, 3 had tumors harboring activating point mutations at analogous positions of FGFR1 (K656E; n = 2) or FGFR3 (K650E; n = 1) in pretreatment tissue; an FGFR3-TACC3 fusion was detected in the other. Hyperphosphatemia was the most frequently reported treatment-related adverse event (all-grade, 76.9%; grade 3, 3.8%) and is a known on-target toxicity of FGFR inhibitors. Conclusions: FGFR inhibitor monotherapy with infigratinib had limited efficacy in a population of patients with recurrent gliomas and different FGFR genetic alterations, but durable disease control lasting more than 1 year was observed in patients with tumors harboring FGFR1 or FGFR3 point mutations or FGFR3-TACC3 fusions. A follow-up study with refined biomarker inclusion criteria and centralized FGFR testing is warranted.
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Keywords: Oncology, Cancer Research, Journal Article
ISSN: 1078-0432
Publisher: American Association for Cancer Research Inc.
Note: Funding Information: A.B. Lassman reports grants, personal fees, and nonfinancial support from QED Therapeutics, Orbus Therapeutics, and Karyopharm Therapeutics; grants and nonfinancial support from Novartis, Agios/Servier, Kadmon, VBI Vaccines, BeiGene, Oncoceutics/Chimerix, Pfizer, Genentech/Roche, Bristol Myers Squibb, AbbVie, Global Coalition for Adaptive Research (GCAR), and Semus; and grants and personal fees from NIH/NCI during the conduct of the study. A.B. Lassman also reports personal fees and nonfinancial support from Bioclinica as an expert blinded independent reviewer of clinical and imaging data for a Bristol Myers Squibb–sponsored trial, Forma, Bayer, PER/MJH Holdings, Abbott Molecular, and Society for Neuro-Oncology; nonfinancial support from Aeterna Zentaris, American Society of Clinical Oncology, Matheson Foundation, National Brain Tumor Society, FDA, NextSource, DelMar Kintara, Corden Pharma, and Kazia; personal fees from Novocure, Sapience Therapeutics, Vivacitas, Fondazione AIRC (Italian Foundation for Cancer Research), and Elsevier; grants from RTOG Foundation; and nonfinancial support from Oligo Nation outside the submitted work. J.M. Sepúlveda-Sánchez reports other support from Novartis during the conduct of the study. J.M. Sepúlveda-Sánchez also reports grants from Pfizer, other support from Bristol Myers Squibb, personal fees from GlaxoSmithKline, and nonfinancial support from Ipsen outside the submitted work. T.F. Cloughesy reports personal fees from QED Therapeutics during the conduct of the study. T.F. Cloughesy also reports personal fees from SDP, Novartis, Kintara Therapeutics, Boehringer Ingelheim, Odonate Therapeutics, Medfield Pharmaceuticals, Pascal Biosciences, Karyopharm Therapeutics, VBI Vaccines, Novocure, Jubilant Pharma, Break Through Cancer, Immvira, SonALAsense, Gan & Lee Pharmaceuticals, Brainstorm Cell Therapeutics, Inovio Pharmaceuticals, Sapience Therapeutics, and GW Pharmaceuticals; grants and personal fees from Roche, QED Therapeutics, Tocagen, and AbbVie; and personal fees and other support from Global Coalition for Adaptive Research outside the submitted work. In addition, T.F. Cloughesy has a patent for 62/819,322 issued and licensed to Katmai Pharmaceuticals. M.J. Gil-Gil reports personal fees from Novartis, Daiichi Sankyo, Pfizer, AstraZeneca, Roche, and Pierre Fabre outside the submitted work. V.K. Puduvalli reports grants and nonfinancial support from Novartis during the conduct of the study, as well as personal fees from Orbus Therapeutics, Novocure, Servier, and Bayer outside the submitted work. J.J. Raizer reports grants from Novartis during the conduct of the study, as well as personal fees from Astellas outside the submitted work. F.Y.F. De Vos reports other support from QED Therapeutics during the conduct of the study; F.Y.F. De Vos also reports other support from Bristol Myers Squibb, Novartis, AbbVie, BioClin Therapeutics, and GlaxoSmithKline, as well as grants from STOPBraintu-mors.org outside the submitted work. P.Y. Wen reports personal fees and other support from Agios, AstraZeneca/MedImmune, Vascular Biogenics, and VBI Vaccines; other support from BeiGene, Celgene, Eli Lily, Genentech/Roche, Kazia, MediciNova, Oncoceutics, Elsevier, and UpToDate; and personal fees from Merck, Novartis, Nuvation Bio, Bayer, Boston Pharmaceuticals, CNS Pharmaceuticals, ElevateBio, Immunomic Therapeutics, Imvax, Karyopharm Therapeutics, Voyager Therapeutics, and QED Therapeutics outside the submitted work. P.M.J. Clement reports nonfinancial support from Novartis during the conduct of the study. P.M.J. Clement also reports personal fees from Bayer, Bristol Myers Squibb, Daiichi Sankyo, Leo Pharma, Merck, Merck Sharp & Dohme, Rakuten Medical, and Takeda Pharmaceutical Company; grants from AstraZeneca; and nonfinancial support from Teva Pharmaceuticals outside the submitted work. P. Giglio reports grants from QED Therapeutics during the conduct of the study, as well as grants from Agios, Prelude Therapeutics, Denovo Biopharma, and Novocure outside the submitted work. H.S. Soifer reports other support from QED Therapeutics during the conduct of the study, as well as other support from Biotheranostics outside the submitted work. F. Avogadri reports other support from QED Therapeutics during the conduct of the study. S. Moran reports personal fees from QED Therapeutics during the conduct of the study, as well as personal fees from RayzeBio and BioAtla outside the submitted work; in addition, S. Moran has a patent for PCT/US20/34881 pending and a patent for PCT/ US20/35140 pending. P. Roth reports other support from Novartis during the conduct of the study; P. Roth also reports personal fees from Debiopharm, Roche, Bristol Myers Squibb, and QED Therapeutics, as well as grants and personal fees from Novocure and Merck Sharp & Dohme outside the submitted work. No disclosures were reported by the other authors. Funding Information: The study was sponsored by Novartis and QED Therapeutics, an affiliate of BridgeBio Pharma. The field is indebted to Drs. Antonio Iavarone, Anna Lasorella, and their colleagues and collaborators for seminal discoveries regarding FGFR fusions. Medical writing support was provided by Harriet Lamb and Lee Miller of Miller Medical Communications, and funded by QED Therapeutics Inc and Helsinn Healthcare S.A. Randi Isaacs (formerly Clinical Site Head, Translational Clinical Oncology, Novartis Institutes for Biomedical Research, East Hanover, NJ) provided historical perspective and critical review of the manuscript. Outside of the reported study, A.B. Lassman was supported in part by The William Rhodes and Louise Tilzer-Rhodes Center for Glioblastoma at New York-Presbyterian Hospital, The Michael Weiner Glioblastoma Research Into Treatment Fund, Voices Against Brain Cancer, and the NIH/NCI grants P30CA013696 and UG1CA189960. Publisher Copyright: © 2022 The Authors.
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