INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models.
Phillip C.C. Liu,Holly Koblish,Liangxing Wu,Kevin Bowman,Sharon Diamond,Darlise DiMatteo,Yue Zhang,Michael Hansbury,Mark Rupar,Xiaoming Wen,Paul Collier,Patricia Feldman,Ronald M. Klabe,Krista A. Burke,Maxim Soloviev,Christine Gardiner,Xin He,Alla Volgina,Maryanne B. Covington,Bruce Ruggeri,Richard Wynn,Timothy Burn,Peggy Scherle,Swamy Yeleswaram,Wenqing Yao,Reid Huber,Gregory Hollis +26 more
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The preclinical data presented for INCB054828, together with preliminary clinical observations, support continued investigation in patients with FGFR alterations, such as fusions and activating mutations, and suggest target inhibition is achievable by INCB 19054828 in vivo with low oral doses.Abstract:
Alterations in fibroblast growth factor receptor (FGFR) genes have been identified as potential driver oncogenes. Pharmacological targeting of FGFRs may therefore provide therapeutic benefit to selected cancer patients, and proof-of-concept has been established in early clinical trials of FGFR inhibitors. Here, we present the molecular structure and preclinical characterization of INCB054828 (pemigatinib), a novel, selective inhibitor of FGFR 1, 2, and 3, currently in phase 2 clinical trials. INCB054828 pharmacokinetics and pharmacodynamics were investigated using cell lines and tumor models, and the antitumor effect of oral INCB054828 was investigated using xenograft tumor models with genetic alterations in FGFR1, 2, or 3. Enzymatic assays with recombinant human FGFR kinases showed potent inhibition of FGFR1, 2, and 3 by INCB054828 (half maximal inhibitory concentration [IC50] 0.4, 0.5, and 1.0 nM, respectively) with weaker activity against FGFR4 (IC50 30 nM). INCB054828 selectively inhibited growth of tumor cell lines with activation of FGFR signaling compared with cell lines lacking FGFR aberrations. The preclinical pharmacokinetic profile suggests target inhibition is achievable by INCB054828 in vivo with low oral doses. INCB054828 suppressed the growth of xenografted tumor models with FGFR1, 2, or 3 alterations as monotherapy, and the combination of INCB054828 with cisplatin provided significant benefit over either single agent, with an acceptable tolerability. The preclinical data presented for INCB054828, together with preliminary clinical observations, support continued investigation in patients with FGFR alterations, such as fusions and activating mutations.read more
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Clinicogenomic Analysis of FGFR2-Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib.
Ian M. Silverman,Antoine Hollebecque,Luc Friboulet,Sherry Owens,Robert C. Newton,Hui-Ling Zhen,Luis Féliz,Camilla Zecchetto,Davide Melisi,Timothy Burn +9 more
TL;DR: This study provides a framework for molecularly-guided clinical trials and underscores the importance of genomic profiling to enable a deeper understanding of the molecular basis for response and nonresponse to targeted therapy.
Journal ArticleDOI
Pemigatinib: First Approval
TL;DR: This article summarizes the milestones in the development of pemigatinib leading to this first approval for the treatment of adults with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma and a FGFR2 fusion or other rearrangement, as detected by a US FDA-approved test.
Journal ArticleDOI
FIGHT-302: first-line pemigatinib vs gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements
Tanios Bekaii-Saab,Juan W. Valle,Eric Van Cutsem,Lorenza Rimassa,Junji Furuse,Tatsuya Ioka,Davide Melisi,Teresa Macarulla,John Bridgewater,Harpreet Wasan,Mitesh J. Borad,Ghassan K. Abou-Alfa,Ghassan K. Abou-Alfa,Ping Jiang,Christine F. Lihou,Hui-Ling Zhen,Ekaterine Asatiani,Luis Féliz,Arndt Vogel +18 more
TL;DR: The study design of FIGHT-302 is described, an open-label, randomized, active-controlled, multicenter, global, Phase III study comparing the efficacy and safety of first-line pemigatinib versus gemcitabine plus cisplatin in patients with advanced CCA with FGFR2 rearrangements.
Journal ArticleDOI
Futibatinib, an investigational agent for the treatment of intrahepatic cholangiocarcinoma: evidence to date and future perspectives.
TL;DR: This review provides an overview regarding the current scenario of FGFR2 targeted therapies in iCCA, especially focusing on the mechanism of action and clinical development of futibatinib (TAS-120), a highly selective irreversible pan-FGFR antagonist.
Journal ArticleDOI
Targeting FGFR inhibition in cholangiocarcinoma.
TL;DR: The most common adverse event associated with FGFR inhibitors is hyperphosphatemia, an on-target off-tumour effect of FGFR1 inhibition, and strategies to manage this include dose adjustment, chelators, and the use of a low phosphate diet.
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