Advertisement

Targeting FGFR inhibition in cholangiocarcinoma

Open AccessPublished:February 26, 2021DOI:https://doi.org/10.1016/j.ctrv.2021.102170

      Highlights

      • Cholangiocarcinomas (CCAs) are rare but aggressive tumours of the bile ducts.
      • Almost half of CCAs harbour potentially targetable somatic alterations.
      • Fibroblast growth factor receptor 2 (FGFR2) alterations occur in up 15% of iCCAs.
      • Selective FGFR inhibitors show promise to improve outcomes in FGFR-driven CCA.
      • Research to further optimise the use of new and emerging FGFR inhibitors is ongoing.

      Abstract

      Cholangiocarcinomas (CCAs) are rare but aggressive tumours of the bile ducts, which are often diagnosed at an advanced stage and have poor outcomes on systemic therapy. Somatic alterations with therapeutic implications have been identified in almost half of CCAs, in particular in intrahepatic CCA (iCCA), the subtype arising from bile ducts within the liver. Among patients with CCA, fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements occur almost exclusively in iCCA, where they are estimated to be found in up to 10–15% of patients. Clinical trials for selective FGFR kinase inhibitors have shown consistent activity of these agents in previously treated patients with iCCA harbouring FGFR alterations. Current FGFR kinase inhibitors show differences in their structure, mechanisms of target engagement, and specificities for FGFR1, 2, 3 and 4 and other related kinases. These agents offer the potential to improve outcomes in FGFR-driven CCA, and the impact of variations in the molecular profiles of the FGFR inhibitors on efficacy, safety, acquired resistance mechanisms, and patients’ health-related quality of life remains to be fully characterized. 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. As FGFR inhibitors and other targeted agents enter the clinic for use in FGFR-driven CCA, molecular testing for actionable mutations and monitoring for the emergence of acquired resistance will be essential.

      Keywords

      Introduction

      Cholangiocarcinomas (CCAs) are heterogeneous epithelial tumours arising from the biliary tree with features of cholangiocyte differentiation [
      • Guest R.V.
      • Boulter L.
      • Kendall T.J.
      • Minnis-Lyons S.E.
      • Walker R.
      • Wigmore S.J.
      • et al.
      Cell lineage tracing reveals a biliary origin of intrahepatic cholangiocarcinoma.
      ]. The anatomical subtypes of cholangiocarcinoma include intrahepatic cholangiocarcinoma (iCCA), which arises in the bile ducts within the liver, and extrahepatic cholangiocarcinoma (eCCA), which involves the ducts outside of the liver including the left and right hepatic ducts and the common bile duct. The prognosis of both types of CCA is poor, but is particularly poor in iCCA, where only 30–40% of patients present with surgically resectable disease [
      • Bridgewater J.
      • Galle P.R.
      • Khan S.A.
      • Llovet J.M.
      • Park J.-W.
      • Patel T.
      • et al.
      Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma.
      ] and unfortunately, the majority of cases recur even in apparently resectable disease. The 5-year overall survival for patients with iCCA is < 10% [

      American Cancer Society. Survival Rates for Bile Duct Cancer Where do these numbers come from? 2020. https://www.cancer.org/cancer/bile-duct-cancer/detection-diagnosis-staging/survival-by-stage.html.

      ], so treatments to improve survival are urgently needed. As iCCA symptoms may be non-specific, such as vague abdominal discomfort, nausea, fatigue, and weight loss, delayed diagnosis is particularly common [
      • Banales J.M.
      • Marin J.J.G.
      • Lamarca A.
      • Rodrigues P.M.
      • Khan S.A.
      • Roberts L.R.
      • et al.
      Cholangiocarcinoma 2020: the next horizon in mechanisms and management.
      ]
      In recent years, precision oncology has emerged as an promising approach for CCA. One of the most promising range of targets are the fibroblast growth factor receptor 2 (FGFR2) fusions, gene alterations present in 10–15% of iCCAs, but in almost no eCCAs. Multiple efforts to drug this target led to the first US Food and Drug Administration (FDA) approval in CCA. Pemigatinib, an oral selective FGFR inhibitor with potent activity against FGFR1–3, gained approval for treatment of patients with previously treated, locally advanced or metastatic CCA harbouring an FGFR2 fusion or rearrangement [

      Administration USF and D. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pemigatinib-cholangiocarcinoma-fgfr2-rearrangement-or-fusion.

      ]. This review focuses on the molecular biology driving biliary tract malignancies, the clinical development of FGFR inhibitors in FGFR-altered CCA, and future considerations as this promising new precision medicine-based option moves into the clinic.

      Molecular biology of the FGFR gene

      The FGF-FGFR signaling pathway

      Fibroblast growth factors (FGFs) and their associated fibroblast growth factor receptors (FGFRs) have been studied extensively, with a focus to exploit the therapeutic potential of FGF-FGFR signaling being made over the past 10 years [
      • Teven C.M.
      • Farina E.M.
      • Rivas J.
      • Reid R.R.
      Fibroblast growth factor (FGF) signaling in development and skeletal diseases.
      ]. The FGF pathway consists of 22 human FGFs and four highly conserved transmembrane receptors with intracellular tyrosine kinase domains, FGFR 1–4 [
      • Touat M.
      • Ileana E.
      • Postel-Vinay S.
      • André F.
      • Soria J.-C.
      Targeting FGFR signaling in cancer.
      ]. The FGFRs are expressed on multiple cell types [
      • Helsten T.
      • Elkin S.
      • Arthur E.
      • Tomson B.N.
      • Carter J.
      • Kurzrock R.
      The FGFR landscape in cancer: Analysis of 4,853 tumors by next-generation sequencing.
      ]. FGF-FGFR signaling is triggered by the ligand-dependent receptor dimerization following binding of FGF at the cell surface. This leads to intracellular phosphorylation of receptor kinase domains, a cascade of intracellular signaling, and gene transcription that activates a number of intracellular survival and proliferative pathways (Fig. 1A) [
      • Presta M.
      • Chiodelli P.
      • Giacomini A.
      • Rusnati M.
      • Ronca R.
      Fibroblast growth factors (FGFs) in cancer: FGF traps as a new therapeutic approach.
      ]. The specificity of the FGF-FGFR interaction is influenced by the differing ligand binding capacities of the receptor paralogues, by alternative splicing of FGFR, and by tissue-specific expression of ligands and receptors, coupled with cell surface or secreted proteins that facilitate the FGF-FGFR interactions and increase ligand specificity [
      • Turner N.
      • Grose R.
      Fibroblast growth factor signalling: From development to cancer.
      ]. Alterations in FGFR genes, including activating mutations, chromosomal translocations, gene fusions, and gene amplifications, can result in ligand-independent signaling which, in turn, leads to constitutive receptor activation (Fig. 1B).
      Figure thumbnail gr1
      Fig. 1A and 1B. FGF-FGFR signaling pathway A) FGF-FGFR signaling under physiologic conditions: Binding of FGF ligands to FGFRs at the cell surface causes the receptors to dimerize, leading to intracellular phosphorylation of receptor kinase domains, a cascade of intracellular signaling, and gene transcription. Through this signaling cascade, the FGF ligands activate intracellular survival and proliferative pathways. B) Deregulated FGF signaling: Chromosomal translocation can result in fusion of the kinase domain of an FGFR to a dimerisation domain (DM) from another protein that promotes oligomerization, leading to constitutive kinase activation. The aberrant signaling cascades then activate oncogenesis through progressive growth and invasiveness, neoangiogenesis as well as promote chemoresistance. FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; RAS: Rat Sarcoma; RAF: Serine/Threonine Kinase; MAPK, mitogen activated protein kinase; JAK: Janus kinase; STAT: signal transducer and activator of transcription; PI3K: Phosphatidylinositol‐4,5‐Bisphosphate 3‐Kinase; AKT: Protein kinase B (PKB); mTOR: mammalian target of rapamycin.
      FGF-FGFR signaling has been shown to have oncogenic roles in many cancers. Key downstream signaling pathways altered by FGF-FGFR activation are the Ras-Raf-MEK-ERK pathway, the PI3-AKT-mTOR pathway, and JAK-STAT pathway (Fig. 1A) [
      • Eswarakumar V.P.
      • Lax I.
      • Schlessinger J.
      Cellular signaling by fibroblast growth factor receptors.
      ]. In an analysis of 4,853 solid tumours, FGFR aberrations were found in 7.1% of all cancers, with the majority (66%) being gene amplifications, followed by mutations (26%), and rearrangements (8%) [
      • Helsten T.
      • Elkin S.
      • Arthur E.
      • Tomson B.N.
      • Carter J.
      • Kurzrock R.
      The FGFR landscape in cancer: Analysis of 4,853 tumors by next-generation sequencing.
      ]. Among the CCA tumours in that study (N = 115), 7% harboured FGFR aberrations. These aberrations were mostly in the gene encoding for FGFR2 (6.1%), with a small proportion in the FGFR1 gene, and none identified in the FGFR3 or FGFR4 genes.

      Genomic profiling of CCA

      Biliary tract cancers (BTCs) arise from epithelial cells lining the bile duct and can occur at distinct anatomical locations: intrahepatic, extrahepatic and in the gallbladder [
      • Nakamura H.
      • Arai Y.
      • Totoki Y.
      • Shirota T.
      • Elzawahry A.
      • Kato M.
      • et al.
      Genomic spectra of biliary tract cancer.
      ]. Analyses of the genomic and transcriptomic landscape of the anatomical subtypes of BTC show that molecular profiles vary between iCCA, eCCA, and gallbladder cancer (GBC), with multiple small cohorts of patients having mutually exclusive or co-existent aberrations [
      • Nakamura H.
      • Arai Y.
      • Totoki Y.
      • Shirota T.
      • Elzawahry A.
      • Kato M.
      • et al.
      Genomic spectra of biliary tract cancer.
      ,
      • Jusakul A.
      • Cutcutache I.
      • Yong C.H.
      • Lim J.Q.
      • Huang M.N.
      • Padmanabhan N.
      • et al.
      Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma.
      ,
      • Lowery M.A.
      • Ptashkin R.
      • Jordan E.
      • Berger M.F.
      • Zehir A.
      • Capanu M.
      • et al.
      Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: Potential targets for intervention.
      ,
      • Javle M.
      • Zhao H.
      • Abou-Alfa G.K.
      Systemic therapy for gallbladder cancer.
      ]. Given the heterogenous nature of BTCs, it is unsurprising that multiple genetic factors are implicated in CCA development, including chromosomal aberrations, and genetic and epigenetic alterations in tumour suppressor genes and oncogenes.
      The most prevalent genetic alterations identified in CCA influence key networks such as DNA repair (TP53), the WNT–CTNNB1 pathway, protein kinase signaling (KRAS, BRAF, SMAD4 and FGFR2), protein tyrosine phosphatase (PTPN3), epigenetic modifiers (IDH1 and IDH2), chromatin-remodeling factors (MLL3, ARID1A, PBRM1 and BAP1) [
      • Chan-on W.
      • Nairismägi M.-L.
      • Ong C.K.
      • Lim W.K.
      • Dima S.
      • Pairojkul C.
      • et al.
      Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers.
      ,
      • Jiao Y.
      • Pawlik T.M.
      • Anders R.A.
      • Selaru F.M.
      • Streppel M.M.
      • Lucas D.J.
      • et al.
      Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas.
      ], and Notch signaling, which is involved in cholangiocyte differentiation and biliary duct development [

      Sekiya S, Suzuki A. Brief report Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes. The Journal of Clinical Investigation 2012;122. https://doi.org/10.1172/JCI63065DS1.

      ]. In patients with iCCA, the main targetable aberrations identified were FGFR2 fusions [
      • Wu Y.-M.
      • Su F.
      • Kalyana-Sundaram S.
      • Khazanov N.
      • Ateeq B.
      • Cao X.
      • et al.
      Identification of targetable FGFR gene fusions in diverse cancers.
      ,
      • Arai Y.
      • Totoki Y.
      • Hosoda F.
      • Shirota T.
      • Hama N.
      • Nakamura H.
      • et al.
      Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma.
      ,

      Borad MJ, Champion MD, Egan JB, Liang WS, Fonseca R, Bryce AH, et al. Integrated Genomic Characterization Reveals Novel, Therapeutically Relevant Drug Targets in FGFR and EGFR Pathways in Sporadic Intrahepatic Cholangiocarcinoma. PLoS Genetics 2014;10. https://doi.org/10.1371/journal.pgen.1004135.

      ], IDH1 mutations [
      • Borger D.R.
      • Tanabe K.K.
      • Fan K.C.
      • Lopez H.U.
      • Fantin V.R.
      • Straley K.S.
      • et al.
      Frequent Mutation of Isocitrate Dehydrogenase (IDH)1 and IDH2 in Cholangiocarcinoma Identified Through Broad-Based Tumor Genotyping.
      ], NTRK fusions [
      • Drilon A.
      • Laetsch T.W.
      • Kummar S.
      • DuBois S.G.
      • Lassen U.N.
      • Demetri G.D.
      • et al.
      Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children.
      ], and microsatellite instability [
      • Marabelle A.
      • Le D.T.
      • Ascierto P.A.
      • Di Giacomo A.M.
      • De Jesus-Acosta A.
      • Delord J.-P.
      • et al.
      Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.
      ].

      Discovery of targetable FGFR2 aberrations in iCCA

      The earliest report of FGFR2 fusions in CCA was in 2013 by Wu and colleagues [
      • Wu Y.-M.
      • Su F.
      • Kalyana-Sundaram S.
      • Khazanov N.
      • Ateeq B.
      • Cao X.
      • et al.
      Identification of targetable FGFR gene fusions in diverse cancers.
      ]. The two fusions identified occurred in patients with iCCA, and subsequent studies have shown that FGFR2 fusions occur nearly exclusively in iCCA compared to other BTCs and epithelial cancers, making them a useful diagnostic marker. Across multiple tumour genotyping studies in CCA, the frequency of FGFR2 fusions in iCCA is estimated to be approximately 10–15% [
      • Arai Y.
      • Totoki Y.
      • Hosoda F.
      • Shirota T.
      • Hama N.
      • Nakamura H.
      • et al.
      Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma.
      ,
      • Ross J.S.
      • Wang K.
      • Gay L.
      • Al‐Rohil R.
      • Rand J.V.
      • Jones D.M.
      • et al.
      New Routes to Targeted Therapy of Intrahepatic Cholangiocarcinomas Revealed by Next-Generation Sequencing.
      ,
      • Farshidfar F.
      • Zheng S.
      • Gingras M.-C.
      • Newton Y.
      • Shih J.
      • Robertson A.G.
      • et al.
      Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.
      ,
      • Jain A.
      • Borad M.J.
      • Kelley R.K.
      • Wang Y.
      • Abdel-Wahab R.
      • Meric-Bernstam F.
      • et al.
      Cholangiocarcinoma With FGFR Genetic Aberrations: A Unique Clinical Phenotype.
      ]. Geography and etiology may impact reported frequencies in FGFR2 fusions. Kongpetch and colleagues evaluated 193 CCA tumours from Thailand, Romania, and Singapore, and reported that rates of FGFR2 fusions were 0.8%, 6.8%, and 15.7%, respectively [
      • Kongpetch S.
      • Jusakul A.
      • Lim J.Q.
      • Ng C.C.Y.
      • Chan J.Y.
      • Rajasegaran V.
      • et al.
      Lack of Targetable FGFR2 Fusions in Endemic Fluke-Associated Cholangiocarcinoma.
      ]. These authors also reported that the rate of FGFR2 fusions in fluke-associated and non-fluke associated CCA were 0.8% and 11.6%, respectively (p = 0.0006), suggesting that FGFR2 fusions might play a crucial role in the evolution of non-liver fluke-associated CCA, but less so in liver fluke-associated CCA. An integrated data analysis from whole-genome sequencing/targeted DNA sequencing with RNA-fusion sequencing showed mutations in FGFR1, FGFR2, FGFR3 and FGFR4 were present in 1.0%, 3.6%, 1.0% and 0.5% of CCAs, respectively. FGFR2 fusions and FGFR mutations were mutually exclusive in this study [
      • Kongpetch S.
      • Jusakul A.
      • Lim J.Q.
      • Ng C.C.Y.
      • Chan J.Y.
      • Rajasegaran V.
      • et al.
      Lack of Targetable FGFR2 Fusions in Endemic Fluke-Associated Cholangiocarcinoma.
      ].
      FGFR2 fusions generally encode a functional fusion protein with FGFR2 fused to a partner gene at the C-terminus that has strong dimerization or oligomerization capabilities [
      • Wu Y.-M.
      • Su F.
      • Kalyana-Sundaram S.
      • Khazanov N.
      • Ateeq B.
      • Cao X.
      • et al.
      Identification of targetable FGFR gene fusions in diverse cancers.
      ,
      • Arai Y.
      • Totoki Y.
      • Hosoda F.
      • Shirota T.
      • Hama N.
      • Nakamura H.
      • et al.
      Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma.
      ]. The most common partner is BICC1, but various other fusion partners with FGFR2 have subsequently been identified in iCCA [
      • Jusakul A.
      • Cutcutache I.
      • Yong C.H.
      • Lim J.Q.
      • Huang M.N.
      • Padmanabhan N.
      • et al.
      Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma.
      ,
      • Wu Y.-M.
      • Su F.
      • Kalyana-Sundaram S.
      • Khazanov N.
      • Ateeq B.
      • Cao X.
      • et al.
      Identification of targetable FGFR gene fusions in diverse cancers.
      ,
      • Arai Y.
      • Totoki Y.
      • Hosoda F.
      • Shirota T.
      • Hama N.
      • Nakamura H.
      • et al.
      Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma.
      ,

      Borad MJ, Champion MD, Egan JB, Liang WS, Fonseca R, Bryce AH, et al. Integrated Genomic Characterization Reveals Novel, Therapeutically Relevant Drug Targets in FGFR and EGFR Pathways in Sporadic Intrahepatic Cholangiocarcinoma. PLoS Genetics 2014;10. https://doi.org/10.1371/journal.pgen.1004135.

      ,
      • Ross J.S.
      • Wang K.
      • Gay L.
      • Al‐Rohil R.
      • Rand J.V.
      • Jones D.M.
      • et al.
      New Routes to Targeted Therapy of Intrahepatic Cholangiocarcinomas Revealed by Next-Generation Sequencing.
      ,
      • Jain A.
      • Borad M.J.
      • Kelley R.K.
      • Wang Y.
      • Abdel-Wahab R.
      • Meric-Bernstam F.
      • et al.
      Cholangiocarcinoma With FGFR Genetic Aberrations: A Unique Clinical Phenotype.
      ,
      • Kongpetch S.
      • Jusakul A.
      • Lim J.Q.
      • Ng C.C.Y.
      • Chan J.Y.
      • Rajasegaran V.
      • et al.
      Lack of Targetable FGFR2 Fusions in Endemic Fluke-Associated Cholangiocarcinoma.
      ,
      • Sia D.
      • Losic B.
      • Moeini A.
      • Cabellos L.
      • Hao K.e.
      • Revill K.
      • et al.
      Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. Nature.
      ] (Table 1), most of which fuse at a consistent breakpoint within the FGFR2 gene on chromosome 10 [

      Borad MJ, Champion MD, Egan JB, Liang WS, Fonseca R, Bryce AH, et al. Integrated Genomic Characterization Reveals Novel, Therapeutically Relevant Drug Targets in FGFR and EGFR Pathways in Sporadic Intrahepatic Cholangiocarcinoma. PLoS Genetics 2014;10. https://doi.org/10.1371/journal.pgen.1004135.

      ]. In vitro and in vivo experiments show that the oncogenic ability of FGFR2 fusion proteins can be suppressed by treatment with FGFR kinase inhibitors [
      • Wu Y.-M.
      • Su F.
      • Kalyana-Sundaram S.
      • Khazanov N.
      • Ateeq B.
      • Cao X.
      • et al.
      Identification of targetable FGFR gene fusions in diverse cancers.
      ,
      • Arai Y.
      • Totoki Y.
      • Hosoda F.
      • Shirota T.
      • Hama N.
      • Nakamura H.
      • et al.
      Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma.
      ,
      • Goyal L.
      • Shi L.
      • Liu L.Y.
      • Fece de la Cruz F.
      • Lennerz J.K.
      • Raghavan S.
      • et al.
      TAS-120 overcomes resistance to atp-competitive FGFR inhibitors in patients with FGFR2 fusion–positive intrahepatic cholangiocarcinoma.
      ], this has been mirrored clinically.
      Table 1FGFR fusions identified in iCCA.
      FGFR fusionFrequencyReferences
      Recurrent FGFR2 fusions
      • FGFR2-BICC1
      2 casesWu 2013
      • Wu Y.-M.
      • Su F.
      • Kalyana-Sundaram S.
      • Khazanov N.
      • Ateeq B.
      • Cao X.
      • et al.
      Identification of targetable FGFR gene fusions in diverse cancers.
      3.0% (2/66)Arai 2014
      • Arai Y.
      • Totoki Y.
      • Hosoda F.
      • Shirota T.
      • Hama N.
      • Nakamura H.
      • et al.
      Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma.
      12.7% (8/63)Jain 2018
      • Jain A.
      • Borad M.J.
      • Kelley R.K.
      • Wang Y.
      • Abdel-Wahab R.
      • Meric-Bernstam F.
      • et al.
      Cholangiocarcinoma With FGFR Genetic Aberrations: A Unique Clinical Phenotype.
      28.9% (31/107)Abou-Alfa 2020
      • Abou-Alfa Ghassan K
      • Sahai Vaibhav
      • Hollebecque Antoine
      • Vaccaro Gina
      • Melisi Davide
      • Al-Rajabi Raed
      • et al.
      Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.
      • FGFR2-AHCYL1
      10.6% (7/66)Arai 2014
      • Arai Y.
      • Totoki Y.
      • Hosoda F.
      • Shirota T.
      • Hama N.
      • Nakamura H.
      • et al.
      Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma.
      • FGFR2-PPHLN1
      16.8% (18/107)Sia 2015
      • Sia D.
      • Losic B.
      • Moeini A.
      • Cabellos L.
      • Hao K.e.
      • Revill K.
      • et al.
      Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. Nature.
      Less frequently observed FGFR fusionsReferences
      • FGFR2-AFF4
      • FGFR2-AFF4, R678G
      • FGFR2-AMPD2
      • FGFR2-ARHGAP24
      • FGFR2-C10
      • FGFR2-CCDC6
      • FGFR2-CELF2
      • FGFR2-CGNL1
      • FGFR2-CTNNA3
      • FGFR2-DCTN2
      • FGFR2-DNAJC12
      • FGFR2-DZIP1
      • FGFR2-f118
      • FGFR2-FOXP1
      • FGFR2-INA
      • FGFR2-KCTD1
      • FGFR2-KIAA1217
      • FGFR2-KIAA1598
      • FGFR2-KIF7
      • FGFR2-LGSN
      • FGFR2-LPXN
      • FGFR2-MGEA5
      • FGFR2-MYPN
      • FGFR2-NOL4
      • FGFR2-NRAP
      • FGFR2-PARK2
      • FGFR2-PCMI
      • FGFR2-Rearrangement intron 17
      • FGFR2-RNF41
      • FGFR2-SH3GLB1
      • FGFR2-SLMAP
      • FGFR2-SORBS1
      • FGFR2-STK26
      • FGFR2-STK3
      • FGFR2-TACC3
      • FGFR2-TBC1D1
      • FGFR2-UBQLN1
      • FGFR2-WAC
      • FGFR2-ZMYM4
      • FGFR3-TACC3
      Abou-Alfa 2020
      • Abou-Alfa Ghassan K
      • Sahai Vaibhav
      • Hollebecque Antoine
      • Vaccaro Gina
      • Melisi Davide
      • Al-Rajabi Raed
      • et al.
      Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.
      ; Borad 2014

      Borad MJ, Champion MD, Egan JB, Liang WS, Fonseca R, Bryce AH, et al. Integrated Genomic Characterization Reveals Novel, Therapeutically Relevant Drug Targets in FGFR and EGFR Pathways in Sporadic Intrahepatic Cholangiocarcinoma. PLoS Genetics 2014;10. https://doi.org/10.1371/journal.pgen.1004135.

      ; Ross 2014
      • Ross J.S.
      • Wang K.
      • Gay L.
      • Al‐Rohil R.
      • Rand J.V.
      • Jones D.M.
      • et al.
      New Routes to Targeted Therapy of Intrahepatic Cholangiocarcinomas Revealed by Next-Generation Sequencing.
      ; Jusakul 2017
      • Jusakul A.
      • Cutcutache I.
      • Yong C.H.
      • Lim J.Q.
      • Huang M.N.
      • Padmanabhan N.
      • et al.
      Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma.
      ; Jain 2018
      • Jain A.
      • Borad M.J.
      • Kelley R.K.
      • Wang Y.
      • Abdel-Wahab R.
      • Meric-Bernstam F.
      • et al.
      Cholangiocarcinoma With FGFR Genetic Aberrations: A Unique Clinical Phenotype.
      ; Javle 2017
      • Javle Milind
      • Lowery Maeve
      • Shroff Rachna T.
      • Weiss Karl Heinz
      • Springfeld Christoph
      • Borad Mitesh J.
      • et al.
      Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma.
      ; Goyal 2019
      • Goyal L.
      • Shi L.
      • Liu L.Y.
      • Fece de la Cruz F.
      • Lennerz J.K.
      • Raghavan S.
      • et al.
      TAS-120 overcomes resistance to atp-competitive FGFR inhibitors in patients with FGFR2 fusion–positive intrahepatic cholangiocarcinoma.
      ; Kongpetch 2020
      • Kongpetch S.
      • Jusakul A.
      • Lim J.Q.
      • Ng C.C.Y.
      • Chan J.Y.
      • Rajasegaran V.
      • et al.
      Lack of Targetable FGFR2 Fusions in Endemic Fluke-Associated Cholangiocarcinoma.
      FGFR2 fusions in iCCA have been associated with a better prognosis [
      • Jain A.
      • Borad M.J.
      • Kelley R.K.
      • Wang Y.
      • Abdel-Wahab R.
      • Meric-Bernstam F.
      • et al.
      Cholangiocarcinoma With FGFR Genetic Aberrations: A Unique Clinical Phenotype.
      ,
      • Graham R.P.
      • Barr Fritcher E.G.
      • Pestova E.
      • Schulz J.
      • Sitailo L.A.
      • Vasmatzis G.
      • et al.
      Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma.
      ] and younger age at diagnosis [
      • Jain A.
      • Borad M.J.
      • Kelley R.K.
      • Wang Y.
      • Abdel-Wahab R.
      • Meric-Bernstam F.
      • et al.
      Cholangiocarcinoma With FGFR Genetic Aberrations: A Unique Clinical Phenotype.
      ,
      • Kongpetch S.
      • Jusakul A.
      • Lim J.Q.
      • Ng C.C.Y.
      • Chan J.Y.
      • Rajasegaran V.
      • et al.
      Lack of Targetable FGFR2 Fusions in Endemic Fluke-Associated Cholangiocarcinoma.
      ] in some studies. They are also mutually exclusive with KRAS and BRAF [
      • Arai Y.
      • Totoki Y.
      • Hosoda F.
      • Shirota T.
      • Hama N.
      • Nakamura H.
      • et al.
      Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma.
      ] and ERBB2/BRAF/NRAS alterations [
      • Kongpetch S.
      • Jusakul A.
      • Lim J.Q.
      • Ng C.C.Y.
      • Chan J.Y.
      • Rajasegaran V.
      • et al.
      Lack of Targetable FGFR2 Fusions in Endemic Fluke-Associated Cholangiocarcinoma.
      ] in some studies. FGFR2 fusions have been found to be frequently co-altered with mutations in the chromatin-remodeling gene BAP1 [
      • Jain A.
      • Borad M.J.
      • Kelley R.K.
      • Wang Y.
      • Abdel-Wahab R.
      • Meric-Bernstam F.
      • et al.
      Cholangiocarcinoma With FGFR Genetic Aberrations: A Unique Clinical Phenotype.
      ], which acts as a tumour suppressor in iCCA [
      • Chen X.-X.
      • Yin Y.
      • Cheng J.-W.
      • Huang A.o.
      • Hu B.o.
      • Zhang X.
      • et al.
      BAP1 acts as a tumor suppressor in intrahepatic cholangiocarcinoma by modulating the ERK1/2 and JNK/c-Jun pathways.
      ]. The implications of these genetics on the therapeutic potential of combination therapy have yet to be realized.

      iCCA epidemiology and current systemic treatment for iCCA

      CCA epidemiology and risk factors for developing CCA

      Globally, the incidence and mortality rates of CCA show substantial geographical variation, which may reflect exposure to different geographical risk factors and genetic determinants [
      • Khan S.A.
      • Tavolari S.
      • Brandi G.
      Cholangiocarcinoma: Epidemiology and risk factors.
      ,
      • Florio A.A.
      • Ferlay J.
      • Znaor A.
      • Ruggieri D.
      • Alvarez C.S.
      • Laversanne M.
      • et al.
      Global trends in intrahepatic and extrahepatic cholangiocarcinoma incidence from 1993 to 2012.
      ]. Multiple studies from Europe, the USA, Japan and Australia have reported rising rates of iCCA [
      • Khan S.A.
      • Tavolari S.
      • Brandi G.
      Cholangiocarcinoma: Epidemiology and risk factors.
      ,
      • Saha S.K.
      • Zhu A.X.
      • Fuchs C.S.
      • Brooks G.A.
      Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise.
      ], which appear to have plateaued over the past 10 years. This increase may be due to advances in imaging, molecular diagnostics and pathology, enabling more accurate diagnosis of iCCA [
      • Florio A.A.
      • Ferlay J.
      • Znaor A.
      • Ruggieri D.
      • Alvarez C.S.
      • Laversanne M.
      • et al.
      Global trends in intrahepatic and extrahepatic cholangiocarcinoma incidence from 1993 to 2012.
      ,
      • Saha S.K.
      • Zhu A.X.
      • Fuchs C.S.
      • Brooks G.A.
      Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise.
      ], however, in contrast, the incidence of both perihilar CCA and distal CCA appears to be stable or decreasing [
      • Khan S.A.
      • Tavolari S.
      • Brandi G.
      Cholangiocarcinoma: Epidemiology and risk factors.
      ,
      • Saha S.K.
      • Zhu A.X.
      • Fuchs C.S.
      • Brooks G.A.
      Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise.
      ] suggesting the increase is real. However, a recent international analysis of population-based incidence rates of CCA, the Cancer Incidence in Five Continents Plus (CI5plus), showed that the incidence rates of both iCCA and eCCA increased in a majority of countries worldwide during the period 1993–2012, with iCCA incidence rates being higher than eCCA incidence rates in most countries between 2008 and 2012 [
      • Florio A.A.
      • Ferlay J.
      • Znaor A.
      • Ruggieri D.
      • Alvarez C.S.
      • Laversanne M.
      • et al.
      Global trends in intrahepatic and extrahepatic cholangiocarcinoma incidence from 1993 to 2012.
      ].
      The highest rates of CCA are in South East Asia (Northeast Thailand, Cambodia, and Laos), where the incidence is approximately 80/100,000 per year compared to 1–2/100,000 in the UK and USA, the former primarily associated with liver fluke infection [
      • Banales J.M.
      • Marin J.J.G.
      • Lamarca A.
      • Rodrigues P.M.
      • Khan S.A.
      • Roberts L.R.
      • et al.
      Cholangiocarcinoma 2020: the next horizon in mechanisms and management.
      ,
      • Jusakul A.
      • Kongpetch S.
      • Teh B.T.
      Genetics of Opisthorchis viverrini -related cholangiocarcinoma.
      ]. Other risk factors include primary sclerosing cholangitis, hepatolithiasis, liver fluke infections, chronic viral hepatitis, metabolic syndrome, alcohol use, and congenital anomalies of the bile ducts, such as choledochal cysts [
      • Banales J.M.
      • Marin J.J.G.
      • Lamarca A.
      • Rodrigues P.M.
      • Khan S.A.
      • Roberts L.R.
      • et al.
      Cholangiocarcinoma 2020: the next horizon in mechanisms and management.
      ,
      • Khan S.A.
      • Tavolari S.
      • Brandi G.
      Cholangiocarcinoma: Epidemiology and risk factors.
      ]. Risk factors may overlap, for example, parasitic infection often induces hepatholithiasis [
      • Feng X.
      • Zheng S.
      • Xia F.
      • Ma K.
      • Wang S.
      • Bie P.
      • et al.
      Classification and management of hepatolithiasis: A high-volume, single-center’s experience.
      ]. In Western countries about 50% of cases are still diagnosed without any identifiable risk factor despite advances in the knowledge of CCA etiology [
      • Khan S.A.
      • Tavolari S.
      • Brandi G.
      Cholangiocarcinoma: Epidemiology and risk factors.
      ].

      Current systemic treatment for iCCA

      The standard of care for patients with unresectable or metastatic disease is combination chemotherapy with gemcitabine and cisplatin, based on the ABC-02 and BT22 trials showing an improved median overall survival (mOS) with this combination compared to gemcitabine alone [
      • Valle J.W.
      • Borbath I.
      • Khan S.A.
      • Huguet F.
      • Gruenberger T.
      • Arnold D.
      • et al.
      Biliary cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • Okusaka T.
      • Nakachi K.
      • Fukutomi A.
      • Mizuno N.
      • Ohkawa S.
      • Funakoshi A.
      • et al.
      Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: A comparative multicentre study in Japan.
      ]. In patients with unresectable, liver-confined disease, liver-directed therapy with external beam radiation, radioembolization, chemoembolization or ablation can be considered [

      NCCN Guidelines Version 2.2020 Hepatobiliary Cancers. 2020. https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf.

      ].
      If the disease progresses, second-line treatment with FOLFOX is the preferred regimen based on the ABC-06 trial findings, which demonstrated a mOS of 6.2 months for modified FOLFOX plus active symptom control versus 5.3 months for active symptom control alone [
      • Lamarca A.
      • Palmer D.H.
      • Wasan H.S.
      • Ross P.J.
      • Ma Y.T.
      • Arora A.
      • et al.
      ABC-06 | A randomised phase III, multi-centre, open-label study of active symptom control (ASC) alone or ASC with oxaliplatin / 5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers (ABC) previously-tr.
      ]. The response rate of 5% and disease control rate (DCR) of 33% for patients in that study underline the urgent need for improvements in therapy for refractory patients with iCCA. Although the overall survival for iCCA treated with standard chemotherapy seems to be better than that for other BTCs [
      • Lamarca A.
      • Ross P.
      • Wasan H.S.
      • Hubner R.A.
      • McNamara M.G.
      • Lopes A.
      • et al.
      Advanced Intrahepatic Cholangiocarcinoma: Post Hoc Analysis of the ABC-01, -02, and -03 Clinical Trials.
      ], overall, systemic chemotherapy has a low survival benefit for patients with unresectable iCCA as the majority of patients have a chemorefractory course [
      • Köhler M.
      • Harders F.
      • Lohöfer F.
      • Paprottka P.M.
      • Schaarschmidt B.M.
      • Theysohn J.
      • et al.
      Prognostic Factors for Overall Survival in Advanced Intrahepatic Cholangiocarcinoma Treated with Yttrium-90 Radioembolization.
      ].
      A recently published multicenter, randomized, double-blind, placebo-controlled phase III trial demonstrated the efficacy of the IDH1 inhibitor, ivosidenib, in a majority intrahepatic CCA study population [
      • Abou-Alfa G.K.
      • Macarulla T.
      • Javle M.M.
      • Kelley R.K.
      • Lubner S.J.
      • Adeva J.
      • et al.
      Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study.
      ]. It is anticipated that this will be licensed for second line in iCCA patients with an IDH1 mutation.

      Targeting FGFR in iCCA

      History of FGFR-targeted therapies in CCA

      Several candidate drugs targeting this pathway are under development, including non-selective and selective FGFR tyrosine kinase inhibitors (TKIs), anti-FGF/FGFR monoclonal antibodies, and FGF traps [
      • Ghedini G.C.
      • Ronca R.
      • Presta M.
      • Giacomini A.
      Future applications of FGF/FGFR inhibitors in cancer.
      ]. Although the non-selective TKIs pazopanib and ponatinib showed anecdotal anti-tumour activity in patients with iCCA harbouring an FGFR2 fusion [

      Borad MJ, Champion MD, Egan JB, Liang WS, Fonseca R, Bryce AH, et al. Integrated Genomic Characterization Reveals Novel, Therapeutically Relevant Drug Targets in FGFR and EGFR Pathways in Sporadic Intrahepatic Cholangiocarcinoma. PLoS Genetics 2014;10. https://doi.org/10.1371/journal.pgen.1004135.

      ], other preclinical and clinical trials have highlighted the pitfalls of using non-selective FGFR TKIs, including issues with off-target side effects [
      • Ghedini G.C.
      • Ronca R.
      • Presta M.
      • Giacomini A.
      Future applications of FGF/FGFR inhibitors in cancer.
      ]. The use of selective FGFR kinase inhibitors has therefore been a rational approach to address these issues. Several FGFR inhibitors have been evaluated in early phase clinical trials in patients with refractory iCCA harbouring FGFR2 gene rearrangements, either in trials specifically enrolling patients with iCCA or in trials evaluating a variety of advanced solid tumours harbouring FGFR2 gene rearrangements or other alterations (Table 2 and Table 3). Derazantinib differs in that it is not a selective FGFR inhibitor, but rather a multi-kinase inhibitor with potent pan-FGFR activity [
      • Mazzaferro V.
      • El-Rayes B.F.
      • Droz dit Busset M.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • et al.
      Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma.
      ].
      Table 2Current status of FGFRi in clinical development for iCCA harbouring FGFR gene rearrangements.
      CompoundCurrent development status in CCACCA population studiedDosage regimenEfficacy resultsTreatment-emergent adverse events
      Debio 1347Phase II basket trial ongoing in pts with solid tumors with FGFR1, FGFR2 or FGFR3 fusions after ≥ 1 line of ST (FUZE, NCT03834220)5 of 18 pts in a phase I expansion cohort had CCA (FGFR2 fusions, n = 4; FGFR1 fusion, n = 1); all had prior ST (NCT01948297)
      • Guest R.V.
      • Boulter L.
      • Kendall T.J.
      • Minnis-Lyons S.E.
      • Walker R.
      • Wigmore S.J.
      • et al.
      Cell lineage tracing reveals a biliary origin of intrahepatic cholangiocarcinoma.
      80 mg QD (used in phase I and in ongoing phase II)From 4 CCA pts with FGFR2 fusions in phase I:

      2 (50%) achieved PR

      2 (50%) had SD;[PD was seen in the CCA pt with an FGFR1 fusion]
      In phase I safety analysis cohort (n = 18), the most common TEAEs reported were:

      Fatigue (n = 9; 50.0%);

      Hyperphosphatemia (n = 8; 44.4%);

      Anemia (n = 7; 38.9%);

      No grade ≥ 3 AEs related to study drug

      One pt needed dose reduction due to grade 2 nails toxicity

      Ocular toxicity: none reported, and no findings on ocular exams were compatible with retinal detachment
      DerazantinibPivotal phase II study ongoing in pts with iCCA with FGFR2 alterations after ≥ 1 line of ST (FIDES-01; NCT03230318)29 pts with FGFR2-fusion positive iCCA in an open-label phase I/II study; 27 (93%) had prior ST (NCT01752920)
      • Bridgewater J.
      • Galle P.R.
      • Khan S.A.
      • Llovet J.M.
      • Park J.-W.
      • Patel T.
      • et al.
      Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma.
      300 mg QDFrom 29 iCCA pts in phase I/II study:

      20.7% ORR, with 6 confirmed PR from 29 evaluable pts; 82.8% DCR; estimated mPFS 5.7 months (95% CI:4.04–9.2 months)
      In the phase I/II study iCCA pts (n = 29), the most common TEAEs reported were:

      Hyperphosphatemia (n = 22; 75.9%)

      Dry mouth and nausea (n = 13; 44.8%)

      Asthenia, fatigue (n = 10; 34.5%)

      Dysgeusia, vomiting (n = 9; 31.0%)

      Grade 3/4 TRAEs observed in 8 pts (27.6%)

      Ocular toxicity: reported in 12 pts (41%), this included dry eye (5 pts; 17.2%), conjunctivitis (4 pts; 13.8%) blurred vision (3 pts; 10.3%), and photophobia (2 pts; 6.9%); two events were grade 3 (1 each for dry eye and blurred vision)
      ErdafitinibPhase IIb study ongoing as tumour agnostic therapy for advanced solid tumours with FGFR alterations after ≥ 1 line of ST (NCT04083976)Interim results from ongoing phase IIa open-label study in which 17 Asian pts with CCA with FGFR alterations were treated (all had prior ST) (NCT02699606)

      American Cancer Society. Survival Rates for Bile Duct Cancer Where do these numbers come from? 2020. https://www.cancer.org/cancer/bile-duct-cancer/detection-diagnosis-staging/survival-by-stage.html.

      8 mg QD (could be uptitrated to 9 mg QD in phase IIa study)From 17 treated pts, 15 were response evaluable:

      7 (46.7%) achieved PR;

      5 (33.3%) had SD;

      PD was seen in 3 (20.0%) pts;

      ORR was 7/15 (47%) and DCR was 12/15 (80%)
      In the phase IIa study safety analysis cohort (n = 17), the most common TEAEs reported were:

      Hyperphosphatemia (n = 17; 100%);

      Stomatitis (n = 11; 64.7%);

      Dry mouth (n = 10; 58.8%);

      Elevated AST, elevated ALT (n = 7; 41.2%);

      TEAEs led to dose interruption in 16 (94%) and to dose reduction in 8 (47.0%) of the 17 pts

      Ocular toxicity: dry eye (n = 3; 17.6%), no cases were grade ≥ 3
      FutibatinibPivotal phase II study ongoing in iCCA with FGFR2 alterations after ≥ 1 line of ST (FOENIX-CCA2, NCT02052778), interim data reported
      • Banales J.M.
      • Marin J.J.G.
      • Lamarca A.
      • Rodrigues P.M.
      • Khan S.A.
      • Roberts L.R.
      • et al.
      Cholangiocarcinoma 2020: the next horizon in mechanisms and management.
      ;

      Phase III study versus chemotherapy as 1L in iCCA planned (FOENIX-CCA3, NCT04093362)
      Interim analysis from phase II open-label FOENIX-CCA2 study in 67 pts with iCCA with FGFR2 fusions/other rearrangements (all had prior ST)
      • Banales J.M.
      • Marin J.J.G.
      • Lamarca A.
      • Rodrigues P.M.
      • Khan S.A.
      • Roberts L.R.
      • et al.
      Cholangiocarcinoma 2020: the next horizon in mechanisms and management.
      20 mg QD (dose reduction to 16 or 12 mg was permitted to manage TEAEs)From interim analysis of 67 pts with ≥ 6 months of follow-up in FOENIX-CCA2:

      1 (1.5%) achieved CR;

      24 (35.8% achieved PR;

      30 (44.8%) had SD

      ORR was 25/67 (37.3%) and DCR was 55/67 (82.1%)

      mPFS was 7.2 months (95% CI: 4.9 to 15.2)
      In the FOENIX-CCA2 interim analysis cohort (n = 67), the most common TEAEs reported were:

      Hyperphosphatemia (n = 54; 80.6%);

      Diarrhoea (n = 25; 37.3%);

      Dry mouth (n = 22; 32.8%);



      TEAEs led to dose interruption in 37 (55.2%) and to dose reduction in 34 (50.7%) of the 67 pts; 1pt discontinued because of TEAEs

      Ocular toxicity: Central serious retinopathy (n = 6; 9.0%), no cases were Grade ≥ 3
      InfigratinibPhase II study ongoing (NCT02150967), initial results reported

      Administration USF and D. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pemigatinib-cholangiocarcinoma-fgfr2-rearrangement-or-fusion.

      , QED Therapeutics planning to submit NDA for 2L use of infigratinib in CCA to the US FDA;

      Phase III study versus chemotherapy as 1L in CCA ongoing (PROOF, NCT03773302)
      Final results from an ongoing open-label phase II study were reported for 108 pts with iCCA having FGFR2 alterations (all had prior ST)

      Administration USF and D. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pemigatinib-cholangiocarcinoma-fgfr2-rearrangement-or-fusion.

      125 mg QD for 3w Q4WFrom final analysis of 108 iCCA pts with FGFR2 alterations in phase II study:

      Confirmed ORR was 23.0% (95% CI: 15.6–32.2%);

      Median duration of response was 5.0 months (range 0.9–19.1 months)

      mPFS was 7.3 months (95% CI: 5.6–7.6);

      mOS was 12.2 months (95% CI: 10.7–14.9)
      In the phase II final analysis cohort (n = 108), the most common TEAEs reported were:

      Hyperphosphatemia (n = 83; 76.9%)

      Eye disorders excluding CSR/RPED (n = 73; 67.6%)

      Stomatitis (n = 59; 54.6%)

      Fatigue (n = 43; 39.8%)

      Ocular toxicity:CSR/RPED (n = 18, 16.7%), 1 case was grade 3, no cases were grade 4.
      PemigatinibUS FDA approved for previously treated unresectable advanced/metastatic CCA with FGFR2 alterations based on phase II FIGHT-202 results
      • Teven C.M.
      • Farina E.M.
      • Rivas J.
      • Reid R.R.
      Fibroblast growth factor (FGF) signaling in development and skeletal diseases.
      ;

      Phase III study versus chemotherapy as 1L in CCA ongoing (FIGHT-302, NCT03656536)
      Open-label phase II FIGHT-202 study evaluated pemigatinib in 146 pts with CCA, including 107 with FGFR2 fusions or rearrangements (all had prior ST)
      • Teven C.M.
      • Farina E.M.
      • Rivas J.
      • Reid R.R.
      Fibroblast growth factor (FGF) signaling in development and skeletal diseases.
      13.5 mg QD for 2w Q3WFrom 107 pts with FGFR2 fusions or rearrangements in FIGHT-202:

      3 (2.8%) achieved CR;

      35 (32.7%) achieved PR;

      50 (46.7%) achieved SD;

      PD seen in 16 (14.9%) pts;

      ORR was 35.5% (95% CI: 26.5–45.4);

      mPFS

      was 6.9 months (95% CI: 6.2–9.6);



      mOS was 21.1 months (95% CI: 14.8–Not estimable)
      In FIGHT-202, across all 146 pts enrolled, the most common TEAEs reported were:

      Hyperphosphatemia (n = 88; 60.3%)

      Alopecia (n = 72; 49.3%)

      Diarrhoea (n = 69; 47.2%)

      Fatigue (n = 61; 41.8%)

      Dysgeusia (n = 58; 39.7%)

      13 (8.9%) of pts discontinued treatment due to a TEAE;



      20 (13.7%) of pts had TEAEs leading to dose reductions

      Ocular toxicity: dry eye (n = 30, 20.5%), 1 case (0.7%) was grade 3, all others were grade 1 or 2; serious retinal detachment due to subretinal fluid accumulation occurred in 6 pts (4.1%), all events were grade 1 or 2, except for one grade 3 event that was classified as of rhegmatogenous origin and unrelated to treatment
      1L, first-line; 2L, second-line; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CCA, Cholangiocarcinoma; CI, confidence interval; CSR/RPED, central serious retinopathy/retinal pigment epithelial detachment; DCR, disease control rate; mOS, median overall survival; mPFS, median progression-free survival; N.R., not reported; ORR, objective response rate; PD, progressive disease; PR, partial response; Pt/Pts, patient(s); SD, stable disease; ST, systemic therapy; TEAE, treatment-emergent adverse events; US FDA, United States Food and Drug Administration
      Compiled from: 1. Cleary 2020
      • Cleary James M.
      • Iyer Gopa
      • Oh Do-Youn
      • Mellinghoff Ingo K.
      • Goyal Lipika
      • Ng Matthew C.H.
      • et al.
      Final results from the phase I study expansion cohort of the selective FGFR inhibitor Debio 1,347 in patients with solid tumors harboring an FGFR gene fusion.
      ; 2. Mazzaferro 2019
      • Mazzaferro V.
      • El-Rayes B.F.
      • Droz dit Busset M.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • et al.
      Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma.
      ; 3. Park 2019
      • Park Joon Oh
      • Feng Yin-Hsun
      • Chen Yen-Yang
      • Su Wu-Chou
      • Oh Do-Youn
      • Shen Lin
      • et al.
      Updated results of a phase IIa study to evaluate the clinical efficacy and safety of erdafitinib in Asian advanced cholangiocarcinoma (CCA) patients with FGFR alterations.
      ; 4. Goyal 2020
      • Goyal Lipika
      • Meric-Bernstam Funda
      • Hollebecque Antoine
      • Valle Juan W.
      • Morizane Chigusa
      • Karasic Thomas Benjamin
      • et al.
      FOENIX-CCA2: A phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements.
      ; 5. Javle 2021

      Javle, Milind M.; Roychodhury, Sameek; Kelley, Robin Kate; Sadeghi, Saeed; Macarulla, Teresa; Dirk-Thomas, Waldschmidt; Goyal L. Final results from a phase II study of infigratinib (BGJ398), an FGFRselective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement. J Clin Oncol 39: 2021 (Suppl; Abstr 265) 2021;39:66.

      ; 6. Abou-Alfa 2020
      • Abou-Alfa Ghassan K
      • Sahai Vaibhav
      • Hollebecque Antoine
      • Vaccaro Gina
      • Melisi Davide
      • Al-Rajabi Raed
      • et al.
      Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.
      Table 3Target selectivity and binding features of FGFRi.
      CompoundBinding featuresIC50 (nM)Structure
      Debio 1347 (CHF5183284; FF284)Selective FGFR1–3 inhibitor, reversibleFGFR1: 9.3

      FGFR2: 7.6

      FGFR3: 22

      FGFR4: 290
      Derazantinib (ARQ 087)Multikinase inhibitor, reversibleFGFR1: 4.5

      FGFR2: 1.8

      FGFR3: 4.5

      FGFR4: 34
      Erdafitinib (JNJ-42756493)Selective FGFR1–4 inhibitor, reversibleFGFR1: 1.2

      FGFR2: 2.5

      FGFR3: 3.0

      FGFR4: 5.7
      Futibatinib (TAS-120)Selective FGFR1–4 inhibitor, irreversibleFGFR1: 3.9

      FGFR2: 1.3

      FGFR3: 1.6

      FGFR4: 8.3
      Infigratinib (BGJ398)Selective FGFR1–3 inhibitor, reversibleFGFR1: 0.9

      FGFR2: 1.4

      FGFR3: 1.0

      FGFR4: 60.0
      Pemigatinib (INCB054828)Selective FGFR1–3 inhibitor, reversibleFGFR1: 0.4

      FGFR2: 0.5

      FGFR3: 1

      FGFR4: 30
      Adapted from: Dai 2019
      • Dai S.
      • Zhou Z.
      • Chen Z.
      • Xu G.
      • Chen Y.
      Fibroblast Growth Factor Receptors (FGFRs): Structures and Small Molecule Inhibitors.
      ; Guagnano 2011
      • Guagnano Vito
      • Furet Pascal
      • Spanka Carsten
      • Bordas Vincent
      • Le Douget Mickaël
      • Stamm Christelle
      • et al.
      Discovery of 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl- piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), A potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase.
      ; Hall 2016

      Hall TG, Yu Y, Eathiraj S, Wang Y, Savage RE, Lapierre JM, et al. Preclinical activity of ARQ 087, a novel inhibitor targeting FGFR dysregulation. PLoS ONE 2016;11. https://doi.org/10.1371/journal.pone.0162594.

      ; Liu 2020
      • Liu Phillip C.C.
      • Koblish Holly
      • Wu Liangxing
      • Bowman Kevin
      • Diamond Sharon
      • DiMatteo Darlise
      • et al.
      INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models.
      ; Nakanishi 2014
      • Nakanishi Yoshito
      • Akiyama Nukinori
      • Tsukaguchi Toshiyuki
      • Fujii Toshihiko
      • Sakata Kiyoaki
      • Sase Hitoshi
      • et al.
      The Fibroblast Growth Factor Receptor Genetic Status as a Potential Predictor of the Sensitivity to CH5183284/Debio 1347, a Novel Selective FGFR Inhibitor.
      ; Perera 2017
      • Perera T.P.S.
      • Jovcheva E.
      • Mevellec L.
      • Vialard J.
      • de Lange D.
      • Verhulst T.
      • et al.
      Discovery & pharmacological characterization of JNJ-42756493 (Erdafitinib), a functionally selective small-molecule FGFR family inhibitor.
      All of the compounds discussed in the following section and shown in Table 2 and Table 3 bind reversibly to FGFR, with the exception of futibatinib which covalently binds to a highly conserved P-loop cysteine residue in the ATP pocket of FGFR (C492 in the FGFR2-IIIb isoform) [

      Kalyukina M, Yosaatmadja Y, Middleditch MJ, Patterson A v., Smaill JB, Squire CJ. TAS-120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) Irreversible Structure. ChemMedChem 2019;14:494–500. https://doi.org/10.1002/cmdc.201800719.

      ]. The earliest reported data of selective FGFR inhibition in patients with CCA was with the oral agent infigratinib [
      • Javle Milind
      • Lowery Maeve
      • Shroff Rachna T.
      • Weiss Karl Heinz
      • Springfeld Christoph
      • Borad Mitesh J.
      • et al.
      Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma.
      ], while pemigatinib is the first FGFR-targeted agent to gain regulatory approval from the US FDA for use in previously treated patients with iCCA with FGFR2 fusions or rearrangements [

      Administration USF and D. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pemigatinib-cholangiocarcinoma-fgfr2-rearrangement-or-fusion.

      ,
      • Abou-Alfa Ghassan K
      • Sahai Vaibhav
      • Hollebecque Antoine
      • Vaccaro Gina
      • Melisi Davide
      • Al-Rajabi Raed
      • et al.
      Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.
      ]. Note that in the following section, the FGFR-targeted agents of interest are presented and discussed in alphabetical order.

      Debio 1347

      Debio 1347 is an ATP-competitive, oral TKI with high selectivity for FGFR1–3 [
      • Voss Martin H.
      • Hierro Cinta
      • Heist Rebecca S.
      • Cleary James M.
      • Meric-Bernstam Funda
      • Tabernero Josep
      • et al.
      A phase I, open-label, multicenter, dose-escalation study of the oral selective FGFR inhibitor debio 1347 in patients with advanced solid tumors harboring FGFR gene alterations.
      ]. In a first-in-human, open-label study in patients with advanced solid tumours harbouring FGFR13 gene alterations (NCT01948297), 58 patients were treated with
      Debio 1347 at doses from 10 to 150 mg/day. The preliminary efficacy observed in the dose-escalation phase was encouraging, and tolerability acceptable up to 80 mg/day, so this dose was used for the expansion phase of the study [
      • Voss Martin H.
      • Hierro Cinta
      • Heist Rebecca S.
      • Cleary James M.
      • Meric-Bernstam Funda
      • Tabernero Josep
      • et al.
      A phase I, open-label, multicenter, dose-escalation study of the oral selective FGFR inhibitor debio 1347 in patients with advanced solid tumors harboring FGFR gene alterations.
      ]. In the expansion phase, 5 of the 18 patients treated with Debio 1347 had CCA (one patient had an FGFR1 fusion; four patients had an FGFR2 fusion). At the 80 mg once daily (QD) dose, Debio 1347 was generally well tolerated, and in the patients with FGFR2 fusions, two patients had stable disease (SD) and two patients achieved partial response (PR). The patient with an FGFR1 fusion did not respond to treatment and showed progressive disease (PD) [
      • Cleary James M.
      • Iyer Gopa
      • Oh Do-Youn
      • Mellinghoff Ingo K.
      • Goyal Lipika
      • Ng Matthew C.H.
      • et al.
      Final results from the phase I study expansion cohort of the selective FGFR inhibitor Debio 1,347 in patients with solid tumors harboring an FGFR gene fusion.
      ].
      The adaptive phase II, non-controlled, open-label, multicenter FUZE trial (NCT03834220) was designed to evaluate Debio 1347 (80 mg QD) in previously treated FGFR fusion-positive advanced solid tumours, irrespective of the tumour histology. Recruitment for this study started in February 2019 and the trial planned to enroll 125 patients made up of cohorts of patients with BTC cancer, urothelial cancer, and other solid tumour histologies [
      • Hyman David Michael
      • Goyal Lipika
      • Grivas Petros
      • Meric-Bernstam Funda
      • Tabernero Josep
      • Hu Youyou
      • et al.
      FUZE clinical trial: a phase 2 study of Debio 1347 in FGFR fusion-positive advanced solid tumors irrespectively of tumor histology.
      ]. At the time of writing (January 2021), the FUZE trial had completed enrolment of 63 participants and was closed for further enrolment.

      Derazantanib

      Derazantinib is an oral, potent, ATP-competitive, pan-FGFR inhibitor with strong activity against FGFR1–3 kinases [

      Hall TG, Yu Y, Eathiraj S, Wang Y, Savage RE, Lapierre JM, et al. Preclinical activity of ARQ 087, a novel inhibitor targeting FGFR dysregulation. PLoS ONE 2016;11. https://doi.org/10.1371/journal.pone.0162594.

      ]. Derazantinib also inhibits a number of other kinases, including RET, DDR2, VEGFR1, and KIT (IC50 values [nM]: 3, 3.6, 11, and 8.2, respectively) [

      Hall TG, Yu Y, Eathiraj S, Wang Y, Savage RE, Lapierre JM, et al. Preclinical activity of ARQ 087, a novel inhibitor targeting FGFR dysregulation. PLoS ONE 2016;11. https://doi.org/10.1371/journal.pone.0162594.

      ]. A phase I study (NCT01752920) in 80 patients with advanced solid tumours identified 300 mg QD as the recommended phase II dose (RP2D) for derazantinib. A follow-on multicenter, phase I/II, open-label study (NCT01752920) enrolled 29 adult patients with unresectable iCCA with an FGFR2 fusion, who progressed on, were intolerant to, or not eligible for first-line chemotherapy [
      • Mazzaferro V.
      • El-Rayes B.F.
      • Droz dit Busset M.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • et al.
      Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma.
      ]. In this study, treatment with derazantinib
      300 mg QD provided an overall response rate of 20.7% and the DCR was 82.8%.
      Based on the results from the phase I/II study, the pivotal, open-label, single-arm, phase II FIDES-01 (NCT03230318) trial of derazantinib 300 mg QD is now ongoing in previously treated iCCA patients with one cohort for patients with FGFR2 gene fusions and another for patients with FGFR2 mutations or amplifications. Enrolment into the first cohort of
      100 patients in FIDES-01 has been completed [

      Basilea Pharmaceuticals. Basilea announces completion of patient enrolment into first cohort of phase 2 study FIDES-01 with derazantinib in bile duct cancer (iCCA). 2020. https://www.globenewswire.com/news-release/2020/07/20/2064138/0/e…FIDES-01-with-derazantinib-in-bile-duct-cancer-iCCA.html.

      ].

      Erdafitinib

      Erdafitinib (Balversa™) is an orally active small molecule with potent tyrosine kinase inhibitory activity against all four FGFR family members and selectivity versus other highly related kinases [
      • Perera T.P.S.
      • Jovcheva E.
      • Mevellec L.
      • Vialard J.
      • de Lange D.
      • Verhulst T.
      • et al.
      Discovery & pharmacological characterization of JNJ-42756493 (Erdafitinib), a functionally selective small-molecule FGFR family inhibitor.
      ].
      In an open-label phase IIa study conducted in China, Korea and Taiwan (NCT02699606), adults with advanced CCA containing FGFR alterations who had failed at least one prior systemic treatment, received erdafitinib 8 mg QD on a 28-day cycle with the option of pharmacodynamically-guided uptitration to 9 mg QD (the dose could be increased to 9 mg QD if a patient’s serum phosphate level on cycle 1 day 14 was < 5.5 mg/dL, in the absence of significant drug-related toxicity). In interim results from this ongoing study, 15 of the 17 treated Asian patients with advanced CCA and FGFR alterations (10 FGFR2 fusion, 4 FGFR2 mutation, 1 FGFR3 fusion, and 2 FGFR3 mutation) had an evaluable response: 7 (46.7%) achieved PR; 5 (33.3%) had SD; and PD was seen in 3 (20.0%) patients. The objective response rate (ORR) was 7/15 (47%) and the DCR was 12/15 (80%) [
      • Park Joon Oh
      • Feng Yin-Hsun
      • Chen Yen-Yang
      • Su Wu-Chou
      • Oh Do-Youn
      • Shen Lin
      • et al.
      Updated results of a phase IIa study to evaluate the clinical efficacy and safety of erdafitinib in Asian advanced cholangiocarcinoma (CCA) patients with FGFR alterations.
      ].

      Futibatinib

      Futibatinib is an oral, highly selective, irreversible FGFR1-4 inhibitor [

      Ochiiwa H, Fujita H, Itoh K, Sootome H, Hashimoto A, Fujioka Y, et al. Abstract A270: TAS-120, a highly potent and selective irreversible FGFR inhibitor, is effective in tumors harboring various FGFR gene abnormalities., American Association for Cancer Research (AACR); 2013, p. A270–A270. https://doi.org/10.1158/1535-7163.targ-13-a270.

      ,
      • Sootome Hiroshi
      • Fujita Hidenori
      • Ito Kenjiro
      • Ochiiwa Hiroaki
      • Fujioka Yayoi
      • Ito Kimihiro
      • et al.
      Futibatinib is a novel irreversible FGFR 1–4 inhibitor that shows selective antitumor activity against FGFR-deregulated tumors.
      ]. A phase I dose-escalation study (FOENIX-101; NCT02052778) in 86 patients with heavily-pretreated advanced solid tumours identified 20 mg QD as the RP2D. In FOENIX-101, PRs were observed in five patients (5.8%; three patients with FGFR2 fusion-positive iCCA, and two patients with FGFR1-mutated primary brain tumour), and SD in 41 (48%) of the futibatinib-treated patients. Responses were rapid (mostly occurring within 3 months) and lasted for
      >12 months in 2 of the 5 responders, indicating durable clinical benefit [
      • Bahleda R.
      • Meric-Bernstam F.
      • Goyal L.
      • Tran B.
      • He Y.
      • Yamamiya I.
      • et al.
      Phase I, first-in-human study of futibatinib, a highly selective, irreversible FGFR1–4 inhibitor in patients with advanced solid tumors.
      ]. On the basis of the FOENIX-101 dose-escalation study results, futibatinib has been evaluated in the dose-expansion in 45 patients with FGFR2 fusion- or rearrangement-positive CCA and showed an ORR of 25% [
      • Meric-Bernstam F.
      • Arkenau H.
      • Tran B.
      • Bahleda R.
      • Kelley R.
      • Hierro C.
      • et al.
      Efficacy of TAS-120, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in cholangiocarcinoma patients with FGFR pathway alterations who were previously treated with chemotherapy and other FGFR inhibitors.
      ].
      This promising activity in the phase I expansion led to FOENIX-CCA2, an open-label, multicenter phase II registrational trial in patients with iCCA harbouring FGFR2 gene fusions or other rearrangements (NCT02052778). Interim results from the FOENIX-CCA2 study (NCT02052778) were reported after enrolment of 103 patients, who had progressed on previous standard therapies, or for whom standard therapy was not tolerated [
      • Goyal Lipika
      • Meric-Bernstam Funda
      • Hollebecque Antoine
      • Valle Juan W.
      • Morizane Chigusa
      • Karasic Thomas Benjamin
      • et al.
      FOENIX-CCA2: A phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements.
      ]. Among the 67 patients having ≥ 6 months of follow-up included in this analysis for efficacy and safety, the ORR was 37.3% and the DCR was 82.1%. FOENIX-CCA2 has completed enrolment, and updated results from the entire cohort are anticipated in 2021.
      The irreversible binding currently unique to futibatinib may confer an efficacy benefit in specific patients although the data are anecdotal (see below). There appears to be no toxicity difference.

      Infigratinib

      Infigratinib is an oral ATP-competitive FGFR1–3-selective TKI with weaker activity against FGFR4 [
      • Guagnano Vito
      • Furet Pascal
      • Spanka Carsten
      • Bordas Vincent
      • Le Douget Mickaël
      • Stamm Christelle
      • et al.
      Discovery of 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl- piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), A potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase.
      ]. In a multicenter, first-in-human dose-escalation and dose-expansion study (NCT01004224) in 132 patients with advanced solid tumours harbouring FGFR genetic alterations, the RP2D for infigratinib was identified as 125 mg QD given on a 3-weeks-on/1-week-off schedule [

      Nogova L, Sequist L v., Garcia JMP, Andre F, Delord JP, Hidalgo M, et al. Evaluation of BGJ398, a Fibroblast growth factor receptor 1-3 kinase inhibitor, in patientswith advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: Results of a global phase I, dose-escalation and dose-expansion stud. Journal of Clinical Oncology 2017;35:157–65. https://doi.org/10.1200/JCO.2016.67.2048.

      ].
      Final results from an ongoing, multicenter, single-arm, phase II study (NCT02150967) of infigratinib in previously-treated patients with advanced or metastatic CCA having FGFR genetic alterations have been reported [

      Javle, Milind M.; Roychodhury, Sameek; Kelley, Robin Kate; Sadeghi, Saeed; Macarulla, Teresa; Dirk-Thomas, Waldschmidt; Goyal L. Final results from a phase II study of infigratinib (BGJ398), an FGFRselective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement. J Clin Oncol 39: 2021 (Suppl; Abstr 265) 2021;39:66.

      ]. Among 108 patients with FGFR2 fusion/rearrangement, the confirmed ORR was 23.1% (95% CI: 15.6–32.2%). The median duration of response was 5.0 months (range 0.9–19.1 months) and the median PFS was 7.3 months (95% CI: 5.6–7.6 months).

      Pemigatinib

      Pemigatinib (Pemazyre™) is an oral selective inhibitor of FGFR1–3, with weaker activity against FGFR4 [
      • Liu Phillip C.C.
      • Koblish Holly
      • Wu Liangxing
      • Bowman Kevin
      • Diamond Sharon
      • DiMatteo Darlise
      • et al.
      INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models.
      ]. In April 2020, the US FDA approved pemigatinib as the first targeted drug for patients with refractory advanced CCA with an FGFR2 fusion or rearrangement [

      Administration USF and D. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pemigatinib-cholangiocarcinoma-fgfr2-rearrangement-or-fusion.

      ].
      The dose-escalation part of the multicenter, open-label phase I/II, FIGHT-101 study (NCT02393248) of pemigatinib in patients with refractory advanced malignancies with or without FGF/FGFR alteration identified 13.5 mg QD on days 1 to 14 of each 21-day cycle as the RP2D for pemigatinib [

      Subbiah V, Barve M, Iannotti NO, Gutierrez M, Smith DC, Roychowdhury S, et al. Abstract A078: FIGHT-101: A phase 1/2 study of pemigatinib, a highly selective fibroblast growth factor receptor (FGFR) inhibitor, as monotherapy and as combination therapy in patients with advanced malignancies, American Association for Cancer Research (AACR); 2019, p. A078–A078. https://doi.org/10.1158/1535-7163.targ-19-a078.

      ]. This dose was used in the pivotal, multicenter, open-label, single-arm, multicohort, phase II FIGHT-202 (NCT02924376) study [
      • Abou-Alfa Ghassan K
      • Sahai Vaibhav
      • Hollebecque Antoine
      • Vaccaro Gina
      • Melisi Davide
      • Al-Rajabi Raed
      • et al.
      Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.
      ].
      In FIGHT-202, 146 enrolled patients were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements (N = 107), patients with other FGF/FGFR alterations (N = 20), or patients with no FGF/FGFR alterations (N = 18) [
      • Abou-Alfa Ghassan K
      • Sahai Vaibhav
      • Hollebecque Antoine
      • Vaccaro Gina
      • Melisi Davide
      • Al-Rajabi Raed
      • et al.
      Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.
      ]. The primary endpoint was centrally-assessed ORR among those with FGFR2 fusions or rearrangements. After a median follow-up of 17.8 months, 38 (35.5%) of patients with FGFR2 fusions or rearrangements achieved an objective response (3 had complete responses, 35 had PRs). The median duration of response was 7.5 months, with responses lasting ≥ 6 months in 68% of responding patients and ≥ 12 months in 37% of patients.

      Recognized toxicities of FGFR inhibitors

      Toxicities of FGFR inhibitors are very similar, with little to differentiate between them. They are, as a class, very well tolerated and although there are no direct comparisons, are likely to confer a significant improvement in quality of life compared to systemic chemotherapy.
      Hyperphosphatemia: Increased phosphate levels are a pharmacodynamic effect of all FGFR inhibitors, with hyperphosphatemia reported in 55%–81% of patients with CCA and FGFR alterations in clinical trials [
      • Javle Milind
      • Lowery Maeve
      • Shroff Rachna T.
      • Weiss Karl Heinz
      • Springfeld Christoph
      • Borad Mitesh J.
      • et al.
      Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma.
      ,
      • Abou-Alfa Ghassan K
      • Sahai Vaibhav
      • Hollebecque Antoine
      • Vaccaro Gina
      • Melisi Davide
      • Al-Rajabi Raed
      • et al.
      Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.
      ,
      • Goyal Lipika
      • Meric-Bernstam Funda
      • Hollebecque Antoine
      • Valle Juan W.
      • Morizane Chigusa
      • Karasic Thomas Benjamin
      • et al.
      FOENIX-CCA2: A phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements.
      ]. Fibroblast growth factor 23 (FGF23) plays an important role in phosphate homeostasis [
      • Perwad Farzana
      • Zhang Martin Y.H.
      • Tenenhouse Harriet S.
      • Portale Anthony A.
      Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1α-hydroxylase expression in vitro. American Journal of Physiology -.
      ,
      • Degirolamo Chiara
      • Sabbà Carlo
      • Moschetta Antonio
      Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23.
      ] and FGFR1 is the predominant receptor for the hypophosphatemic action of FGF23 in vivo [
      • Gattineni J.
      • Bates C.
      • Twombley K.
      • Dwarakanath V.
      • Robinson M.L.
      • Goetz R.
      • et al.
      FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1.
      ]. If FGFR inhibitors disrupt interactions between FGF23 and FGFR1, this may impair the phosphate-lowering activities of FGF23, which include inhibiting phosphate absorption in the intestine and reducing phosphate reabsorption in the kidney [
      • Xie Yangli
      • Su Nan
      • Yang Jing
      • Tan Qiaoyan
      • Huang Shuo
      • Jin Min
      • et al.
      FGF/FGFR signaling in health and disease. Signal Transduction and Targeted.
      ].
      For patients who develop hyperphosphatemia while being treated with an FGFR inhibitor, phosphate-lowering therapy using phosphate binding agents and a low phosphate diet should be considered (Table 4).
      Table 4Recommendations for hyperphosphatemia management during FGFR inhibitor therapy.
      Serum phosphorus resultGradeAction
      ULN < P < 1.78 mmol/L [ULN < P < 5.51 mg/dL]1Low phosphate diet
      1.78 ≤ P ≤ 2.26 (mmol/L)

      [5.51 ≤ P ≤ 7.00 (mg/dL)]
      2Low phosphate diet

      Sevelamer monotherapy (range from 800 mg TID to 2400 mg TID)

      Acetazolamide 250 mg QD or TID

      Lanthanum carbonate 1.0 g QD or TID
      2.26 < P ≤ 3.23 (mmol/L)

      [7.00 < P ≤ 10.00 (mg/dL)]
      3Interrupt dosing until grade 2

      Dose reduction (1–2 levels) until grade 2
      P > 3.23 mmol/L

      [P > 10 mg/dL]
      4Interrupt dosing until grade 2

      Dose reduction (1–2 levels) until grade 2
      P, serum phosphorus; TID, three times daily; QD, once daily; ULN, upper limit of normal;
      Ophthalmologic toxicity: Retinal toxicities such as retinal pigment epithelial detachment (RPED) and central serous retinopathy (CSR) may cause symptoms such as blurred vision, visual floaters, or photopsia, and CSR is often asymptomatic. RPED and CSR occur in ~ 4% [
      • Abou-Alfa Ghassan K
      • Sahai Vaibhav
      • Hollebecque Antoine
      • Vaccaro Gina
      • Melisi Davide
      • Al-Rajabi Raed
      • et al.
      Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.
      ] and ~ 9% [
      • Goyal Lipika
      • Meric-Bernstam Funda
      • Hollebecque Antoine
      • Valle Juan W.
      • Morizane Chigusa
      • Karasic Thomas Benjamin
      • et al.
      FOENIX-CCA2: A phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements.
      ], respectively, in patients with CCA treated with FGFR inhibitors, and these are generally grade 1 or 2. Comprehensive ophthalmological examination including optical coherence tomography (OCT) is therefore recommended before initiating all FGFR inhibitors and regularly during treatment. If visual symptoms are significant, patients should modify the dose, or discontinue the FGFR inhibitor as recommended; if mild or asymptomatic, patients can often be rechallenged with the same dose with a plan for dose modification if the symptoms recur. In clinical studies, dry eye occurred in 19–21% of patients with CCA treated with FGFR inhibitors [
      • Javle Milind
      • Lowery Maeve
      • Shroff Rachna T.
      • Weiss Karl Heinz
      • Springfeld Christoph
      • Borad Mitesh J.
      • et al.
      Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma.
      ,
      • Abou-Alfa Ghassan K
      • Sahai Vaibhav
      • Hollebecque Antoine
      • Vaccaro Gina
      • Melisi Davide
      • Al-Rajabi Raed
      • et al.
      Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.
      ,
      • Goyal Lipika
      • Meric-Bernstam Funda
      • Hollebecque Antoine
      • Valle Juan W.
      • Morizane Chigusa
      • Karasic Thomas Benjamin
      • et al.
      FOENIX-CCA2: A phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements.
      ]. Other eye toxicities reported with FGFR inhibitors include blepharitis, cataract development, increased lacrimation, trichiasis, trichomegaly, and blurred vision.
      Nail toxicity: Nail toxicities also occur on FGFR inhibitors, especially with increased duration on treatment; most are grade 1 and 2, and grade 3 nail toxicity rarely occurs. Onycholysis, the painless detachment of the nail from the nail bed, occurs in 5–7% of patients [
      • Javle Milind
      • Lowery Maeve
      • Shroff Rachna T.
      • Weiss Karl Heinz
      • Springfeld Christoph
      • Borad Mitesh J.
      • et al.
      Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma.
      ,
      • Abou-Alfa Ghassan K
      • Sahai Vaibhav
      • Hollebecque Antoine
      • Vaccaro Gina
      • Melisi Davide
      • Al-Rajabi Raed
      • et al.
      Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.
      ]. Paronychia, an often tender bacterial or fungal infection that develops at the nailbed, occurs in 5–7% of patients [
      • Javle Milind
      • Lowery Maeve
      • Shroff Rachna T.
      • Weiss Karl Heinz
      • Springfeld Christoph
      • Borad Mitesh J.
      • et al.
      Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma.
      ,
      • Abou-Alfa Ghassan K
      • Sahai Vaibhav
      • Hollebecque Antoine
      • Vaccaro Gina
      • Melisi Davide
      • Al-Rajabi Raed
      • et al.
      Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.
      ]. Other nail toxicities reported with FGFR inhibitors include nail discoloration, nail disorder, nail dystrophy, nail hypertrophy, nail infection, onychalgia, and paronychia [
      • Javle Milind
      • Lowery Maeve
      • Shroff Rachna T.
      • Weiss Karl Heinz
      • Springfeld Christoph
      • Borad Mitesh J.
      • et al.
      Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma.
      ,
      • Abou-Alfa Ghassan K
      • Sahai Vaibhav
      • Hollebecque Antoine
      • Vaccaro Gina
      • Melisi Davide
      • Al-Rajabi Raed
      • et al.
      Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.
      ,
      • Goyal Lipika
      • Meric-Bernstam Funda
      • Hollebecque Antoine
      • Valle Juan W.
      • Morizane Chigusa
      • Karasic Thomas Benjamin
      • et al.
      FOENIX-CCA2: A phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements.
      ].

      Future directions in targeting FGFR in iCCA

      Resistance to FGFR kinase inhibitors in iCCA treatment

      Primary and acquired resistance limits the efficacy of FGFR inhibitors, similar to other TKIs in oncogene-driven cancers [
      • Zhou Yangyang
      • Wu Chengyu
      • Lu Guangrong
      • Hu Zijing
      • Chen Qiuxiang
      • Du Xiaojing
      FGF/FGFR signaling pathway involved resistance in various cancer types.
      ].
      With respect to primary resistance, Silverman and colleagues describe a tendency towards a shorter progression-free survival amongst FGFR fusion patients with co-occurring tumour suppressor gene alterations including BAP1, CDKN2A/B, PBRM1 and TP53, although the numbers of patients do not allow any significant conclusions [
      • Silverman Ian M.
      • Hollebecque Antoine
      • Friboulet Luc
      • Owens Sherry
      • Newton Robert C.
      • Zhen Huiling
      • et al.
      Clinicogenomic Analysis of FGFR2 -Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib.
      ]. Assembly of datasets as we have greater clinical experience will be critical in describing the optimal genomic environment to predict benefit from treatment.
      With respect to acquired resistance, Goyal and colleagues reported the first evidence of clinically-acquired resistance to a selective FGFR inhibitor in three patients with FGFR2 fusion-positive iCCA treated with infigratinib [
      • Goyal Lipika
      • Saha Supriya K.
      • Liu Leah Y.
      • Siravegna Giulia
      • Leshchiner Ignaty
      • Ahronian Leanne G.
      • et al.
      Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma.
      ]. All three patients developed the FGFR2 V565F gatekeeper mutation, and two patients developed polyclonal secondary mutations in the FGFR2 kinase domain with a total of 5 FGFR2 mutations each. This study also demonstrated, as have other studies [
      • Krook Melanie A.
      • Lenyo Alexandria
      • Wilberding Max
      • Barker Hannah
      • Dantuono Mikayla
      • Bailey Kelly M.
      • et al.
      Efficacy of FGFR inhibitors and combination therapies for acquired resistance in FGFR2-fusion cholangiocarcinoma.
      ], that circulating tumour DNA (ctDNA) analysis captured more putative resistance mechanisms than single tumour biopsy alone, suggesting that tumour heterogeneity may play a role in resistance and the commonly seen mixed responses on FGFR inhibitors. Rapid autopsy studies in patients with FGFR2 fusion-positive iCCA treated with selective ATP-competitive FGFR inhibitors have confirmed that different resistant subclones evolve in different metastatic nodules [
      • Goyal Lipika
      • Saha Supriya K.
      • Liu Leah Y.
      • Siravegna Giulia
      • Leshchiner Ignaty
      • Ahronian Leanne G.
      • et al.
      Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma.
      ,
      • Krook Melanie A.
      • Bonneville Russell
      • Chen Hui-Zi
      • Reeser Julie W.
      • Wing Michele R.
      • Martin Dorrelyn M.
      • et al.
      Tumor heterogeneity and acquired drug resistance in FGFR2-fusion-positive cholangiocarcinoma through rapid research autopsy.
      ], including the finding of two FGFR2 mutant subclones in the same nodule. It is clear that single tumour sampling by biopsy or even multi-tumour sampling by autopsy may not capture the full spectrum of FGFR2 kinase domain mutations identified on ctDNA analysis, and thus serial ctDNA analysis can provide useful complementary information about FGFR resistance mechanisms. Additionally, the success of next generation FGFR inhibitors depends on their ability to overcome multiple FGFR2 mutations in the kinase domain.
      Unlike other extant inhibitors, futibatinib binds covalently to FGFR, and preclinical studies demonstrate that it has strong potency against multiple FGFR2 kinase domain mutations. Goyal and colleagues showed in a proof-of-concept study in four patients with FGFR2 fusion-positive iCCA that sequential treatment with futibatinib after progression on the ATP-competitive inhibitors infigratinib or Debio 1347 led to prolonged clinical benefit from FGFR inhibition [
      • Goyal L.
      • Shi L.
      • Liu L.Y.
      • Fece de la Cruz F.
      • Lennerz J.K.
      • Raghavan S.
      • et al.
      TAS-120 overcomes resistance to atp-competitive FGFR inhibitors in patients with FGFR2 fusion–positive intrahepatic cholangiocarcinoma.
      ]. Among these four patients, two patients had a PR on futibatinib, and they stayed on drug for 16 and 17 additional months beyond their first FGFR inhibitor. Furthermore, in silico structural modelling suggested that futibatinib retained activity against several mutations that conferred infigratinib or Debio 1347 resistance by altering conformational dynamics of FGFR2, rather than directly interacting with mutated residues. In iCCA cell line models, each containing one of nine clinically observed secondary FGFR2 kinase domain mutations, several of these mutations conferred resistance to infigratinib and Debio 1347, whereas futibatinib remained active against all mutations, except the FGFR2 V565F gatekeeper mutation. Additionally, Debio 1347 showed reduced potency against most mutants, but remained relatively active against V565F compared to infigratinib and futibatinib. These results highlight the critical role of serial biopsy and ctDNA analysis to identify resistance mechanisms; this can guide selection of the next FGFR inhibitor for patients currently in the clinic, and also guide the development of the next generation of FGFR inhibitors beyond futibatinib. This study also showed that such a guided approach is feasible and effective in prolonging benefit for patients from FGFR inhibition in these FGFR-dependent tumours [
      • Goyal L.
      • Shi L.
      • Liu L.Y.
      • Fece de la Cruz F.
      • Lennerz J.K.
      • Raghavan S.
      • et al.
      TAS-120 overcomes resistance to atp-competitive FGFR inhibitors in patients with FGFR2 fusion–positive intrahepatic cholangiocarcinoma.
      ].
      Beyond the development of more effective FGFR inhibitors, combination strategies may also improve outcomes for patients with FGFR resistance in the setting of upregulation of alternative pathways in FGFR. Krook and colleagues showed via proteomic analysis of FGFR2 pE565A mutant cells that the PI3K/AKT pathway was potentiated compared to non-mutant cells and that the mTOR pathway was activated [
      • Krook Melanie A.
      • Lenyo Alexandria
      • Wilberding Max
      • Barker Hannah
      • Dantuono Mikayla
      • Bailey Kelly M.
      • et al.
      Efficacy of FGFR inhibitors and combination therapies for acquired resistance in FGFR2-fusion cholangiocarcinoma.
      ]. Combination treatment combining an FGFR inhibitor with an mTOR inhibitor showed synergistic effects in mutant cells. These types of preclinical studies are key to understanding FGFR biology and evaluating therapeutic strategies in models to aid in designing combination clinical trials for patients.

      Confirmatory trials and evaluation of FGFR targeting in first-line in iCCA

      Several large phase III randomized controlled trials are now underway or being planned to evaluate the efficacy of FGFR kinase inhibitors compared to gemcitabine plus cisplatin in the first-line treatment of FGFR2 fusion- or rearrangement-positive CCA. For example, the phase III PROOF trial (NCT03773302) for infigratinib, and the phase III FIGHT-302 (NCT03656536) trial for pemigatinib are currently recruiting, while a similar study for futibatinib, FOENIX-CCA3 (NCT04093362) is preparing to open for enrolment. Accrual to these trials has been slow given this is a biomarker-driven frontline strategy in a subgroup of an uncommon cancer.

      Incorporation of molecular testing within iCCA algorithm

      The approval of FGFR kinase inhibitors and the emergence of first line trials with these agents require the wider and potentially earlier ordering of molecular testing in iCCA. As discussed previously, the number of potentially actionable targets in iCCA is growing (e.g. FGFR fusions, IDH1/2 mutations, NTRK fusions), so the National Comprehensive Cancer Network (NCCN) recommends consideration of molecular testing for patients with unresectable and metastatic CCA [

      NCCN Guidelines Version 2.2020 Hepatobiliary Cancers. 2020. https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf.

      ].
      The European Society for Medical Oncology (ESMO) Precision Medicine Working Group has recommended that tumour multigene next generation sequencing (NGS) could be used to assess level I actionable alterations in advanced CCAs based on the ESMO Scale for Actionability of molecular Targets (ESCAT) criteria. Larger panels can be used only on the basis of specific agreements with payers taking into account the overall cost of the strategy (drug included), and if they report accurate ranking of alterations. RNA-based NGS can be used [
      • Mosele F.
      • Remon J.
      • Mateo J.
      • Westphalen C.B.
      • Barlesi F.
      • Lolkema M.P.
      • et al.
      Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group.
      ].
      In the UK, genomic testing in the National Health Service (NHS) will be incorporated into the Genomic Laboratory Hubs of which there will be seven in the country. As targeted therapies, specifically FGFR inhibitors for iCCA, requiring genomic description become approved for standard of care, these centres will undertake standard of care profiling.

      Combining FGFR inhibition with other therapy approaches

      Although the clinical use of FGFR kinase inhibitors as monotherapy is still in an early stage, future trial results may support combination strategies using FGFRis with standard of care drug therapy options in solid tumours (see Supplemental information online, Table S1 for a listing of current studies). For example, Debio 1347 (NCT03344536), erdafitinib (NCT03238196), futibatinib (NCT04024436), and infigratinib (NCT04504331) are each being evaluated in combination with the hormonal therapy drug fulvestrant for hormone receptor positive, HER-2 negative metastatic breast cancer having FGFR genetic alterations.
      Combinations of FGFRis with immune checkpoint inhibitors of programmed death ligand 1 (PD-L1) are being evaluated in patients with urothelial cancer having FGFR2 genetic alterations (derazantinib plus atezolizumab: FIDES02 study, NCT04045613; futibatinib plus pembrolizumab, NCT04601857; and pemigatinib plus pembrolizumab, FIGHT-205 study, NCT04003610). Such trials will provide insights on whether targeting non-FGFR pathways involved in tumour growth and/or immune evasion in combination with FGFRi treatment improves outcomes over FGFRi monotherapy.

      Patient and provider education

      Given the demonstrated promise of FGFR inhibitors in clinical trials, patients and their caregivers are also closely following developments in this area. Fig. 2 illustrates the multiple issues that physicians and patients must address when considering targeted therapy. Various barriers remain, for instance the availability of material, the accuracy and funding of the test, the availability and funding of the therapy, and finally, the toxicity and efficacy of the treatment. Despite these obstacles, the potential advantages of oral therapies are evident. In addition to being an option a non-fusion patient would not receive, there would appear to be clear advantages of the FGFR inhibitors over chemotherapy with respect to toxicity, efficacy and quality of life, although data have yet to be generated. The increased complexity consequent on testing for FGFR alterations and treating with FGFR inhibitors does have resource implications that need to be addressed and acknowledged.

      Conclusions

      After a decade of chemotherapy being the only standard option for patients with advanced CCA, 2020 saw the first approval of a targeted therapy for this disease, ushering in the era of precision medicine in BTC. Since the discovery of FGFR2 fusions in iCCA in 2013, multiple selective FGFR TKIs have been evaluated in clinical trials for patients with advanced refractory CCA harbouring an FGFR2 fusion or rearrangement, and pemigatinib was the first to gain regulatory approval in April 2020. The response rate to the FGFR inhibitors is 20–37% and the mPFS is 6 to 8 months in this population, and this is welcome efficacy compared to the efficacy of chemotherapy in an unselected population. This discovery highlights the importance of molecular profiling for all patients with iCCA and also shows that understanding the biological underpinnings of cholangiocarcinogenesis can successfully lead to therapeutic breakthroughs. While the efficacy of FGFR inhibitors is encouraging, the response rates and durations of response fall short of those traditionally seen in other oncogene-addicted tumours such as EGFR- or ALK-driven lung cancer. We have learned that acquired resistance in the form of polyclonal FGFR2 kinase domain mutations shortens the duration of benefit and that serial biopsy and ctDNA analysis can help identify mechanisms of resistance and guide the sequential use of FGFR inhibitors. Ultimately, to expand and prolong the benefit of FGFR inhibition for patients, we need to better understand both primary and secondary resistance and develop combination and next generation inhibitors that can delay or overcome resistance. In a historically difficult-to-treat disease, the approval of a targeted therapy represents an important milestone that paves the way for additional personalized medicine approaches in CCA.
      Declaration of Competing Interest
      Dr. Bridgewater reports personal fees from Taiho, Merck-Serono, BMS, Roche, Bayer, and Servier outside the submitted work.
      Dr. Kongpetch reports grants from the Cholangiocarcinoma Screening and Care Program (CASCAP020), and grants from the Thailand Research Fund (MRG6180079) outside the submitted work.
      Dr. Goyal reports personal fees from Agios Pharmaceuticals, Alentis Therapeutics AG, AstraZeneca, Debiopharm Group, H3 Biomedicine, Incyte Pharmaceuticals, SIRTEX, Taiho Pharmaceuticals, and QED therapeutics, outside the submitted work.
      Dr. Crolley declares no conflicts of interest that pertain to this work.
      Financial support
      Medical writing and editorial assistance were provided by Patrick Foley, PhD, of NexGen Healthcare (London, UK) and funded by Taiho Oncology, Inc.
      Authors’ contributions
      Drafting of the manuscript, revision of the manuscript, and approval of the final version of the manuscript: JB, LG, SK and VEC.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

      References

        • Guest R.V.
        • Boulter L.
        • Kendall T.J.
        • Minnis-Lyons S.E.
        • Walker R.
        • Wigmore S.J.
        • et al.
        Cell lineage tracing reveals a biliary origin of intrahepatic cholangiocarcinoma.
        Cancer Res. 2014; 74: 1005-1010https://doi.org/10.1158/0008-5472.CAN-13-1911
        • Bridgewater J.
        • Galle P.R.
        • Khan S.A.
        • Llovet J.M.
        • Park J.-W.
        • Patel T.
        • et al.
        Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma.
        J Hepatol. 2014; 60: 1268-1289https://doi.org/10.1016/j.jhep.2014.01.021
      1. American Cancer Society. Survival Rates for Bile Duct Cancer Where do these numbers come from? 2020. https://www.cancer.org/cancer/bile-duct-cancer/detection-diagnosis-staging/survival-by-stage.html.

        • Banales J.M.
        • Marin J.J.G.
        • Lamarca A.
        • Rodrigues P.M.
        • Khan S.A.
        • Roberts L.R.
        • et al.
        Cholangiocarcinoma 2020: the next horizon in mechanisms and management.
        Nat Rev Gastroenterol Hepatol. 2020; 17: 557-588https://doi.org/10.1038/s41575-020-0310-z
      2. Administration USF and D. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pemigatinib-cholangiocarcinoma-fgfr2-rearrangement-or-fusion.

        • Teven C.M.
        • Farina E.M.
        • Rivas J.
        • Reid R.R.
        Fibroblast growth factor (FGF) signaling in development and skeletal diseases.
        Genes and Diseases. 2014; 1: 199-213https://doi.org/10.1016/j.gendis.2014.09.005
        • Touat M.
        • Ileana E.
        • Postel-Vinay S.
        • André F.
        • Soria J.-C.
        Targeting FGFR signaling in cancer.
        Clin Cancer Res. 2015; 21: 2684-2694https://doi.org/10.1158/1078-0432.CCR-14-2329
        • Helsten T.
        • Elkin S.
        • Arthur E.
        • Tomson B.N.
        • Carter J.
        • Kurzrock R.
        The FGFR landscape in cancer: Analysis of 4,853 tumors by next-generation sequencing.
        Clin Cancer Res. 2016; 22: 259-267https://doi.org/10.1158/1078-0432.CCR-14-3212
        • Presta M.
        • Chiodelli P.
        • Giacomini A.
        • Rusnati M.
        • Ronca R.
        Fibroblast growth factors (FGFs) in cancer: FGF traps as a new therapeutic approach.
        Pharmacol Ther. 2017; 179: 171-187https://doi.org/10.1016/j.pharmthera.2017.05.013
        • Turner N.
        • Grose R.
        Fibroblast growth factor signalling: From development to cancer.
        Nat Rev Cancer. 2010; 10: 116-129https://doi.org/10.1038/nrc2780
        • Eswarakumar V.P.
        • Lax I.
        • Schlessinger J.
        Cellular signaling by fibroblast growth factor receptors.
        Cytokine Growth Factor Rev. 2005; 16: 139-149https://doi.org/10.1016/j.cytogfr.2005.01.001
        • Nakamura H.
        • Arai Y.
        • Totoki Y.
        • Shirota T.
        • Elzawahry A.
        • Kato M.
        • et al.
        Genomic spectra of biliary tract cancer.
        Nat Genet. 2015; 47: 1003-1010https://doi.org/10.1038/ng.3375
        • Jusakul A.
        • Cutcutache I.
        • Yong C.H.
        • Lim J.Q.
        • Huang M.N.
        • Padmanabhan N.
        • et al.
        Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma.
        Cancer Discovery. 2017; 7: 1116-1135https://doi.org/10.1158/2159-8290.CD-17-0368
        • Lowery M.A.
        • Ptashkin R.
        • Jordan E.
        • Berger M.F.
        • Zehir A.
        • Capanu M.
        • et al.
        Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: Potential targets for intervention.
        Clin Cancer Res. 2018; 24: 4154-4161https://doi.org/10.1158/1078-0432.CCR-18-0078
        • Javle M.
        • Zhao H.
        • Abou-Alfa G.K.
        Systemic therapy for gallbladder cancer.
        Chinese Clinical Oncology. 2019; 8: 44
        • Chan-on W.
        • Nairismägi M.-L.
        • Ong C.K.
        • Lim W.K.
        • Dima S.
        • Pairojkul C.
        • et al.
        Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers.
        Nat Genet. 2013; 45: 1474-1478https://doi.org/10.1038/ng.2806
        • Jiao Y.
        • Pawlik T.M.
        • Anders R.A.
        • Selaru F.M.
        • Streppel M.M.
        • Lucas D.J.
        • et al.
        Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas.
        Nat Genet. 2013; 45: 1470-1473https://doi.org/10.1038/ng.2813
      3. Sekiya S, Suzuki A. Brief report Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes. The Journal of Clinical Investigation 2012;122. https://doi.org/10.1172/JCI63065DS1.

        • Wu Y.-M.
        • Su F.
        • Kalyana-Sundaram S.
        • Khazanov N.
        • Ateeq B.
        • Cao X.
        • et al.
        Identification of targetable FGFR gene fusions in diverse cancers.
        Cancer Discovery. 2013; 3: 636-647https://doi.org/10.1158/2159-8290.CD-13-0050
        • Arai Y.
        • Totoki Y.
        • Hosoda F.
        • Shirota T.
        • Hama N.
        • Nakamura H.
        • et al.
        Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma.
        Hepatology. 2014; 59: 1427-1434https://doi.org/10.1002/hep.26890
      4. Borad MJ, Champion MD, Egan JB, Liang WS, Fonseca R, Bryce AH, et al. Integrated Genomic Characterization Reveals Novel, Therapeutically Relevant Drug Targets in FGFR and EGFR Pathways in Sporadic Intrahepatic Cholangiocarcinoma. PLoS Genetics 2014;10. https://doi.org/10.1371/journal.pgen.1004135.

        • Borger D.R.
        • Tanabe K.K.
        • Fan K.C.
        • Lopez H.U.
        • Fantin V.R.
        • Straley K.S.
        • et al.
        Frequent Mutation of Isocitrate Dehydrogenase (IDH)1 and IDH2 in Cholangiocarcinoma Identified Through Broad-Based Tumor Genotyping.
        Oncologist. 2012; 17: 72-79https://doi.org/10.1634/theoncologist.2011-0386
        • Drilon A.
        • Laetsch T.W.
        • Kummar S.
        • DuBois S.G.
        • Lassen U.N.
        • Demetri G.D.
        • et al.
        Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children.
        N Engl J Med. 2018; 378: 731-739https://doi.org/10.1056/NEJMoa1714448
        • Marabelle A.
        • Le D.T.
        • Ascierto P.A.
        • Di Giacomo A.M.
        • De Jesus-Acosta A.
        • Delord J.-P.
        • et al.
        Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.
        J Clin Oncol. 2020; 38: 1-10https://doi.org/10.1200/JCO.19.02105
        • Ross J.S.
        • Wang K.
        • Gay L.
        • Al‐Rohil R.
        • Rand J.V.
        • Jones D.M.
        • et al.
        New Routes to Targeted Therapy of Intrahepatic Cholangiocarcinomas Revealed by Next-Generation Sequencing.
        Oncologist. 2014; 19: 235-242https://doi.org/10.1634/theoncologist.2013-0352
        • Farshidfar F.
        • Zheng S.
        • Gingras M.-C.
        • Newton Y.
        • Shih J.
        • Robertson A.G.
        • et al.
        Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.
        Cell Reports. 2017; 18: 2780-2794https://doi.org/10.1016/j.celrep.2017.02.033
        • Jain A.
        • Borad M.J.
        • Kelley R.K.
        • Wang Y.
        • Abdel-Wahab R.
        • Meric-Bernstam F.
        • et al.
        Cholangiocarcinoma With FGFR Genetic Aberrations: A Unique Clinical Phenotype.
        JCO Precision Oncology. 2018; : 1-12https://doi.org/10.1200/PO.17.00080
        • Kongpetch S.
        • Jusakul A.
        • Lim J.Q.
        • Ng C.C.Y.
        • Chan J.Y.
        • Rajasegaran V.
        • et al.
        Lack of Targetable FGFR2 Fusions in Endemic Fluke-Associated Cholangiocarcinoma.
        JCO Global Oncology. 2020; : 628-638https://doi.org/10.1200/GO.20.00030
        • Sia D.
        • Losic B.
        • Moeini A.
        • Cabellos L.
        • Hao K.e.
        • Revill K.
        • et al.
        Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. Nature.
        Communications. 2015; 6https://doi.org/10.1038/ncomms7087
        • Goyal L.
        • Shi L.
        • Liu L.Y.
        • Fece de la Cruz F.
        • Lennerz J.K.
        • Raghavan S.
        • et al.
        TAS-120 overcomes resistance to atp-competitive FGFR inhibitors in patients with FGFR2 fusion–positive intrahepatic cholangiocarcinoma.
        Cancer Discovery. 2019; 9: 1064-1079https://doi.org/10.1158/2159-8290.CD-19-0182
        • Graham R.P.
        • Barr Fritcher E.G.
        • Pestova E.
        • Schulz J.
        • Sitailo L.A.
        • Vasmatzis G.
        • et al.
        Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma.
        Hum Pathol. 2014; 45: 1630-1638https://doi.org/10.1016/j.humpath.2014.03.014
        • Chen X.-X.
        • Yin Y.
        • Cheng J.-W.
        • Huang A.o.
        • Hu B.o.
        • Zhang X.
        • et al.
        BAP1 acts as a tumor suppressor in intrahepatic cholangiocarcinoma by modulating the ERK1/2 and JNK/c-Jun pathways.
        Cell Death Dis. 2018; 9https://doi.org/10.1038/s41419-018-1087-7
        • Khan S.A.
        • Tavolari S.
        • Brandi G.
        Cholangiocarcinoma: Epidemiology and risk factors.
        Liver International. 2019; 39: 19-31https://doi.org/10.1111/liv.2019.39.issue-S110.1111/liv.14095
        • Florio A.A.
        • Ferlay J.
        • Znaor A.
        • Ruggieri D.
        • Alvarez C.S.
        • Laversanne M.
        • et al.
        Global trends in intrahepatic and extrahepatic cholangiocarcinoma incidence from 1993 to 2012.
        Cancer. 2020; 126: 2666-2678https://doi.org/10.1002/cncr.32803
        • Saha S.K.
        • Zhu A.X.
        • Fuchs C.S.
        • Brooks G.A.
        Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise.
        Oncologist. 2016; 21: 594-599https://doi.org/10.1634/theoncologist.2015-0446
        • Jusakul A.
        • Kongpetch S.
        • Teh B.T.
        Genetics of Opisthorchis viverrini -related cholangiocarcinoma.
        Current Opinion in Gastroenterology. 2015; 31: 258-263https://doi.org/10.1097/MOG.0000000000000162
        • Feng X.
        • Zheng S.
        • Xia F.
        • Ma K.
        • Wang S.
        • Bie P.
        • et al.
        Classification and management of hepatolithiasis: A high-volume, single-center’s experience.
        Intractable & Rare Diseases Research. 2012:151–6.; https://doi.org/10.5582/irdr.2012.v1.4.151
        • Valle J.W.
        • Borbath I.
        • Khan S.A.
        • Huguet F.
        • Gruenberger T.
        • Arnold D.
        • et al.
        Biliary cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2016; 27: v28-v37https://doi.org/10.1093/annonc/mdw324
        • Okusaka T.
        • Nakachi K.
        • Fukutomi A.
        • Mizuno N.
        • Ohkawa S.
        • Funakoshi A.
        • et al.
        Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: A comparative multicentre study in Japan.
        Br J Cancer. 2010; 103: 469-474https://doi.org/10.1038/sj.bjc.6605779
      5. NCCN Guidelines Version 2.2020 Hepatobiliary Cancers. 2020. https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf.

        • Lamarca A.
        • Palmer D.H.
        • Wasan H.S.
        • Ross P.J.
        • Ma Y.T.
        • Arora A.
        • et al.
        ABC-06 | A randomised phase III, multi-centre, open-label study of active symptom control (ASC) alone or ASC with oxaliplatin / 5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers (ABC) previously-tr.
        J Clin Oncol. 2019; 37: 4003https://doi.org/10.1200/JCO.2019.37.15_suppl.4003
        • Lamarca A.
        • Ross P.
        • Wasan H.S.
        • Hubner R.A.
        • McNamara M.G.
        • Lopes A.
        • et al.
        Advanced Intrahepatic Cholangiocarcinoma: Post Hoc Analysis of the ABC-01, -02, and -03 Clinical Trials.
        J Natl Cancer Inst. 2020; 112: 200-210https://doi.org/10.1093/jnci/djz071
        • Köhler M.
        • Harders F.
        • Lohöfer F.
        • Paprottka P.M.
        • Schaarschmidt B.M.
        • Theysohn J.
        • et al.
        Prognostic Factors for Overall Survival in Advanced Intrahepatic Cholangiocarcinoma Treated with Yttrium-90 Radioembolization.
        Journal of Clinical Medicine. 2019; 9: 56https://doi.org/10.3390/jcm9010056
        • Abou-Alfa G.K.
        • Macarulla T.
        • Javle M.M.
        • Kelley R.K.
        • Lubner S.J.
        • Adeva J.
        • et al.
        Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study.
        Lancet Oncol. 2020; 21: 796-807https://doi.org/10.1016/S1470-2045(20)30157-1
        • Ghedini G.C.
        • Ronca R.
        • Presta M.
        • Giacomini A.
        Future applications of FGF/FGFR inhibitors in cancer.
        Expert Rev Anticancer Ther. 2018; 18: 861-872https://doi.org/10.1080/14737140.2018.1491795
        • Mazzaferro V.
        • El-Rayes B.F.
        • Droz dit Busset M.
        • Cotsoglou C.
        • Harris W.P.
        • Damjanov N.
        • et al.
        Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma.
        Br J Cancer. 2019; 120: 165-171https://doi.org/10.1038/s41416-018-0334-0
      6. Kalyukina M, Yosaatmadja Y, Middleditch MJ, Patterson A v., Smaill JB, Squire CJ. TAS-120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) Irreversible Structure. ChemMedChem 2019;14:494–500. https://doi.org/10.1002/cmdc.201800719.

        • Javle Milind
        • Lowery Maeve
        • Shroff Rachna T.
        • Weiss Karl Heinz
        • Springfeld Christoph
        • Borad Mitesh J.
        • et al.
        Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma.
        J Clin Oncol. 2018; 36: 276-282https://doi.org/10.1200/JCO.2017.75.5009
        • Abou-Alfa Ghassan K
        • Sahai Vaibhav
        • Hollebecque Antoine
        • Vaccaro Gina
        • Melisi Davide
        • Al-Rajabi Raed
        • et al.
        Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.
        Lancet Oncol. 2020; 21: 671-684https://doi.org/10.1016/S1470-2045(20)30109-1
        • Voss Martin H.
        • Hierro Cinta
        • Heist Rebecca S.
        • Cleary James M.
        • Meric-Bernstam Funda
        • Tabernero Josep
        • et al.
        A phase I, open-label, multicenter, dose-escalation study of the oral selective FGFR inhibitor debio 1347 in patients with advanced solid tumors harboring FGFR gene alterations.
        Clin Cancer Res. 2019; 25: 2699-2707https://doi.org/10.1158/1078-0432.CCR-18-1959
        • Cleary James M.
        • Iyer Gopa
        • Oh Do-Youn
        • Mellinghoff Ingo K.
        • Goyal Lipika
        • Ng Matthew C.H.
        • et al.
        Final results from the phase I study expansion cohort of the selective FGFR inhibitor Debio 1,347 in patients with solid tumors harboring an FGFR gene fusion.
        J Clin Oncol. 2020; 38: 3603https://doi.org/10.1200/JCO.2020.38.15_suppl.3603
        • Hyman David Michael
        • Goyal Lipika
        • Grivas Petros
        • Meric-Bernstam Funda
        • Tabernero Josep
        • Hu Youyou
        • et al.
        FUZE clinical trial: a phase 2 study of Debio 1347 in FGFR fusion-positive advanced solid tumors irrespectively of tumor histology.
        J Clin Oncol. 2019; 37: TPS3157https://doi.org/10.1200/JCO.2019.37.15_suppl.TPS3157
      7. Hall TG, Yu Y, Eathiraj S, Wang Y, Savage RE, Lapierre JM, et al. Preclinical activity of ARQ 087, a novel inhibitor targeting FGFR dysregulation. PLoS ONE 2016;11. https://doi.org/10.1371/journal.pone.0162594.

      8. Basilea Pharmaceuticals. Basilea announces completion of patient enrolment into first cohort of phase 2 study FIDES-01 with derazantinib in bile duct cancer (iCCA). 2020. https://www.globenewswire.com/news-release/2020/07/20/2064138/0/e…FIDES-01-with-derazantinib-in-bile-duct-cancer-iCCA.html.

        • Perera T.P.S.
        • Jovcheva E.
        • Mevellec L.
        • Vialard J.
        • de Lange D.
        • Verhulst T.
        • et al.
        Discovery & pharmacological characterization of JNJ-42756493 (Erdafitinib), a functionally selective small-molecule FGFR family inhibitor.
        Mol Cancer Ther. 2017; 16: 1010-1020https://doi.org/10.1158/1535-7163.MCT-16-0589
        • Park Joon Oh
        • Feng Yin-Hsun
        • Chen Yen-Yang
        • Su Wu-Chou
        • Oh Do-Youn
        • Shen Lin
        • et al.
        Updated results of a phase IIa study to evaluate the clinical efficacy and safety of erdafitinib in Asian advanced cholangiocarcinoma (CCA) patients with FGFR alterations.
        J Clin Oncol. 2019; 37: 4117https://doi.org/10.1200/JCO.2019.37.15_suppl.4117
      9. Ochiiwa H, Fujita H, Itoh K, Sootome H, Hashimoto A, Fujioka Y, et al. Abstract A270: TAS-120, a highly potent and selective irreversible FGFR inhibitor, is effective in tumors harboring various FGFR gene abnormalities., American Association for Cancer Research (AACR); 2013, p. A270–A270. https://doi.org/10.1158/1535-7163.targ-13-a270.

        • Sootome Hiroshi
        • Fujita Hidenori
        • Ito Kenjiro
        • Ochiiwa Hiroaki
        • Fujioka Yayoi
        • Ito Kimihiro
        • et al.
        Futibatinib is a novel irreversible FGFR 1–4 inhibitor that shows selective antitumor activity against FGFR-deregulated tumors.
        Cancer Res. 2020; 80: 4986-4997https://doi.org/10.1158/0008-5472.CAN-19-2568
        • Bahleda R.
        • Meric-Bernstam F.
        • Goyal L.
        • Tran B.
        • He Y.
        • Yamamiya I.
        • et al.
        Phase I, first-in-human study of futibatinib, a highly selective, irreversible FGFR1–4 inhibitor in patients with advanced solid tumors.
        Ann Oncol. 2020; 31: 1405-1412https://doi.org/10.1016/j.annonc.2020.06.018
        • Meric-Bernstam F.
        • Arkenau H.
        • Tran B.
        • Bahleda R.
        • Kelley R.
        • Hierro C.
        • et al.
        Efficacy of TAS-120, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in cholangiocarcinoma patients with FGFR pathway alterations who were previously treated with chemotherapy and other FGFR inhibitors.
        Ann Oncol. 2018; 29: v100https://doi.org/10.1093/annonc/mdy149
        • Goyal Lipika
        • Meric-Bernstam Funda
        • Hollebecque Antoine
        • Valle Juan W.
        • Morizane Chigusa
        • Karasic Thomas Benjamin
        • et al.
        FOENIX-CCA2: A phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements.
        J Clin Oncol. 2020; 38: 108https://doi.org/10.1200/JCO.2020.38.15_suppl.108
        • Guagnano Vito
        • Furet Pascal
        • Spanka Carsten
        • Bordas Vincent
        • Le Douget Mickaël
        • Stamm Christelle
        • et al.
        Discovery of 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl- piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), A potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase.
        J Med Chem. 2011; 54: 7066-7083https://doi.org/10.1021/jm2006222
      10. Nogova L, Sequist L v., Garcia JMP, Andre F, Delord JP, Hidalgo M, et al. Evaluation of BGJ398, a Fibroblast growth factor receptor 1-3 kinase inhibitor, in patientswith advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: Results of a global phase I, dose-escalation and dose-expansion stud. Journal of Clinical Oncology 2017;35:157–65. https://doi.org/10.1200/JCO.2016.67.2048.

      11. Javle, Milind M.; Roychodhury, Sameek; Kelley, Robin Kate; Sadeghi, Saeed; Macarulla, Teresa; Dirk-Thomas, Waldschmidt; Goyal L. Final results from a phase II study of infigratinib (BGJ398), an FGFRselective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement. J Clin Oncol 39: 2021 (Suppl; Abstr 265) 2021;39:66.

        • Liu Phillip C.C.
        • Koblish Holly
        • Wu Liangxing
        • Bowman Kevin
        • Diamond Sharon
        • DiMatteo Darlise
        • et al.
        INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models.
        PLoS ONE. 2020; 15: e0231877https://doi.org/10.1371/journal.pone.0231877
      12. Subbiah V, Barve M, Iannotti NO, Gutierrez M, Smith DC, Roychowdhury S, et al. Abstract A078: FIGHT-101: A phase 1/2 study of pemigatinib, a highly selective fibroblast growth factor receptor (FGFR) inhibitor, as monotherapy and as combination therapy in patients with advanced malignancies, American Association for Cancer Research (AACR); 2019, p. A078–A078. https://doi.org/10.1158/1535-7163.targ-19-a078.

        • Perwad Farzana
        • Zhang Martin Y.H.
        • Tenenhouse Harriet S.
        • Portale Anthony A.
        Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1α-hydroxylase expression in vitro. American Journal of Physiology -.
        Renal Physiology. 2007; 293: F1577-F1583https://doi.org/10.1152/ajprenal.00463.2006
        • Degirolamo Chiara
        • Sabbà Carlo
        • Moschetta Antonio
        Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23.
        Nat Rev Drug Discovery. 2016; 15: 51-69https://doi.org/10.1038/nrd.2015.9
        • Gattineni J.
        • Bates C.
        • Twombley K.
        • Dwarakanath V.
        • Robinson M.L.
        • Goetz R.
        • et al.
        FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1.
        First Am J Physiol Renal Physiol. 2009; 297: 282-291https://doi.org/10.1152/ajprenal.90742.2008.-Fibro
        • Xie Yangli
        • Su Nan
        • Yang Jing
        • Tan Qiaoyan
        • Huang Shuo
        • Jin Min
        • et al.
        FGF/FGFR signaling in health and disease. Signal Transduction and Targeted.
        Therapy. 2020; 5https://doi.org/10.1038/s41392-020-00222-7
        • Zhou Yangyang
        • Wu Chengyu
        • Lu Guangrong
        • Hu Zijing
        • Chen Qiuxiang
        • Du Xiaojing
        FGF/FGFR signaling pathway involved resistance in various cancer types.
        Journal of Cancer. 2020; 11: 2000-2007https://doi.org/10.7150/jca.40531
        • Silverman Ian M.
        • Hollebecque Antoine
        • Friboulet Luc
        • Owens Sherry
        • Newton Robert C.
        • Zhen Huiling
        • et al.
        Clinicogenomic Analysis of FGFR2 -Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib.
        Cancer Discovery. 2021; 11: 326-339https://doi.org/10.1158/2159-8290.CD-20-0766
        • Goyal Lipika
        • Saha Supriya K.
        • Liu Leah Y.
        • Siravegna Giulia
        • Leshchiner Ignaty
        • Ahronian Leanne G.
        • et al.
        Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma.
        Cancer Discovery. 2017; 7: 252-263https://doi.org/10.1158/2159-8290.CD-16-1000
        • Krook Melanie A.
        • Lenyo Alexandria
        • Wilberding Max
        • Barker Hannah
        • Dantuono Mikayla
        • Bailey Kelly M.
        • et al.
        Efficacy of FGFR inhibitors and combination therapies for acquired resistance in FGFR2-fusion cholangiocarcinoma.
        Mol Cancer Ther. 2020; 19: 847-857https://doi.org/10.1158/1535-7163.MCT-19-0631
        • Krook Melanie A.
        • Bonneville Russell
        • Chen Hui-Zi
        • Reeser Julie W.
        • Wing Michele R.
        • Martin Dorrelyn M.
        • et al.
        Tumor heterogeneity and acquired drug resistance in FGFR2-fusion-positive cholangiocarcinoma through rapid research autopsy.
        Cold Spring Harbor Mol Case Stud. 2019; 5: a004002https://doi.org/10.1101/mcs.a004002
        • Mosele F.
        • Remon J.
        • Mateo J.
        • Westphalen C.B.
        • Barlesi F.
        • Lolkema M.P.
        • et al.
        Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group.
        Ann Oncol. 2020; 31: 1491-1505https://doi.org/10.1016/j.annonc.2020.07.014
        • Dai S.
        • Zhou Z.
        • Chen Z.
        • Xu G.
        • Chen Y.
        Fibroblast Growth Factor Receptors (FGFRs): Structures and Small Molecule Inhibitors.
        Cells. 2019; 8: 614https://doi.org/10.3390/cells8060614
        • Nakanishi Yoshito
        • Akiyama Nukinori
        • Tsukaguchi Toshiyuki
        • Fujii Toshihiko
        • Sakata Kiyoaki
        • Sase Hitoshi
        • et al.
        The Fibroblast Growth Factor Receptor Genetic Status as a Potential Predictor of the Sensitivity to CH5183284/Debio 1347, a Novel Selective FGFR Inhibitor.
        Mol Cancer Ther. 2014; 13: 2547-2558https://doi.org/10.1158/1535-7163.MCT-14-0248