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Molecular targeted therapies: Ready for “prime time” in biliary tract cancer

  • Angela Lamarca
    Correspondence
    (J.W. Valle), or Medical Oncology Department, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, United Kingdom. Tel.: +44 (0) 161 446 8370, fax: +44 (0) 161 446 3468 (A. Lamarca).
    Affiliations
    Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK

    Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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  • Jorge Barriuso
    Affiliations
    Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK

    Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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  • Mairéad G. McNamara
    Affiliations
    Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK

    Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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  • Juan W. Valle
    Correspondence
    Corresponding authors. Addresses: Medical Oncology Department, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, United Kingdom. Tel.: +44 (0)161 446 8106, fax: +44 (0) 161 446 3468
    Affiliations
    Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK

    Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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Published:March 12, 2020DOI:https://doi.org/10.1016/j.jhep.2020.03.007

      Summary

      The prognosis for patients with biliary tract cancers (cholangiocarcinoma and gallbladder cancer) is poor, while the incidence of these cancers is increasing. Most patients are diagnosed with advanced disease when treatment options are limited to palliative approaches, mainly focused on chemotherapy. In recent years, novel treatment targets of relevance to biliary tract cancers, mainly present in patients with intrahepatic cholangiocarcinoma, have been identified and are rapidly changing the field. These include fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH)-1 and -2 mutations which are each present in around 10–20% of patients with intrahepatic cholangiocarcinoma. In addition, inhibition of other pathways/molecules is currently being explored, including human epidermal growth factor receptor (HER) family members, the Wnt pathway, neurotropic tyrosine kinase receptor (NTRK) fusions and BRAF mutations. The IDH1 inhibitor ivosidenib has already been tested in a phase III clinical trial in pretreated cholangiocarcinoma and showed benefit in terms of progression-free survival. Multiple FGFR inhibitors have consistently shown high response rates in phase II/III trials, especially for patients harbouring FGFR2 fusions. Herein, we provide an overview of the status of targeted therapies in biliary tract cancers, discussing the current clinical development of IDH and FGFR inhibitors in detail, as well as reviewing current caveats and future steps.

      Keywords

      Introduction

      Biliary tract cancers, including cholangiocarcinoma (CCA) and gallbladder cancer (GBC), are rare (particularly in Western countries) and represent 3% of all gastrointestinal malignancies in adults. Their incidence is increasing, mainly due to intrahepatic cholangiocarcinoma (iCCA);
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      is becoming a reality. The aim of this review is to provide an overview of the current development of targeted therapies for biliary tract cancer, focusing on those in later stages of clinical development.

      Current state of play

       Adjuvant therapy

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       First-line palliative chemotherapy

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      The study showed an advantage in overall survival (OS) in favour of CisGem (11.7 vs. 8.1 months; hazard ratio [HR] 0.64; 95% CI 0.52–0.80; p <0.001). This benefit was confirmed in a Japanese randomised phase II study, BT22.
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      Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan.
      Based on these findings, CisGem is currently considered standard of care in the first-line setting for treatment of advanced CCA and GBC.
      Efforts are being made to identify more effective first-line strategies, with the aim of improving patient outcomes, which remain poor.
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       Second-line chemotherapy

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      The ABC-06 study reported a benefit from second-line chemotherapy in terms of OS (adjusted HR 0.69; 95% CI 0.50–0.97; p = 0.031). Although differences in terms of median OS were modest (5.3 months vs. 6.2 months in the ASC vs. ASC+FOLFOX arms, respectively), differences in survival rate at 6 months (35.5% [ASC arm] vs. 50.6% [ASC+FOLFOX arm]) and 12 months (11.4% [ASC arm] vs. 25.9% [ASC+FOLFOX arm]) were considered to be clinically meaningful. Based on this, FOLFOX may be considered following CisGem for patients with advanced CCA and GBC who remain fit for second-line chemotherapy. However, there is a need for additional, effective treatments for patients with advanced disease.
      Alternative agents such as bintrafusp alfa (M7824), a bifunctional monoclonal antibody targeting transforming growth factor-beta trap and anti-PD-L1, have been explored in pre-treated biliary tract cancers and granted orphan drug designation by the FDA, based on promising phase I findings (ORR of 20% in unselected biliary tract cancer population).
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       Other therapeutic options: liver-directed therapies and immunotherapy

      For selected patients with liver-predominant or locally advanced disease, strategies involving liver-directed therapies
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      The role of immunotherapy is still to be elucidated in biliary tract cancer.
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      Targeted therapies in CCA and GBC

      Despite efforts to identify potential targeted strategies
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      involving multiple pathways such as angiogenesis, human epidermal growth factor receptor (HER [or ERBB]) family, HGF/c-MET, Hedgehog, KRAS-BRAF-MEK-ERK and PI3K/AKT/mTOR, these have been unsuccessful in biliary tract cancers to date.
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      New horizons for precision medicine in biliary tract cancers.
      None of the studies showed superiority of the additional targeted therapy compared to systemic cytotoxic chemotherapy in biliary tract cancer.
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      • et al.
      Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild-type KRAS advanced biliary tract cancer: a randomized phase 2 trial (Vecti-BIL study).
      • Lee J.
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      • et al.
      Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study.
      • Goyal L.
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      • et al.
      A phase II trial of cabozantinib (XL-184) in patients with advanced cholangiocarcinoma.
      • Bridgewater J.
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      • Lee D.
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      • et al.
      A phase 1b study of selumetinib in combination with cisplatin and gemcitabine in advanced or metastatic biliary tract cancer: the ABC-04 study.
      • Ahn D.H.
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      • Doyle A.
      • Marshall J.L.
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      • et al.
      Results of an abbreviated phase-II study with the Akt inhibitor MK-2206 in patients with advanced biliary cancer.
      • Yeung Y.H.
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      • Tran H.
      • Fang G.
      • et al.
      Phase II study of everolimus monotherapy as first-line treatment in advanced biliary tract cancer: RADichol. 2014 ASCO Annual Meeting.
      • Ramanathan R.K.
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      • Tanaka M.
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      • Yen Y.
      • et al.
      A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer.
      • Peck J.
      • Wei L.
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      HER2/neu may not be an interesting target in biliary cancers: results of an early phase II study with lapatinib.
      • Chen J.S.
      • Hsu C.
      • Chiang N.J.
      • Tsai C.S.
      • Tsou H.H.
      • Huang S.F.
      • et al.
      A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer.
      The lack of relevant targets and inadequate patient selection/enrichment may be a reasonable explanation for such a failure. One of the latest studies reporting activity of targeted therapy in unselected populations was the REACHIN study.
      • Demols A.
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      • Peeters M.
      • Maréchal R.
      • et al.
      Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced (nonresectable) and metastatic biliary tumors: a randomized double-blinded placebo-controlled phase II trial.
      This study recruited 66 patients diagnosed with biliary tract cancer who had already progressed on gemcitabine and platinum chemotherapy and who were randomised in a phase II study to receive regorafenib or placebo. The study showed a marginal (median progression-free survival [PFS] of 3 months with regorafenib vs. 1.5 months with placebo) albeit statistically significant (HR 0.49; 95% CI 0.29–0.81; p = 0.005) improvement in PFS; however, no objective responses or benefit in OS were identified. A study is currently exploring the role of regorafenib combined with systemic chemotherapy (gemcitabine and oxaliplatin) in the first-line setting (NCT02386397). The failure of targeted therapies to show an improvement in OS, PFS, or ORR in one of the most recent studies (the JSBF trial explored the role of ramucirumab or merestinib combined with CisGem compared to placebo
      • Valle J.W.
      • Bai L.-Y.
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      • Chen L.-T.
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      Ramucirumab (RAM) or merestinib (MER) or placebo (PL) plus gemcitabine (GEM) and cisplatin (CIS) as first-line treatment for advanced or metastatic biliary tract cancer (BTC): a randomized, double-blind, phase II study.
      ) probably represents the end of an era of clinical trials testing targeted therapies in biologically unselected patients.
      A “Precision Medicine” strategy for treatment of advanced biliary tract cancers is supported by data from the biliary tract subgroup of the MOSCATO-01 trial.
      • Verlingue L.
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      • et al.
      Precision medicine for patients with advanced biliary tract cancers: an effective strategy within the prospective MOSCATO-01 trial.
      A total of 43 patients diagnosed with biliary tract cancer were recruited into the MOSCATO-01 trial; of these, druggable molecular aberrations were identified in 23 (68%) patients and targeted therapy administered in 18. The study reported an improved median OS for those patients who received targeted therapy based on identified molecular findings compared to those treated with unselected therapies (median OS 17 vs. 5 months; p = 0.008). However, the success of this approach has only been validated when therapeutic targets of relevance were identified, allowing for adequate patient selection, thus opening the doors to real “Precision Medicine” in biliary tract cancers.

       Current genetic landscape and actionable aberrations

      As stated above, the success of “Precision Medicine” came with a better understanding of the molecular biology driving biliary tract malignancies. Currently, the most promising targets are IDH inhibitors for patients with IDH-mutated cholangiocarcinoma and molecules targeting FGFR2 gene fusions, both of specific relevance in CCA. Other potential targets for future “Precision Medicine” strategies involve chromatin remodelling genes (ARID1, BAP1 and PBRM1) or DNA damage repair aberrations.
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      Small molecule inhibitors of bromodomain-acetyl-lysine interactions.
      • Lamarca A.
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      • McNamara M.G.
      • Valle J.W.
      Biliary tract cancer: state of the Art and potential role of DNA damage repair.
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      • Chang H.M.
      • et al.
      Therapeutic relevance of targeted sequencing in management of patients with advanced biliary tract cancer: DNA damage repair gene mutations as a predictive biomarker.
      There has been some pre-clinical and early clinical research targeting BRAF and RNF43 mutations, as well as HER2 (also known as ERBB2).
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      Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma.
      • Koo B.K.
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      • Clevers H.
      Porcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43;Znrf3-mutant neoplasia.
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      • Rogan J.
      • et al.
      The HER3 pathway as a potential target for inhibition in patients with biliary tract cancers.
      In addition, some tumour-agnostic targets such as NTRK may also play a role for a small proportion of patients with biliary tract tumours (3%).
      • Valle J.W.
      • Lamarca A.
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      • Barriuso J.
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      New horizons for precision medicine in biliary tract cancers.
      ,
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      Safety and antitumor activity of the multi-targeted pan-TRK, ROS1, and ALK inhibitor entrectinib (RXDX-101): combined results from two phase 1 trials (ALKA-372-001 and STARTRK-1).
      ,
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      • et al.
      New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing.
      In-depth sequencing of biliary tract cancers has shown that molecular profiles vary between iCCA, eCCA and GBC (Fig. 1).
      • Valle J.W.
      • Lamarca A.
      • Goyal L.
      • Barriuso J.
      • Zhu A.X.
      New horizons for precision medicine in biliary tract cancers.
      The main targetable aberrations are clustered within patients with iCCA in the form of IDH and FGFR, while HER2 aberrations were the most frequent in eCCA and GBC.
      • Valle J.W.
      • Lamarca A.
      • Goyal L.
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      New horizons for precision medicine in biliary tract cancers.
      ,
      • Ross J.S.
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      • Gay L.
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      • Rand J.V.
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      New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing.
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      Exome sequencing of liver fluke-associated cholangiocarcinoma.
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      • Dima S.
      • Pairojkul C.
      • et al.
      Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers.
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      Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma.
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      Activating mutations in PTPN3 promote cholangiocarcinoma cell proliferation and migration and are associated with tumor recurrence in patients.
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      Tumor profiling of biliary tract carcinomas to reveal distinct molecular alterations and potential therapeutic targets.
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      • et al.
      Comprehensive genomic profiling of biliary tract cancers to reveal tumor-specific differences and genomic alterations.
      • Javle M.
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      • Jain A.
      • Wang Y.
      • Kelley R.K.
      • Wang K.
      • et al.
      Biliary cancer: utility of next-generation sequencing for clinical management.
      • Jiao Y.
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      • 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.
      Research by Farshidfar and colleagues also suggested that mutations tend to cluster together; for example, tumours with IDH mutations were found to have distinct mRNA, copy number, and DNA methylation features with increased methylation of the ARID1A promoter and subsequent lower expression of ARID1A.
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      • et al.
      Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles.
      In contrast, FGFR2-positive tumours seem to associate with BAP1 mutations
      • Farshidfar F.
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      Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles.
      and are characterised by a better prognosis.
      • Jain A.
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      Genomic profiling of biliary tract cancers and implications for clinical practice.
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      • Wang Y.
      • Rashid A.
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      • et al.
      Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications.
      In contrast, the presence of an IDH mutation did not seem to impact on patients' prognosis.
      • Boscoe A.N.
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      Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review.
      Such findings have been confirmed by others, including a trend toward mutual exclusion of FGFR2 fusions and IDH1 mutations.
      • Javle M.M.
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      • Shroff R.T.
      • Borad M.J.
      • Abdel-Wahab R.
      • Schrock A.B.
      • et al.
      Profiling of 3,634 cholangiocarcinomas (CCA) to identify genomic alterations (GA), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH).
      Figure thumbnail gr1
      Fig. 1Molecular profiling of biliary tract cancers.
      Percentage of main targetable and non-targetable genetic alterations are summarised for iCCA, eCCA, and GBC. Within targetable alterations, there are clear variations within the molecular profiling of these tumours with predominance of IDH and FGFR alterations in iCCA and ERBB2/3 (HER2/3) in eCCA and GBC. Adapted from.
      • Valle J.W.
      • Lamarca A.
      • Goyal L.
      • Barriuso J.
      • Zhu A.X.
      New horizons for precision medicine in biliary tract cancers.
      CCA, cholangicarcinoma; eCCA, extraheptic CCA; GBC, gallbladder cancer; iCCA, intrahepatic CCA.
      In addition, molecular findings seem to vary depending on aetiology, especially for iCCA. Non-Opistorchis viverrini (OV)-related iCCA demonstrated statistically significant increased prevalence of BAP1, IDH1/IDH2
      • Chan-On W.
      • Nairismagi M.L.
      • Ong C.K.
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      • Dima S.
      • Pairojkul C.
      • et al.
      Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers.
      and FGFR alterations,
      • Chan-On W.
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      • 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.
      ,
      • Jusakul A.
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      Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma.
      while OV-related iCCA showed more TP53 mutations,
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      • Huang M.N.
      • Padmanabhan N.
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      Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma.
      KRAS and SMAD4 mutations
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      • Cutcutache I.
      • Yu W.
      • et al.
      Exome sequencing of liver fluke-associated cholangiocarcinoma.
      and HER2 amplifications.
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      • 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.
      Variations have also been identified depending on the presence/absence of hepatitis-related cirrhosis, with more KRAS
      • Zou S.
      • Li J.
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      Mutational landscape of intrahepatic cholangiocarcinoma.
      and IDH mutations reported in hepatitis-negative iCCA.
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      • et al.
      Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity.
      For GBC and eCCA, the main targetable findings rely on the HER gene family.
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      HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?.
      Mutations in the ERBB family of proteins (including their downstream genes) were found in 35.8% of GBC tumours,
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      Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway.
      and may be targeted with novel tyrosine kinase inhibitors (TKIs) and monoclonal antibody strategies.
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      An absence of IDH mutations
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      Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping.
      and the presence of activating mutations in PIK3CA
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      Mutational profiling reveals PIK3CA mutations in gallbladder carcinoma.
      have also been shown in GBC.

      Isocitrate dehydrogenase as a target

      Around 10–20% of iCCAs are expected to harbour a mutation in IDH1
      • Valle J.W.
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      • Barriuso J.
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      Biliary cancer: utility of next-generation sequencing for clinical management.
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      Comprehensive genomic profiling in FIGHT-202 reveals the landscape of actionable alterations in advanced cholangiocarcinoma.
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      Mutant IDH inhibits HNF-4alpha to block hepatocyte differentiation and promote biliary cancer.
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      Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma.
      (Fig. 1). Of the 3 isoforms of IDH, IDH1 and IDH2 are the ones of relevance in cancer, due to their involvement in cell metabolism.
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      These somatic gain-of-function mutations appear early in tumour development. Increased IDH1/2 activity induces changes in cell metabolism and subsequent accumulation of the oncometabolite 2-hydroxyglutarate (2-HG),
      • Mondesir J.
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      IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives.
      which can be detected in both tumour tissue and blood
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      • Fantin V.R.
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      Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping.
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      • Poon R.T.
      • Ancukiewicz M.
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      Circulating oncometabolite 2-hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase-mutant intrahepatic cholangiocarcinoma.
      and is able to induce blockage of normal cell differentiation and promotion of tumorigenesis.
      • Dang L.
      • Yen K.
      • Attar E.C.
      IDH mutations in cancer and progress toward development of targeted therapeutics.
      Fig. 2 summarises the role of IDH in cell metabolism.
      Precision medicine is of particular relevance for patients with intrahepatic cholangiocarcinoma.
      Figure thumbnail gr2
      Fig. 2IDH involvement in cell metabolism.
      IDH1 and IDH2 are enzymes located in the cytoplasm and mitochondria, respectively. They are involved in cell metabolism and transform decarboxylation of isocitrate to α-KG, resulting in the reduction of NADP+ to NADPH. In the presence of mutant IDH1 or IDH2, there is a pathogenic accumulation of the oncometabolite 2-HG which can activate cancer-related processes. Adapted from.
      • Valle J.W.
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      ,
      • Mondesir J.
      • Willekens C.
      • Touat M.
      • de Botton S.
      IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives.
      2-HG, 2-hydroxyglutarate; α-KG, α-ketoglutarate; IDH, isocitrate dehydrogenase.
      As previously mentioned, IDH1 mutations are more frequent than IDH2 mutations and tend to appear in non-OV-related and hepatitis-negative iCCA.
      • Chan-On W.
      • Nairismagi 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.
      ,
      • Fujimoto A.
      • Furuta M.
      • Shiraishi Y.
      • Gotoh K.
      • Kawakami Y.
      • Arihiro K.
      • et al.
      Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity.
      The presence of IDH1 mutations did not seem to have a prognostic implication.
      • Boscoe A.N.
      • Rolland C.
      • Kelley R.K.
      Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review.
      IDH1 mutations frequently appear together with lower expression of ARID1A
      • 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.
      and rarely together with FGFR2 fusions.
      • Javle M.M.
      • Murugesan K.
      • Shroff R.T.
      • Borad M.J.
      • Abdel-Wahab R.
      • Schrock A.B.
      • et al.
      Profiling of 3,634 cholangiocarcinomas (CCA) to identify genomic alterations (GA), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH).
      IDH1 and IDH2 mutations seem to be point mutations located in the arginine 132 (R132) and 172 (R172) residue, respectively.
      • 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.
      ,
      • 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.
      ,
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      Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas.
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      • Cosgrove D.
      • Ejaz A.
      • Alexandrescu S.
      • et al.
      Genomic profiling of intrahepatic cholangiocarcinoma: refining prognosis and identifying therapeutic targets.
      • Goyal L.
      • Govindan A.
      • Sheth R.A.
      • Nardi V.
      • Blaszkowsky L.S.
      • Faris J.E.
      • et al.
      Prognosis and clinicopathologic features of patients with advanced stage isocitrate dehydrogenase (IDH) mutant and IDH wild-type intrahepatic cholangiocarcinoma.
      Another genetic footprint of IDH mutations is its link with a hypermethylated phenotype. This was noticed first in acute myeloid leukaemia
      • Figueroa M.E.
      • Abdel-Wahab O.
      • Lu C.
      • Ward P.S.
      • Patel J.
      • Shih A.
      • et al.
      Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation.
      but also in other tumours, such as gliomas and CCAs. However, the methylation patterns derived from IDH mutations seem to be dependent on the cellular and organ context.
      • Unruh D.
      • Zewde M.
      • Buss A.
      • Drumm M.R.
      • Tran A.N.
      • Scholtens D.M.
      • et al.
      Methylation and transcription patterns are distinct in IDH mutant gliomas compared to other IDH mutant cancers.
      This might have implications for patient selection and drug repurposing.
      Multiple IDH-selective inhibitors have been developed to target tumours harbouring IDH mutations. AG-120 (ivosidenib, Agios) is the most developed IDH inhibitor for CCA and will be discussed in detail later in this section. Rohle et al. identified a selective IDH1 inhibitor (AGI-5198, Cayman Chemical) against R132H mutations able to inhibit the growth of IDH-mutant glioma cells.
      • Rohle D.
      • Popovici-Muller J.
      • Palaskas N.
      • Turcan S.
      • Grommes C.
      • Campos C.
      • et al.
      An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells.
      In addition, another compound (AGI-6780, Cayman Chemical) was also able to inhibit leukaemic cells harbouring mutant IDH2-R140Q.
      • Wang F.
      • Travins J.
      • DeLaBarre B.
      • Penard-Lacronique V.
      • Schalm S.
      • Hansen E.
      • et al.
      Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation.
      Currently, other targeted inhibitors of IDH1 and IDH2 are being developed and have been shown, mechanistically, to reduce 2-HG levels.
      • Dang L.
      • Yen K.
      • Attar E.C.
      IDH mutations in cancer and progress toward development of targeted therapeutics.
      Other inhibitors of both IDH1 and IDH2 are being developed for the management of other malignancies also harbouring IDH mutations, such as haematological malignancies, gliomas and sarcomas. IDH305 (Novartis) targets IDH1 mutations and ongoing trials are currently being performed in gliomas and other malignancies with IDH1 R132 mutations (NCT02381886). FT2102 (Forma Therapeutics) and BAY1436032 (Bayer) also target IDH1 R132 tumours (R132X for BAY1436032) and ongoing trials are recruiting patients with multiple tumour types, including CCA (NCT03684811 and NCT02746081). Other inhibitors being developed include AG221 (enasidenib, CC90007; Agios) which targets IDH2 mutations and is currently under development for the treatment of haematological malignancies and gliomas, and AG881 (a pan-IDH1/-2 (Agios) inhibitor) which is being developed for the management of gliomas and sarcomas. This molecule inhibits both the cytoplasmic IDH1 and IDH2 in the mitochondria; AG-881 is also able to penetrate the blood-brain barrier.
      Beyond selective IDH inhibitors, there is some evidence that multi-TKIs, such as dasatinib, can inhibit the growth of IDH-mutant iCCA cells.
      • Saha S.K.
      • Gordan J.D.
      • Kleinstiver B.P.
      • Vu P.
      • Najem M.S.
      • Yeo J.C.
      • et al.
      Isocitrate dehydrogenase mutations confer dasatinib hypersensitivity and SRC-dependence in intrahepatic cholangiocarcinoma.
      This strategy is being explored in a clinical trial recruiting patients with IDH-mutated iCCA (NCT02428855).
      The IDH1 inhibitor ivosidenib has shown benefit in phase III trials for IDH1-mutant cholangiocarcinoma.
      Ivosidenib (AG-120) is an oral, targeted mutant IDH1 inhibitor which has already been approved for the treatment of IDH1-mutant acute myeloid leukaemia.
      • Kucukyurt S.
      • Eskazan A.E.
      New drugs approved for acute myeloid leukaemia in 2018.
      A total of 168 patients with IDH1-mutated cholangiocarcinoma and chondrosarcoma were treated to explore pharmacokinetic and pharmacodynamic profiles.
      • Fan B.
      • Mellinghoff I.K.
      • Wen P.Y.
      • Lowery M.A.
      • Goyal L.
      • Tap W.D.
      • et al.
      Clinical pharmacokinetics and pharmacodynamics of ivosidenib, an oral, targeted inhibitor of mutant IDH1, in patients with advanced solid tumors.
      Ivosidenib demonstrated good oral exposure after single and multiple doses, was rapidly absorbed, and had a long terminal half-life (mean 40–102 hours after a single dose). Steady state was reached by day 15, and its metabolism was not affected by any of the intrinsic or extrinsic factors assessed (including weak CYP3A4 inhibitors/inducers). After multiple doses, plasma 2-HG was reduced by up to 98% (to levels similar to those in healthy individuals). Ivosidenib was later assessed in a phase I clinical trial including 73 patients with advanced IDH1-mutant cholangiocarcinoma.
      • Lowery M.A.
      • Burris III, H.A.
      • Janku F.
      • Shroff R.T.
      • Cleary J.M.
      • Azad N.S.
      • et al.
      Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study.
      This phase I dose escalation and expansion clinical trial involved administering ivosidenib as a single agent to patients with IDH1-mutant solid tumours (including the 73 patients with CCA). No dose-limiting toxicities were reported and the maximum tolerated dose was not reached; the dose of 500 mg daily was selected for use in the expansion cohort. The most common toxicities (regardless of causality) included fatigue (42%; 3% grade ≥3), nausea (34%; 1% grade ≥3), diarrhoea (32%; 3% grade ≥3), abdominal pain (27%; 3% grade ≥3), decreased appetite (27%; 1% grade ≥3), and vomiting (23%). Regarding treatment-related toxicities, 5% of patients had grade ≥3 adverse events (3% fatigue, 1% hypophosphataemia). Within this heavily pretreated population, a total of 5% of patients achieved a partial response with a median PFS of 3.8 months (95% CI 3.6–7.3).
      The ClarIDHy phase III clinical trial evaluated the role of ivosidenib in patients with IDH1-mutant (R132C/L/G/H/S mutation variants) CCA following progression on prior chemotherapy.
      • Abou-Alfa G.K.
      • Macarulla Mercade T.
      • Javle M.
      • Kelley R.K.
      • Lubner S.
      • Adeva J.
      • et al.
      ClarIDHy: a global, phase 3, randomized, double-blind study of ivosidenib (IVO) vs. placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation.
      Patients were randomised 2:1 to ivosidenib or placebo with cross-over permitted from placebo to ivosidenib following disease progression. The primary endpoint was PFS by central review. Following randomisation of 185 patients (91% iCCA; 124 patients to ivosidenib and 61 to placebo), the primary endpoint of PFS was met with an HR of 0.37 (95% CI 0.25–0.54; p <0.001) and median PFS of 2.7 months and 1.4 months for ivosidenib and placebo, respectively. Although the absolute differences in median PFS may not seem clinically meaningful, the PFS rates at 6 and 12 months were superior and clinically relevant (32.0% and 21.9% in ivosidenib arm at 6 and 12 months, respectively; 0% at both 6 and 12 months in the placebo arm). The radiological response rate of ivosidenib was low (2.4%). Ivosidenib did impact on OS, with a median OS of 10.8 months in the ivosidenib arm and 6 months in the placebo arms, when adjusted for cross-over (derived using rank preserved structural failure time model) (HR 0.46; p = 0.0008). Unadjusted OS in the placebo arm (57% of patients receiving placebo crossed over) was 9.7 months. The toxicity profile was in keeping with the previously reported findings.
      • Lowery M.A.
      • Burris III, H.A.
      • Janku F.
      • Shroff R.T.
      • Cleary J.M.
      • Azad N.S.
      • et al.
      Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study.
      Based on these findings, ivosidenib had a positive impact on PFS and OS and is likely to become a new standard of care for patients with IDH1-mutant CCA that is refractory to chemotherapy.
      In order to improve outcomes further for patients with IDH-mutant tumours, it is likely that the effect of IDH inhibition beyond the IDH1 R132C/L/G/H/S mutations needs to be explored since the ClarIDHy trial only included patients with these variants. In addition, mechanisms of resistance need to be understood. Mutant IDH isoform switching (from mutant IDH1 to mutant IDH2 or vice versa) may be one of these mechanisms of resistance. Translational research needs to be incorporated into future studies to improve our understanding of how to overcome such resistance.
      • Harding J.J.
      • Lowery M.A.
      • Shih A.H.
      • Schvartzman J.M.
      • Hou S.
      • Famulare C.
      • et al.
      Isoform switching as a mechanism of acquired resistance to mutant isocitrate dehydrogenase inhibition.
      A combination of IDH inhibitors with chemotherapy is likely to be the next step in the development of this compound (probably in the first-line setting). In addition, other potential combination strategies to enhance the anti-tumour effect include, but are not limited to: poly(adenosine 5′-diphosphate-ribose) polymerase (PARP) inhibitors, based on the fact that IDH1 and IDH2 mutations induce a homologous recombination defect similar to a “BRCAness” phenotype;
      • Sulkowski P.L.
      • Corso C.D.
      • Robinson N.D.
      • Scanlon S.E.
      • Purshouse K.R.
      • Bai H.
      • et al.
      2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity.
      or demethylating agents, due to the capacity of 2HG to inhibit DNA and protein demethylation leading to a hypermethylation profile.
      • Schvartzman J.M.
      • Reuter V.P.
      • Koche R.P.
      • Thompson C.B.
      2-hydroxyglutarate inhibits MyoD-mediated differentiation by preventing H3K9 demethylation.

       The role of fibroblast growth factor receptor

      FGFRs are a family of 4 trans-membrane receptors with intracellular tyrosine kinase domains (FGFR1-4).
      • Touat M.
      • Ileana E.
      • Postel-Vinay S.
      • Andre F.
      • Soria J.C.
      Targeting FGFR signaling in cancer.
      The fifth member of the family (FGFR5) is a co-receptor for FGFR1 and does not contain an intracellular tyrosine kinase domain; it is therefore not considered of relevance in carcinogenesis. Up to 22 FGF ligands have been identified which, when linked to FGFR, activate intracellular survival and proliferative pathways, including angiogenesis
      • Presta M.
      • Chiodelli P.
      • Giacomini A.
      • Rusnati M.
      • Ronca R.
      Fibroblast growth factors (FGFs) in cancer: FGF traps as a new therapeutic approach.
      (Fig. 3).
      Figure thumbnail gr3
      Fig. 3FGFR pathway.
      In the presence of an activated FGFR (due to presence of FGF or due to fusions or activating mutations), the intracellular tyrosine kinase of the FGFR transmembrane receptor will be activated via phosphorylation. This induces activation of intracellular pathways which results in the transcription of genes in the nucleus related to cell proliferation, migration, differentiation and survival. A constitutively activated FGFR may therefore produce pathological transcription of such genes and result in carcinogenesis and cancer-related processes. Adapted from.
      • Presta M.
      • Chiodelli P.
      • Giacomini A.
      • Rusnati M.
      • Ronca R.
      Fibroblast growth factors (FGFs) in cancer: FGF traps as a new therapeutic approach.
      ,
      • 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.
      • Hallinan N.
      • Finn S.
      • Cuffe S.
      • Rafee S.
      • O'Byrne K.
      • Gately K.
      Targeting the fibroblast growth factor receptor family in cancer.
      • Liang G.
      • Liu Z.
      • Wu J.
      • Cai Y.
      • Li X.
      Anticancer molecules targeting fibroblast growth factor receptors.
      FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor.
      FGFR aberrations have been identified in 7.1% of all cancers with a predominance of alterations in FGFR1 (49% [FGFR1] vs. 19% [FGFR2] vs. 26% [FGFR3] vs. 7% [FGFR4] vs. 0% [FGFR5]) when all cancers are analysed together.
      • 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.
      CCA is one of the tumour subtypes in which these are more commonly identified, together with urothelial carcinoma, breast, endometrial, ovarian, unknown primary cancers and gliomas.
      • 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.
      Alterations in FGFR identified in CCA are mostly located in the gene coding for FGFR2 (with a minority of FGFR1 alterations (0.9% [FGFR1] vs. 6.1% [FGFR2] vs. 0% for the other family members); in addition, there is a predominance of rearrangements or fusions (3.5%) over amplifications (2.6%), with few mutation events (0.9%).
      • 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.
      Genome-wide structural analyses identified recurrent FGFR2 translocation.
      • Borad M.J.
      • Champion M.D.
      • Egan J.B.
      • Liang W.S.
      • Fonseca R.
      • Bryce A.H.
      • et al.
      Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma.
      FGFR2 tyrosine kinase fusions are involved in oncogenesis by activation of multiple canonical signalling events downstream of FGFR
      • Presta M.
      • Chiodelli P.
      • Giacomini A.
      • Rusnati M.
      • Ronca R.
      Fibroblast growth factors (FGFs) in cancer: FGF traps as a new therapeutic approach.
      ,
      • 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.
      • Hallinan N.
      • Finn S.
      • Cuffe S.
      • Rafee S.
      • O'Byrne K.
      • Gately K.
      Targeting the fibroblast growth factor receptor family in cancer.
      • Liang G.
      • Liu Z.
      • Wu J.
      • Cai Y.
      • Li X.
      Anticancer molecules targeting fibroblast growth factor receptors.
      • Babina I.S.
      • Turner N.C.
      Advances and challenges in targeting FGFR signalling in cancer.
      (Fig. 3). Wu et al. reported the first 2 cases of patients with iCCA tumours with FGFR2-BICC1 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.
      Even though BICC1 is one of the most frequent fusion companions for FGFR2, multiple other partners have been identified.
      • Borad M.J.
      • Champion M.D.
      • Egan J.B.
      • Liang W.S.
      • Fonseca R.
      • Bryce A.H.
      • et al.
      Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma.
      ,
      • Churi C.R.
      • Shroff R.
      • Wang Y.
      • Rashid A.
      • Kang H.C.
      • Weatherly J.
      • et al.
      Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications.
      ,
      • Javle M.M.
      • Murugesan K.
      • Shroff R.T.
      • Borad M.J.
      • Abdel-Wahab R.
      • Schrock A.B.
      • et al.
      Profiling of 3,634 cholangiocarcinomas (CCA) to identify genomic alterations (GA), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH).
      ,
      • 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.
      ,
      • Sia D.
      • Losic B.
      • Moeini A.
      • Cabellos L.
      • Hao K.
      • Revill K.
      • et al.
      Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma.
      ,
      • 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.
      It seems clear that FGFR2 fusions are more relevant than mutations when it comes to the treatment of iCCA.
      • Javle M.
      • Lowery M.
      • Shroff R.T.
      • Weiss K.H.
      • Springfeld C.
      • Borad M.J.
      • et al.
      Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma.
      Whether specific partners have any relevance in terms of carcinogenesis or response to therapy is still to be elucidated.
      Around 10–20% of iCCAs are expected to harbour fusions in the FGFR2 gene
      • Valle J.W.
      • Lamarca A.
      • Goyal L.
      • Barriuso J.
      • Zhu A.X.
      New horizons for precision medicine in biliary tract cancers.
      ,
      • Nakamura H.
      • Arai Y.
      • Totoki Y.
      • Shirota T.
      • Elzawahry A.
      • Kato M.
      • et al.
      Genomic spectra of biliary tract cancer.
      ,
      • Javle M.
      • Bekaii-Saab T.
      • Jain A.
      • Wang Y.
      • Kelley R.K.
      • Wang K.
      • et al.
      Biliary cancer: utility of next-generation sequencing for clinical management.
      ,
      • Silverman I.M.
      • Murugesan K.
      • Lihou C.F.
      • Féliz L.
      • Frampton G.M.
      • Newton R.C.
      • et al.
      Comprehensive genomic profiling in FIGHT-202 reveals the landscape of actionable alterations in advanced cholangiocarcinoma.
      ,
      • Kipp B.R.
      • Voss J.S.
      • Kerr S.E.
      • Barr Fritcher E.G.
      • Graham R.P.
      • Zhang L.
      • et al.
      Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma.
      (Fig. 1), mainly in non-OV-related iCCA
      • Chan-On W.
      • Nairismagi 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.
      ,
      • 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.
      with increased incidence in females.
      • Javle M.
      • Lowery M.
      • Shroff R.T.
      • Weiss K.H.
      • Springfeld C.
      • Borad M.J.
      • et al.
      Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma.
      ,
      • Mazzaferro V.
      • El-Rayes B.F.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • Masi G.
      • et al.
      ARQ 087, an oral pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with advanced intrahepatic cholangiocarcinoma (iCCA) with FGFR2 genetic aberrations. ASCO Annual Meeting 2017.
      FGFR2 fusion-positive tumours seem to present with concomitant mutations in BAP1
      • 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.
      and have been shown to be associated with indolent disease and a better prognosis.
      • Jain A.
      • Kwong L.N.
      • Javle M.
      Genomic profiling of biliary tract cancers and implications for clinical practice.
      ,
      • Churi C.R.
      • Shroff R.
      • Wang Y.
      • Rashid A.
      • Kang H.C.
      • Weatherly J.
      • et al.
      Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications.
      ,
      • 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.
      Some research groups have also seen an association between BAP1 mutations and skeletal bone metastases.
      • Churi C.R.
      • Shroff R.
      • Wang Y.
      • Rashid A.
      • Kang H.C.
      • Weatherly J.
      • et al.
      Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications.
      FGFR aberrations were initially targeted with non-selective multi-TKIs such as dovitinib, ponatinib, lucitanib, lenvatinib, pazopanib and regorafenib that, in addition to targeting FGFR, also inhibited other tyrosine kinases including c-kit, FLT3, vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), c-SRC and RET.
      • Touat M.
      • Ileana E.
      • Postel-Vinay S.
      • Andre F.
      • Soria J.C.
      Targeting FGFR signaling in cancer.
      ,
      • Presta M.
      • Chiodelli P.
      • Giacomini A.
      • Rusnati M.
      • Ronca R.
      Fibroblast growth factors (FGFs) in cancer: FGF traps as a new therapeutic approach.
      ,
      • Hallinan N.
      • Finn S.
      • Cuffe S.
      • Rafee S.
      • O'Byrne K.
      • Gately K.
      Targeting the fibroblast growth factor receptor family in cancer.
      ,
      • Chae Y.K.
      • Ranganath K.
      • Hammerman P.S.
      • Vaklavas C.
      • Mohindra N.
      • Kalyan A.
      • et al.
      Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application.
      Such molecules did show some activity in iCCA harbouring FGFR2 fusions.
      • Borad M.J.
      • Champion M.D.
      • Egan J.B.
      • Liang W.S.
      • Fonseca R.
      • Bryce A.H.
      • et al.
      Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma.
      Development of selective FGFR TKI inhibitors followed, with development of multiple compounds. Some of these compounds (AZD4547 (AstraZeneca); BAY1163877 (Rogaratinib, Bayer
      • Collin M.P.
      • Lobell M.
      • Hubsch W.
      • Brohm D.
      • Schirok H.
      • Jautelat R.
      • et al.
      Discovery of Rogaratinib (BAY 1163877): a pan-FGFR inhibitor.
      ); LY2874455 (Lilly
      • Michael M.
      • Bang Y.J.
      • Park Y.S.
      • Kang Y.K.
      • Kim T.M.
      • Hamid O.
      • et al.
      A phase 1 study of LY2874455, an oral selective pan-FGFR inhibitor, in patients with advanced cancer.
      )) are not being developed for iCCA and will therefore not be discussed further.
      • Touat M.
      • Ileana E.
      • Postel-Vinay S.
      • Andre F.
      • Soria J.C.
      Targeting FGFR signaling in cancer.
      ,
      • Presta M.
      • Chiodelli P.
      • Giacomini A.
      • Rusnati M.
      • Ronca R.
      Fibroblast growth factors (FGFs) in cancer: FGF traps as a new therapeutic approach.
      ,
      • Hallinan N.
      • Finn S.
      • Cuffe S.
      • Rafee S.
      • O'Byrne K.
      • Gately K.
      Targeting the fibroblast growth factor receptor family in cancer.
      ,
      • Chae Y.K.
      • Ranganath K.
      • Hammerman P.S.
      • Vaklavas C.
      • Mohindra N.
      • Kalyan A.
      • et al.
      Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application.
      Many FGFR inhibitors are currently being developed, most of which have already shown adequate safety in phase I trials and early efficacy in phase II studies in patients with refractory iCCA (Table 1).
      • Javle M.
      • Lowery M.
      • Shroff R.T.
      • Weiss K.H.
      • Springfeld C.
      • Borad M.J.
      • et al.
      Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma.
      ,
      • Mazzaferro V.
      • El-Rayes B.F.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • Masi G.
      • et al.
      ARQ 087, an oral pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with advanced intrahepatic cholangiocarcinoma (iCCA) with FGFR2 genetic aberrations. ASCO Annual Meeting 2017.
      ,
      • Hollebecque A.
      • Borad M.
      • Sahai V.
      • Catenacci D.V.T.
      • Murphy A.
      • Vaccaro G.
      • et al.
      Interim results of fight-202, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with previously treated advanced/metastatic or surgically unresectable cholangiocarcinoma (CCA) with/without fibroblast growth factor (FGF)/FGF receptor (FGFR) genetic alterations.
      • Vogel A.
      • Sahai V.
      • Hollebecque A.
      • Vaccaro G.
      • Melisi D.
      • Al-Rajabi R.
      • et al.
      FIGHT-202: a phase 2 study of pemigatinib in patients (pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA).
      • Javle M.
      • Kelley R.K.
      • Roychowdhury S.
      • Weiss K.H.
      • Abou-Alfa G.K.
      • Macarulla T.
      • et al.
      Updated results from a phase II study of infigratinib (BGJ398), a selective pan-FGFR kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions.
      • Meric-Bernstam B.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. ESMO Annual Meeting 2018.
      • Tran B.
      • Meric-Bernstam F.
      • Arkenau H.
      • Bahleda R.
      • Kelley R.K.
      • Hierro C.
      • et al.
      Efficacy of TAS-120, an irreversible fibroblast growth factor receptor inhibitor (FGFRi), in patients with cholangiocarcinoma and FGFR pathway alterations previously treated with chemotherapy and other FGFRi's.
      • Mazzaferro V.
      • El-Rayes B.F.
      • Droz Dit B.M.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • et al.
      Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma.
      • Cleary J.M.
      • Voss M.H.
      • Meric-Bernstam F.
      • Hierro C.
      • Heist R.S.
      • Ishii N.
      • et al.
      safety and efficacy of the selective FGFR inhibitor debio 1347 in phase I study patients with FGFR genomically activated advanced biliary tract cancer (BTC).
      • Ng M.C.H.
      • Goyal L.
      • Bang Y.-J.
      • Oh D.-Y.
      • Chao T.-Y.
      • Cleary J.M.
      • et al.
      Debio 1347 in patients with cholangiocarcinoma harboring an FGFR gene alteration: preliminary results.
      • Bahleda R.
      • Italiano A.
      • Hierro C.
      • Mita A.
      • Cervantes A.
      • Chan N.
      • et al.
      Multicenter phase I study of erdafitinib (JNJ-42756493), oral pan-fibroblast growth factor receptor inhibitor, in patients with advanced or refractory solid tumors.
      • Soria J.-C.
      • Strickler J.H.
      • Govindan R.
      • Chai S.
      • Chan N.
      • Quiroga-Garcia V.
      • et al.
      Safety and activity of the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients (Pts) with molecularly selected advanced cholangiocarcinoma (CCA).
      Table 1Current status of development of FGFR2 inhibitors in iCCA.
      Drug; Author, referenceType of moleculeCurrent status of drug developmentCCA population testedTreatment administeredResponse rate achievedTreatment-related toxicity
      Pemigatinib-INCB054828 (Incyte®)
      • Hollebecque A.
      • Borad M.
      • Sahai V.
      • Catenacci D.V.T.
      • Murphy A.
      • Vaccaro G.
      • et al.
      Interim results of fight-202, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with previously treated advanced/metastatic or surgically unresectable cholangiocarcinoma (CCA) with/without fibroblast growth factor (FGF)/FGF receptor (FGFR) genetic alterations.
      ,
      • Vogel A.
      • Sahai V.
      • Hollebecque A.
      • Vaccaro G.
      • Melisi D.
      • Al-Rajabi R.
      • et al.
      FIGHT-202: a phase 2 study of pemigatinib in patients (pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA).
      Selective oral TKI

      Target: FGFR 1-3 and VEGFR2.
      Phase II study (FIGHT-202; NCT02924376) presented ESMO
      • Hollebecque A.
      • Borad M.
      • Sahai V.
      • Catenacci D.V.T.
      • Murphy A.
      • Vaccaro G.
      • et al.
      Interim results of fight-202, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with previously treated advanced/metastatic or surgically unresectable cholangiocarcinoma (CCA) with/without fibroblast growth factor (FGF)/FGF receptor (FGFR) genetic alterations.
      2018 with updated data ESMO 2019.
      • Vogel A.
      • Sahai V.
      • Hollebecque A.
      • Vaccaro G.
      • Melisi D.
      • Al-Rajabi R.
      • et al.
      FIGHT-202: a phase 2 study of pemigatinib in patients (pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA).
      Ongoing Phase III trial in the first-line setting (FIGHT-302; NCT03656536).
      Previously treated CCA (146 patients).

      • Cohort A (FGFR2 fusions): 107 patients (98% iCCA; 93% ≥2 prior therapies)

      • Cohort B (other FGF/FGFR alterations): 20 patients (65% iCCA).

      • Cohort C (no FGF/FGFR alterations): 18 patients (61% iCCA)
      INCB054828 13.5 mg once daily on a 21-day cycle (2 weeks on, 1 week off) until disease progression or unacceptable toxicity.• Cohort A (FGFR2 translocations): ORR: 35.5% (3 CR), mDOR: 7.5 months, DCR: 82% mPFS 6.9 months (95% CI 6.2–9.6)

      • Cohort B (other FGF/FGFR alterations): 0% PR; mPFS 1.4 months
      Data from.145


      • Cohort C (no FGF/FGFR alterations): 0% PR; mPFS 1.5 months
      Data from.145
      Any grade: hyperphosphatemia (60%), alopecia (49%), diarrhoea (47%), fatigue (43%), nail toxicities (42%), and dysgeusia (40%).

      Grade 3/4 toxicities: hyponatremia (8%) and hypophosphatemia (7%)
      Data from.145
      .

      Discontinuation (9%), dose reduction (14%) and interruption (42%) due to AEs.
      Infigratinib-BGJ398 (QED®/Novartis®)
      • Javle M.
      • Lowery M.
      • Shroff R.T.
      • Weiss K.H.
      • Springfeld C.
      • Borad M.J.
      • et al.
      Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma.
      ,
      • Javle M.
      • Kelley R.K.
      • Roychowdhury S.
      • Weiss K.H.
      • Abou-Alfa G.K.
      • Macarulla T.
      • et al.
      Updated results from a phase II study of infigratinib (BGJ398), a selective pan-FGFR kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions.
      Selective oral TKI

      Target: FGFR 1-3 (IC50 0.9, 1.4 and 1 nM, respectively)/FGFR4 (IC50 60 nM).
      Phase II study (NCT02150967) published in 2018
      • Javle M.
      • Lowery M.
      • Shroff R.T.
      • Weiss K.H.
      • Springfeld C.
      • Borad M.J.
      • et al.
      Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma.
      with updated data (+28 patients with FGFR2 fusion) presented ESMO 2018.
      • Javle M.
      • Kelley R.K.
      • Roychowdhury S.
      • Weiss K.H.
      • Abou-Alfa G.K.
      • Macarulla T.
      • et al.
      Updated results from a phase II study of infigratinib (BGJ398), a selective pan-FGFR kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions.
      Ongoing Phase III trial in the first-line setting (PROOF; NCT03773302).
      Previously treated CCA (61 patients → 84
      Data from expanded FGFR2 fusion cohort patients.147
      )

      FGFR2 fusions: 48 patients → expanded up to 71 patients
      • Javle M.
      • Kelley R.K.
      • Roychowdhury S.
      • Weiss K.H.
      • Abou-Alfa G.K.
      • Macarulla T.
      • et al.
      Updated results from a phase II study of infigratinib (BGJ398), a selective pan-FGFR kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions.
      Data from expanded FGFR2 fusion cohort patients.147


      FGFR2 mutation: 8 patients

      FGFR2 amplification: 3 patients
      BGJ398 125 mg once daily for 21 days, then 7 days off (28-day cycles).• PR: 14.8%; DCR: 75.4%

      FGFR2 fusions: 18.8% PR; DCR 83.3%; mPFS 5.8 months (9% CI 4.3–7.6) → expanded cohort
      Data from expanded FGFR2 fusion cohort patients.147
      : 31.0% PR; DCR 83.6%, mPFS 6.8 months (95% CI 5.3–7.6)

      FGFR2 mutation: 0% PR

      FGFR2 amplification: 0% PR
      Any grade: hyperphosphatemia (72.1%), fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%).

      Grade 3/4 (41%/66.2%
      Data from expanded FGFR2 fusion cohort patients.147
      ): hyperphosphatemia (16.4%/12.7%
      Data from expanded FGFR2 fusion cohort patients.147
      ), hypophosphatemia (14.1%
      Data from expanded FGFR2 fusion cohort patients.147
      ), mucositis (6.6%), and palmar-plantar erythrodysaesthesia (4.9%).

      Most common any grade TEAEs: hyperphosphatemia (73.2%), fatigue (49.3%), stomatitis (45.1%), alopecia (38.0%), and constipation (35.2%).
      TAS-120 (futibatinib) (Taiho®)
      • Meric-Bernstam B.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. ESMO Annual Meeting 2018.
      ,
      • Tran B.
      • Meric-Bernstam F.
      • Arkenau H.
      • Bahleda R.
      • Kelley R.K.
      • Hierro C.
      • et al.
      Efficacy of TAS-120, an irreversible fibroblast growth factor receptor inhibitor (FGFRi), in patients with cholangiocarcinoma and FGFR pathway alterations previously treated with chemotherapy and other FGFRi's.
      Highly selective (irreversible) oral TKI

      Target: FGFR 1-4 (inhibits all 4 subtypes of FGFR with enzyme IC50 values of 3.9 nM, 1.3 nM, 1.6 nM and 8.3 nM for FGFR1, FGFR2, FGFR3 and FGFR4, respectively)

      Inhibits mutant and wild-type FGFR2 with similar IC50 (wild-type FGFR2, 0.9 nM; V5651, 1–3 nM; N550H, 3.6 nM; E566G, 2.4 nM).
      Safety and preliminary efficacy data available from phase I/II trial (presented ESMO Asia and ESMO GI 2018) (NCT02052778); phase II part currently recruiting.Cohort of pretreated CCA (45 patients) harbouring FGF/FGFR aberrations.

      FGFR2 gene fusions: 28 patients (62%)

      • Other FGF/FGFR aberrations: 17 (38%)

      13 patients received ≥1 prior reversible FGFRi.
      TAS-120 (maximum tolerated dose defined as 20 mg once a day) until disease progression or unacceptable toxicity. CCA pts were enrolled at 16 mg (24 patients), 20 mg (14 patients), and 24 mg (7 patients) dosing levels.FGFR2 fusions: 25% PR; SD 54%; DCR: 79%

      • Other FGF/FGFR aberrations: 3/17 (17.6%) PR (all had FGFR2 rearrangements; 1 also had FGFR2 amplification)

      • Prior FGFRi: 4/13 (30.8%) PR (3 with FGFR2 gene fusions, 1 with FGFR2 amplification)
      Any grade: hyperphosphatemia (78%), increased aspartate aminotransferase (29%), dry skin (29%), diarrhoea (27%), and dry mouth (27%).

      Grade ≥3 (51%): hyperphosphatemia (22%).
      ARQ087-Derazantinib (Basilea/ArQule®)
      • Mazzaferro V.
      • El-Rayes B.F.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • Masi G.
      • et al.
      ARQ 087, an oral pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with advanced intrahepatic cholangiocarcinoma (iCCA) with FGFR2 genetic aberrations. ASCO Annual Meeting 2017.
      ,
      • Mazzaferro V.
      • El-Rayes B.F.
      • Droz Dit B.M.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • et al.
      Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma.
      Non-selective oral multi-TKI with potent pan-FGFR activity.

      Targets: RET, PDGFR, KIT, SRC, and FGFR1-3 (IC50 1.8 for FGFR2 IC50 4.5 for FGFR1 and FGFR3). IC50 for FGFR4 34 nM.
      Preliminary data from the phase I/II basket trial indicated activity in FGFR2 fusion-positive iCCA (3/12 (25%) PR) (NCT01752920).
      • Mazzaferro V.
      • El-Rayes B.F.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • Masi G.
      • et al.
      ARQ 087, an oral pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with advanced intrahepatic cholangiocarcinoma (iCCA) with FGFR2 genetic aberrations. ASCO Annual Meeting 2017.
      Data for iCCA with FGFR2 fusion were separately reported.
      • Mazzaferro V.
      • El-Rayes B.F.
      • Droz Dit B.M.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • et al.
      Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma.


      Currently being evaluated in a phase II trial in iCCA (FIDES-01 trial; NCT03230318).
      Pretreated iCCA patients (35 patients) with FGFR2 genetic aberrations. 29/35 patients had FGFR2 fusion-positive tumours.ARQ087 300 (33 patients) or 400 mg (2 patients) daily until disease progression or unacceptable toxicity. Recommended phase II dose: 300 mg QD.
      • Papadopoulos K.P.
      • El-Rayes B.F.
      • Tolcher A.W.
      • Patnaik A.
      • Rasco D.W.
      • Harvey R.D.
      • et al.
      A phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours.
      • 30 patients evaluable for response: 20% PR (all FGFR2 fusion-positive)

      FGFR2 fusion-positive patients
      Data for patients with FGFR2 fusion only.150
      : 20.7% PR; 82.8% DCR, mPFS 5.7 months.
      Any grade (89%): nausea (37%), dry mouth (29%), asthenia (26%), fatigue (23%), vomiting (23%), abnormal LFTs (20%), dysgeusia (20%), alopecia (14%), diarrhoea (14%), vision blurred (14%), and conjunctivitis (11%).

      Grade 3/4: asthenia (6%), and abnormal LFTs (6%).
      Debio1347 (Debiopharm Group ®)
      • Cleary J.M.
      • Voss M.H.
      • Meric-Bernstam F.
      • Hierro C.
      • Heist R.S.
      • Ishii N.
      • et al.
      safety and efficacy of the selective FGFR inhibitor debio 1347 in phase I study patients with FGFR genomically activated advanced biliary tract cancer (BTC).
      ,
      • Ng M.C.H.
      • Goyal L.
      • Bang Y.-J.
      • Oh D.-Y.
      • Chao T.-Y.
      • Cleary J.M.
      • et al.
      Debio 1347 in patients with cholangiocarcinoma harboring an FGFR gene alteration: preliminary results.
      Selective oral TKI

      Target: FGFR 1-3 (IC50 of 9.3 nM, 7.6 nM, 22 nM, and 290 nM for FGFR1, FGFR2, FGFR3, and FGFR4, respectively).
      Safety shown in phase I trial (NCT1948297). CCA data reported by Cleary et al.
      • Cleary J.M.
      • Voss M.H.
      • Meric-Bernstam F.
      • Hierro C.
      • Heist R.S.
      • Ishii N.
      • et al.
      safety and efficacy of the selective FGFR inhibitor debio 1347 in phase I study patients with FGFR genomically activated advanced biliary tract cancer (BTC).
      and Ng 2019.
      • Ng M.C.H.
      • Goyal L.
      • Bang Y.-J.
      • Oh D.-Y.
      • Chao T.-Y.
      • Cleary J.M.
      • et al.
      Debio 1347 in patients with cholangiocarcinoma harboring an FGFR gene alteration: preliminary results.
      Currently phase II basket trial ongoing recruiting patients with FGFR1-3 fusions (tumour-agnostic) (FUZE trial; NCT03834220).
      Patients with pretreated biliary tract (iCCA (6 patients; 3 FGFR2 fusion) and GBC (2 patients; none with FGFR2 fusions) with alterations of FGFR 1, 2, or 3.

      Separately, data on 9 CCA
      • Ng M.C.H.
      • Goyal L.
      • Bang Y.-J.
      • Oh D.-Y.
      • Chao T.-Y.
      • Cleary J.M.
      • et al.
      Debio 1347 in patients with cholangiocarcinoma harboring an FGFR gene alteration: preliminary results.
      (all iCCA; 5 FGFR2 fusion) were reported
      Cohort of 9 patients with CCA.152
      .
      Debio 1347 at doses between 60 and 150 mg orally daily in 28-day cycles until disease progression or unacceptable toxicity.• 1/8 PR (FGFR2 deletion); DCR 62.5%.

      • For the iCCA updated cohort
      Cohort of 9 patients with CCA.152
      : 2/9 (22%) PR (1 in a patient with FGFR2 translocation).
      Any grade: hyperphosphatemia (8/8), nail changes (5/8), nausea (5/8), dry mouth (4/8) and stomatitis (3/8).

      Grade ≥3: hyperphosphatemia (4/8); (33%
      Cohort of 9 patients with CCA.152
      ).
      JNJ-42756493-Erdafitinib (Janssen®)
      • Bahleda R.
      • Italiano A.
      • Hierro C.
      • Mita A.
      • Cervantes A.
      • Chan N.
      • et al.
      Multicenter phase I study of erdafitinib (JNJ-42756493), oral pan-fibroblast growth factor receptor inhibitor, in patients with advanced or refractory solid tumors.
      ,
      • Soria J.-C.
      • Strickler J.H.
      • Govindan R.
      • Chai S.
      • Chan N.
      • Quiroga-Garcia V.
      • et al.
      Safety and activity of the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients (Pts) with molecularly selected advanced cholangiocarcinoma (CCA).
      Selective oral TKI

      Target: FGFR 1–4 (IC50 <1 nM).
      Phase I trial data available (NCT01703481); new trial ongoing and recruiting cohort of cholangiocarcinoma (NCT02699606).Patients with re-treated solid tumours harbouring activating FGFR genomic alterations (187 patients; 11 CCA).JNJ-42756493-dose escalation: 9 mg once daily and 10 mg intermittently (7 days on/7 days off), as previously published.
      • Tabernero J.
      • Bahleda R.
      • Dienstmann R.
      • Infante J.R.
      • Mita A.
      • Italiano A.
      • et al.
      Phase I dose-escalation study of JNJ-42756493, an oral pan-fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors.
      • CCA cohort in response evaluable patients with FGFR mutation/fusion: 27.3% (3/11) PR (all at 10 mg dose).

      • Updated data
      Updated data CCA cohort.154
      : mDOR 12.9 months; DCR: 55%; mPFS: 5.1 months (1.6–16.4).
      Any grade
      Updated data CCA cohort.154
      : stomatitis (82%), hyperphosphatemia (64%), dry mouth (55%), dysgeusia (45%), dry skin (45%), and asthenia (45%)

      Grade ≥3
      Updated data CCA cohort.154
      : stomatitis (18%).
      Data extracted from.
      • Javle M.
      • Lowery M.
      • Shroff R.T.
      • Weiss K.H.
      • Springfeld C.
      • Borad M.J.
      • et al.
      Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma.
      ,
      • Mazzaferro V.
      • El-Rayes B.F.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • Masi G.
      • et al.
      ARQ 087, an oral pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with advanced intrahepatic cholangiocarcinoma (iCCA) with FGFR2 genetic aberrations. ASCO Annual Meeting 2017.
      ,
      • Hollebecque A.
      • Borad M.
      • Sahai V.
      • Catenacci D.V.T.
      • Murphy A.
      • Vaccaro G.
      • et al.
      Interim results of fight-202, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with previously treated advanced/metastatic or surgically unresectable cholangiocarcinoma (CCA) with/without fibroblast growth factor (FGF)/FGF receptor (FGFR) genetic alterations.
      • Vogel A.
      • Sahai V.
      • Hollebecque A.
      • Vaccaro G.
      • Melisi D.
      • Al-Rajabi R.
      • et al.
      FIGHT-202: a phase 2 study of pemigatinib in patients (pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA).
      • Javle M.
      • Kelley R.K.
      • Roychowdhury S.
      • Weiss K.H.
      • Abou-Alfa G.K.
      • Macarulla T.
      • et al.
      Updated results from a phase II study of infigratinib (BGJ398), a selective pan-FGFR kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions.
      • Meric-Bernstam B.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. ESMO Annual Meeting 2018.
      • Tran B.
      • Meric-Bernstam F.
      • Arkenau H.
      • Bahleda R.
      • Kelley R.K.
      • Hierro C.
      • et al.
      Efficacy of TAS-120, an irreversible fibroblast growth factor receptor inhibitor (FGFRi), in patients with cholangiocarcinoma and FGFR pathway alterations previously treated with chemotherapy and other FGFRi's.
      • Mazzaferro V.
      • El-Rayes B.F.
      • Droz Dit B.M.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • et al.
      Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma.
      • Cleary J.M.
      • Voss M.H.
      • Meric-Bernstam F.
      • Hierro C.
      • Heist R.S.
      • Ishii N.
      • et al.
      safety and efficacy of the selective FGFR inhibitor debio 1347 in phase I study patients with FGFR genomically activated advanced biliary tract cancer (BTC).
      • Ng M.C.H.
      • Goyal L.
      • Bang Y.-J.
      • Oh D.-Y.
      • Chao T.-Y.
      • Cleary J.M.
      • et al.
      Debio 1347 in patients with cholangiocarcinoma harboring an FGFR gene alteration: preliminary results.
      • Bahleda R.
      • Italiano A.
      • Hierro C.
      • Mita A.
      • Cervantes A.
      • Chan N.
      • et al.
      Multicenter phase I study of erdafitinib (JNJ-42756493), oral pan-fibroblast growth factor receptor inhibitor, in patients with advanced or refractory solid tumors.
      • Soria J.-C.
      • Strickler J.H.
      • Govindan R.
      • Chai S.
      • Chan N.
      • Quiroga-Garcia V.
      • et al.
      Safety and activity of the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients (Pts) with molecularly selected advanced cholangiocarcinoma (CCA).
      IC50 data also extracted from.
      Selleck Chemicals LLC.
      AEs, adverse events; CCA, cholangiocarcinoma; CR, complete response; DCR, disease control rate; FGFR, fibroblast growth factor receptor; GBC, gallbladder cancer; IC50, half maximal inhibitory concentration; iCCA, intrahepatic cholangiocarcinoma; LFTs, liver function tests; mDOR, median duration of response; mPFS, median progression-free survival; PDGFR, platelet-derived growth factor receptor; PR, partial response; ORR, objective response rate; TEAEs, treatment-emergent adverse events; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor.
      Data from.
      • Hollebecque A.
      • Borad M.
      • Sahai V.
      • Catenacci D.V.T.
      • Murphy A.
      • Vaccaro G.
      • et al.
      Interim results of fight-202, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with previously treated advanced/metastatic or surgically unresectable cholangiocarcinoma (CCA) with/without fibroblast growth factor (FGF)/FGF receptor (FGFR) genetic alterations.
      $ Data from expanded FGFR2 fusion cohort patients.
      • Javle M.
      • Kelley R.K.
      • Roychowdhury S.
      • Weiss K.H.
      • Abou-Alfa G.K.
      • Macarulla T.
      • et al.
      Updated results from a phase II study of infigratinib (BGJ398), a selective pan-FGFR kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions.
      £ Data for patients with FGFR2 fusion only.
      • Mazzaferro V.
      • El-Rayes B.F.
      • Droz Dit B.M.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • et al.
      Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma.
      & Cohort of 9 patients with CCA.
      • Ng M.C.H.
      • Goyal L.
      • Bang Y.-J.
      • Oh D.-Y.
      • Chao T.-Y.
      • Cleary J.M.
      • et al.
      Debio 1347 in patients with cholangiocarcinoma harboring an FGFR gene alteration: preliminary results.
      @ Updated data CCA cohort.
      • Soria J.-C.
      • Strickler J.H.
      • Govindan R.
      • Chai S.
      • Chan N.
      • Quiroga-Garcia V.
      • et al.
      Safety and activity of the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients (Pts) with molecularly selected advanced cholangiocarcinoma (CCA).
      Multiple phase I/II clinical trials have reported a consistently high partial response rate (varying between 20.7% and 35.5%) for heavily pretreated patients with iCCA harbouring an FGFR2 fusion,
      • Hollebecque A.
      • Borad M.
      • Sahai V.
      • Catenacci D.V.T.
      • Murphy A.
      • Vaccaro G.
      • et al.
      Interim results of fight-202, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with previously treated advanced/metastatic or surgically unresectable cholangiocarcinoma (CCA) with/without fibroblast growth factor (FGF)/FGF receptor (FGFR) genetic alterations.
      • Vogel A.
      • Sahai V.
      • Hollebecque A.
      • Vaccaro G.
      • Melisi D.
      • Al-Rajabi R.
      • et al.
      FIGHT-202: a phase 2 study of pemigatinib in patients (pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA).
      • Javle M.
      • Kelley R.K.
      • Roychowdhury S.
      • Weiss K.H.
      • Abou-Alfa G.K.
      • Macarulla T.
      • et al.
      Updated results from a phase II study of infigratinib (BGJ398), a selective pan-FGFR kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions.
      • Meric-Bernstam B.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. ESMO Annual Meeting 2018.
      • Tran B.
      • Meric-Bernstam F.
      • Arkenau H.
      • Bahleda R.
      • Kelley R.K.
      • Hierro C.
      • et al.
      Efficacy of TAS-120, an irreversible fibroblast growth factor receptor inhibitor (FGFRi), in patients with cholangiocarcinoma and FGFR pathway alterations previously treated with chemotherapy and other FGFRi's.
      • Mazzaferro V.
      • El-Rayes B.F.
      • Droz Dit B.M.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • et al.
      Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma.
      ,
      • Ng M.C.H.
      • Goyal L.
      • Bang Y.-J.
      • Oh D.-Y.
      • Chao T.-Y.
      • Cleary J.M.
      • et al.
      Debio 1347 in patients with cholangiocarcinoma harboring an FGFR gene alteration: preliminary results.
      • Bahleda R.
      • Italiano A.
      • Hierro C.
      • Mita A.
      • Cervantes A.
      • Chan N.
      • et al.
      Multicenter phase I study of erdafitinib (JNJ-42756493), oral pan-fibroblast growth factor receptor inhibitor, in patients with advanced or refractory solid tumors.
      • Soria J.-C.
      • Strickler J.H.
      • Govindan R.
      • Chai S.
      • Chan N.
      • Quiroga-Garcia V.
      • et al.
      Safety and activity of the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients (Pts) with molecularly selected advanced cholangiocarcinoma (CCA).
      with a median PFS of around 6 months.
      • Javle M.
      • Lowery M.
      • Shroff R.T.
      • Weiss K.H.
      • Springfeld C.
      • Borad M.J.
      • et al.
      Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma.
      ,
      • Hollebecque A.
      • Borad M.
      • Sahai V.
      • Catenacci D.V.T.
      • Murphy A.
      • Vaccaro G.
      • et al.
      Interim results of fight-202, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with previously treated advanced/metastatic or surgically unresectable cholangiocarcinoma (CCA) with/without fibroblast growth factor (FGF)/FGF receptor (FGFR) genetic alterations.
      • Vogel A.
      • Sahai V.
      • Hollebecque A.
      • Vaccaro G.
      • Melisi D.
      • Al-Rajabi R.
      • et al.
      FIGHT-202: a phase 2 study of pemigatinib in patients (pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA).
      • Javle M.
      • Kelley R.K.
      • Roychowdhury S.
      • Weiss K.H.
      • Abou-Alfa G.K.
      • Macarulla T.
      • et al.
      Updated results from a phase II study of infigratinib (BGJ398), a selective pan-FGFR kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions.
      ,
      • Mazzaferro V.
      • El-Rayes B.F.
      • Droz Dit B.M.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • et al.
      Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma.
      ,
      • Soria J.-C.
      • Strickler J.H.
      • Govindan R.
      • Chai S.
      • Chan N.
      • Quiroga-Garcia V.
      • et al.
      Safety and activity of the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients (Pts) with molecularly selected advanced cholangiocarcinoma (CCA).
      For the majority of compounds under development, responses have been homogeneously absent for patients with other FGFR aberrations.
      • Javle M.
      • Lowery M.
      • Shroff R.T.
      • Weiss K.H.
      • Springfeld C.
      • Borad M.J.
      • et al.
      Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma.
      ,
      • Mazzaferro V.
      • El-Rayes B.F.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • Masi G.
      • et al.
      ARQ 087, an oral pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with advanced intrahepatic cholangiocarcinoma (iCCA) with FGFR2 genetic aberrations. ASCO Annual Meeting 2017.
      ,
      • Hollebecque A.
      • Borad M.
      • Sahai V.
      • Catenacci D.V.T.
      • Murphy A.
      • Vaccaro G.
      • et al.
      Interim results of fight-202, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with previously treated advanced/metastatic or surgically unresectable cholangiocarcinoma (CCA) with/without fibroblast growth factor (FGF)/FGF receptor (FGFR) genetic alterations.
      ,
      • Vogel A.
      • Sahai V.
      • Hollebecque A.
      • Vaccaro G.
      • Melisi D.
      • Al-Rajabi R.
      • et al.
      FIGHT-202: a phase 2 study of pemigatinib in patients (pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA).
      ,
      • Cleary J.M.
      • Voss M.H.
      • Meric-Bernstam F.
      • Hierro C.
      • Heist R.S.
      • Ishii N.
      • et al.
      safety and efficacy of the selective FGFR inhibitor debio 1347 in phase I study patients with FGFR genomically activated advanced biliary tract cancer (BTC).
      ,
      • Bahleda R.
      • Italiano A.
      • Hierro C.
      • Mita A.
      • Cervantes A.
      • Chan N.
      • et al.
      Multicenter phase I study of erdafitinib (JNJ-42756493), oral pan-fibroblast growth factor receptor inhibitor, in patients with advanced or refractory solid tumors.
      ,
      • Soria J.-C.
      • Strickler J.H.
      • Govindan R.
      • Chai S.
      • Chan N.
      • Quiroga-Garcia V.
      • et al.
      Safety and activity of the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients (Pts) with molecularly selected advanced cholangiocarcinoma (CCA).
      Currently, some of these agents are moving into phase III clinical trials exploring their potential role in the first-line setting compared to CisGem chemotherapy (pemigatinib-INCB054828 [FIGHT-302; NCT03656536], infigratinib-BGJ398 [PROOF; NCT03773302], futibatinib-TAS-120 [FOENIX-CCA3; NCT04093362]) for patients with FGFR2 fusion-positive tumours.
      Together with the development of FGFR inhibitors and their assessment in the clinic, research is happening in parallel to understand mechanisms of resistance to these compounds and potential ways to overcome them. Goyal and colleagues reported the first evidence of acquired resistance to FGFR inhibition in CCA.
      • Goyal L.
      • Saha S.K.
      • Liu L.Y.
      • Siravegna G.
      • Leshchiner I.
      • Ahronian L.G.
      • et al.
      Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma.
      Secondary mutations in the FGFR2 kinase domain, including the gatekeeper mutation FGFR2 V564F, were identified in all 3 patients receiving an FGFR inhibitor as a potential resistance mechanism. The presence of mutations in the TKI domain may also represent a mechanism of resistance.
      • Byron S.A.
      • Chen H.
      • Wortmann A.
      • Loch D.
      • Gartside M.G.
      • Dehkhoda F.
      • et al.
      The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib, and ponatinib ATP-competitive inhibitors.
      ,
      • Krook M.A.
      • Bonneville R.
      • Chen H.Z.
      • Reeser J.W.
      • Wing M.R.
      • Martin D.M.
      • et al.
      Tumor heterogeneity and acquired drug resistance in FGFR2-fusion-positive cholangiocarcinoma through rapid research autopsy.
      Development of novel FGFR2 fusions (FGFR2-ACSL5) has also been proposed as a potential mechanism of acquired resistance to these compounds in other disease groups.
      • Kim S.Y.
      • Ahn T.
      • Bang H.
      • Ham J.S.
      • Kim J.
      • Kim S.T.
      • et al.
      Acquired resistance to LY2874455 in FGFR2-amplified gastric cancer through an emergence of novel FGFR2-ACSL5 fusion.
      TAS-120 (futibatinib; Taiho)
      • Meric-Bernstam B.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. ESMO Annual Meeting 2018.
      ,
      • Tran B.
      • Meric-Bernstam F.
      • Arkenau H.
      • Bahleda R.
      • Kelley R.K.
      • Hierro C.
      • et al.
      Efficacy of TAS-120, an irreversible fibroblast growth factor receptor inhibitor (FGFRi), in patients with cholangiocarcinoma and FGFR pathway alterations previously treated with chemotherapy and other FGFRi's.
      is the only irreversible TKI currently available and has shown activity in cohorts of patients with FGF/FGFR aberrations beyond FGFR2 fusions, with a response rate of 17.6% in these patients.
      • Meric-Bernstam B.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. ESMO Annual Meeting 2018.
      ,
      • Tran B.
      • Meric-Bernstam F.
      • Arkenau H.
      • Bahleda R.
      • Kelley R.K.
      • Hierro C.
      • et al.
      Efficacy of TAS-120, an irreversible fibroblast growth factor receptor inhibitor (FGFRi), in patients with cholangiocarcinoma and FGFR pathway alterations previously treated with chemotherapy and other FGFRi's.
      In addition, activity of TAS-120 (futibatinib) seems significant even following progression on previous FGFR inhibitors, with a response rate of 30.8% in this setting, suggesting that it may be able to overcome mechanisms of resistance.
      The toxicity profile of these compounds is summarised in Table 1.
      • Touat M.
      • Ileana E.
      • Postel-Vinay S.
      • Andre F.
      • Soria J.C.
      Targeting FGFR signaling in cancer.
      ,
      • Mazzaferro V.
      • El-Rayes B.F.
      • Droz Dit B.M.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • et al.
      Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma.
      Specific adverse events derived from the inhibition of FGFR signalling pathways include hyperphosphataemia, nail changes with onycholysis, alopecia or hair changes, mucositis, dysgeusia, dry eye, conjunctivitis and other blurred vision/eye disturbances, myalgias/muscle pains and osteoarticular pains. Adverse events, non-specific for FGFR inhibition, include fatigue, anorexia, fever, diarrhoea and liver toxicity. When employing molecules that also target VEGFR, proteinuria, hypertension and other adverse events may appear.
      Hyperphosphataemia is an on-target adverse event that is frequently observed; it appears to be related to blockade of FGF23, which is involved in regulation of phosphorus renal excretion and phosphate bone and kidney reabsorption.
      • Liu S.
      • Quarles L.D.
      How fibroblast growth factor 23 works.
      • Wohrle S.
      • Henninger C.
      • Bonny O.
      • Thuery A.
      • Beluch N.
      • Hynes N.E.
      • et al.
      Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets.
      • Wohrle S.
      • Bonny O.
      • Beluch N.
      • Gaulis S.
      • Stamm C.
      • Scheibler M.
      • et al.
      FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone.
      However, hyperphosphatemia is rarely symptomatic and is usually well managed with dietary restrictions and phosphate binders. Interestingly, hypophosphatemia has also been reported in around 7–15% of patients treated with FGFR inhibitors and was hypothesised to be related to a “too intense” management of hyperphosphataemia or maybe the fact that patients were kept on phosphate binders while off the FGFR inhibitor.
      • Vogel A.
      • Sahai V.
      • Hollebecque A.
      • Vaccaro G.
      • Melisi D.
      • Al-Rajabi R.
      • et al.
      FIGHT-202: a phase 2 study of pemigatinib in patients (pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA).
      ,
      • Javle M.
      • Kelley R.K.
      • Roychowdhury S.
      • Weiss K.H.
      • Abou-Alfa G.K.
      • Macarulla T.
      • et al.
      Updated results from a phase II study of infigratinib (BGJ398), a selective pan-FGFR kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions.
      Despite the fact that treatment is usually well tolerated (only 9% of patients have been reported to discontinue treatment due to toxicity
      • Hollebecque A.
      • Borad M.
      • Sahai V.
      • Catenacci D.V.T.
      • Murphy A.
      • Vaccaro G.
      • et al.
      Interim results of fight-202, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with previously treated advanced/metastatic or surgically unresectable cholangiocarcinoma (CCA) with/without fibroblast growth factor (FGF)/FGF receptor (FGFR) genetic alterations.
      ,
      • Vogel A.
      • Sahai V.
      • Hollebecque A.
      • Vaccaro G.
      • Melisi D.
      • Al-Rajabi R.
      • et al.
      FIGHT-202: a phase 2 study of pemigatinib in patients (pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA).
      ) long-term adverse events (i.e. fatigue, myalgias, nail disturbances) could impact on patients' quality of life and will require management.
      FGFR2 inhibitors have shown promising results in pre-treated FGFR2 fusion-positive iCCA.
      Most of the aforementioned FGFR inhibitors are selective oral TKIs, with the exception of ARQ087 (derazantinib; Basilea/ArQule®)
      • Mazzaferro V.
      • El-Rayes B.F.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • Masi G.
      • et al.
      ARQ 087, an oral pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with advanced intrahepatic cholangiocarcinoma (iCCA) with FGFR2 genetic aberrations. ASCO Annual Meeting 2017.
      ,
      • Mazzaferro V.
      • El-Rayes B.F.
      • Droz Dit B.M.
      • Cotsoglou C.
      • Harris W.P.
      • Damjanov N.
      • et al.
      Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma.
      which is a non-selective oral multi-TKI that inhibits many other targets beyond FGFR. Despite not producing hyperphosphatemia, ARQ087 (derazantinib) had a low IC50 for FGFR inhibition
      Selleck Chemicals LLC.
      and led to adequate phosphate increase (despite few hyperphosphatemia events being reported, serum phosphate increased statistically significantly while on treatment) and a reduction in FGF19 levels in phase I clinical trials, reflecting adequate on-target effects.
      • Papadopoulos K.P.
      • El-Rayes B.F.
      • Tolcher A.W.
      • Patnaik A.
      • Rasco D.W.
      • Harvey R.D.
      • et al.
      A phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours.
      It is in fact suggested that “considering…the lack of clear dose-related increase in FGF23, ARQ 087 may be in the unique position of potently inhibiting cancers with FGFR2 dysregulation without causing hyperphosphataemia”.
      • Papadopoulos K.P.
      • El-Rayes B.F.
      • Tolcher A.W.
      • Patnaik A.
      • Rasco D.W.
      • Harvey R.D.
      • et al.
      A phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours.
      In addition, the dose-dependent response evident with FGF19, suggests that for ARQ087, FGF19 might have potential utility as a biomarker of effective FGFR inhibition.
      An alternative approach to selective TKI development, with the aim of targeting the FGFR pathway, is the design of antibodies able to inhibit the union between the FGF ligands and FGFR, which could be of relevance for situations of FGFR amplification (as mentioned above, this is not as relevant in CCA). FPA-114 (bemarituzumab, FivePrime) is currently being developed for solid tumours (NCT02318329) and gastric cancer (NCT03694522) with FGFR2 protein overexpression or FGFR2 gene amplification.
      • Catenacci D.V.
      • Tesfaye A.
      • Tejani M.
      • Cheung E.
      • Eisenberg P.
      • Scott A.J.
      • et al.
      Bemarituzumab with modified FOLFOX6 for advanced FGFR2-positive gastroesophageal cancer: FIGHT Phase III study design.
      FP-1039 (FivePrime) is a soluble fusion protein consisting of the extracellular domain of FGFR1 linked to the Fc portion of human IgG1 able to inhibit FGFR1 ligands from binding to the receptor
      • Zhang H.
      • Lorianne M.
      • Baker K.
      • Sadra A.
      • Bosch E.
      • Brennan T.
      • et al.
      FP-1039 (FGFR1:Fc), a soluble FGFR1 receptor antagonist, inhibits tumor growth and angiogenesis.
      which is currently under clinical development.
      • Tolcher A.W.
      • Papadopoulos K.P.
      • Patnaik A.
      • Wilson K.
      • Thayer S.
      • Zanghi J.
      • et al.
      A phase I, first in human study of FP-1039 (GSK3052230), a novel FGF ligand trap, in patients with advanced solid tumors.
      Anti-FGFR3 antibodies have also been developed for treatment of urothelial malignancies (Vofatamab (B-701, BioClin Therapeutics/Rainier Therapeutics)
      • Casadei C.
      • Dizman N.
      • Schepisi G.
      • Cursano M.C.
      • Basso U.
      • Santini D.
      • et al.
      Targeted therapies for advanced bladder cancer: new strategies with FGFR inhibitors.
      ). Finally, molecules able to inhibit other FGFR receptors such as Fisogatinib (BLU-554, Caerulum Pharma
      • Kim R.D.
      • Sarker D.
      • Meyer T.
      • Yau T.
      • Macarulla T.
      • Park J.W.
      • et al.
      First-in-human phase I study of fisogatinib (BLU-554) validates aberrant FGF19 signaling as a driver event in hepatocellular carcinoma.
      ), INCB062079 (Incyte; NCT03144661) and FGF401 (Roblitinib, Novartis
      • Weiss A.
      • Adler F.
      • Buhles A.
      • Stamm C.
      • Fairhurst R.A.
      • Kiffe M.
      • et al.
      FGF401, A first-in-class highly selective and potent FGFR4 inhibitor for the treatment of FGF19-driven hepatocellular cancer.
      ,
      • Zhou Z.
      • Chen X.
      • Fu Y.
      • Zhang Y.
      • Dai S.
      • Li J.
      • et al.
      Characterization of FGF401 as a reversible covalent inhibitor of fibroblast growth factor receptor 4.
      ) are being developed; these molecules are both selective FGFR4 inhibitors for the treatment of FGFR4-dependent hepatocellular carcinoma with FGF19 positive immunohistochemistry, but there is not much interest in testing these molecules in CCA as yet.
      • Presta M.
      • Chiodelli P.
      • Giacomini A.
      • Rusnati M.
      • Ronca R.
      Fibroblast growth factors (FGFs) in cancer: FGF traps as a new therapeutic approach.
      As stated, FGFR2 fusions appear to be driver aberrations in iCCA that convey a unique phenotype with sensitivity to FGFR inhibitors, with a high response rate even in heavily pretreated patients. As mentioned, further development of these compounds is ongoing, mainly in the first-line setting. In addition, potential strategies involving FGFR inhibitors in the neoadjuvant and adjuvant setting, as well as in combination with chemotherapy, will likely be explored in the future, together with further transitional research to better understand mechanisms of primary and secondary resistance, and potential ways of overcoming them. Investigation of activity in patients with iCCA with FGF/FGFR aberrations beyond FGFR2 fusions will also require further research.

      Other targets in CCA and GBC

       HER receptor family

      The HER family includes 4 members: epidermal growth factor receptor (EGFR/HER1), HER2, HER3, and HER4.
      • Yarden Y.
      • Sliwkowski M.X.
      Untangling the ErbB signalling network.
      The relevance of this pathway in cancer progression has been shown previously.
      • Mitri Z.
      • Constantine T.
      • O'Regan R.
      The HER2 receptor in breast cancer: Pathophysiology, clinical Use, and new advances in therapy.
      Several trials investigating inhibitors of the HER pathway in HER-overexpressing CCA and GBC have reported disappointing findings (e.g. lapatinib,
      • Ramanathan R.K.
      • Belani C.P.
      • Singh D.A.
      • Tanaka M.
      • Lenz H.J.
      • Yen Y.
      • et al.
      A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer.
      ,
      • Peck J.
      • Wei L.
      • Zalupski M.
      • O'Neil B.
      • Villalona C.M.
      • Bekaii-Saab T.
      HER2/neu may not be an interesting target in biliary cancers: results of an early phase II study with lapatinib.
      erlotinib
      • El-Khoueiry A.B.
      • Rankin C.
      • Siegel A.B.
      • Iqbal S.
      • Gong I.Y.
      • Micetich K.C.
      • et al.
      S0941: a phase 2 SWOG study of sorafenib and erlotinib in patients with advanced gallbladder carcinoma or cholangiocarcinoma.
      ). One of the challenges for assessment of the HER family as a potential target in biliary tract malignancies has been the difficulty in assessing immunohistochemistry.
      • Lamarca A.
      • Galdy S.
      • Barriuso J.
      • Moghadam S.
      • Beckett E.
      • Rogan J.
      • et al.
      The HER3 pathway as a potential target for inhibition in patients with biliary tract cancers.
      The combination of pertuzumab and trastuzumab was investigated in 11 patients with previously treated biliary tract cancer, with HER2 amplification (8 patients) or HER2 mutations (3 patients); ORRs of 7.5% and 33.3% were reported, respectively.
      • Javle M.M.
      • Hainsworth J.D.
      • Swanton C.
      • Burris H.A.
      • Kurzrock R.
      • Sweeney C.
      • et al.
      Pertuzumab + trastuzumab for HER2-positive metastatic biliary cancer: preliminary data from MyPathway.
      Targeting gene mutations rather than amplifications may also have potential (e.g. neratinib
      • Hyman D.M.
      • Piha-Paul S.A.
      • Won H.
      • Rodon J.
      • Saura C.
      • Shapiro G.I.
      • et al.
      HER kinase inhibition in patients with HER2- and HER3-mutant cancers.
      ). An ORR of 10% was reported in the biliary subgroup (20 patients) of the SUMMIT clinical trial exploring the role of neratinib in patients whose tumours harboured HER2 mutations.
      • Harding J.J.
      • Cleary J.
      • Shapiro G.
      • Braña I.
      • Moreno V.
      • Quinn D.
      • et al.
      Treating HER2-mutant advanced biliary tract cancer with neratinib: benefits of HER2-directed targeted therapy in the phase 2 SUMMIT ‘basket’ trial.
      Other targets are being developed: NTRK, HER2, BRAF and RNF43. The role of other members of the HER family beyond HER2 (e.g. HER3) remains unclear.
      • Raderer M.
      • Hejna M.H.
      • Valencak J.B.
      • Kornek G.V.
      • Weinlander G.S.
      • Bareck E.
      • et al.
      Two consecutive phase II studies of 5-fluorouracil/leucovorin/mitomycin C and of gemcitabine in patients with advanced biliary cancer.
      Even though some data exist, and even though HER represents the most frequent targetable aberration for eCCA and GBC, work is still needed for this target to be ready for prime time use in clinical practice. As with IDH and FGFR, adequate patient selection may be the key for the successful development of these drugs
      • Lamarca A.
      • Galdy S.
      • Barriuso J.
      • Moghadam S.
      • Beckett E.
      • Rogan J.
      • et al.
      The HER3 pathway as a potential target for inhibition in patients with biliary tract cancers.
      and further clinical trials are required to confirm the benefit of targeting HER in patients with biliary tract cancers.

       RNF43

      RNF43 (a RING domain E3 ubiquitin ligase) suppresses P53-mediated apoptosis
      • Shinada K.
      • Tsukiyama T.
      • Sho T.
      • Okumura F.
      • Asaka M.
      • Hatakeyama S.
      RNF43 interacts with NEDL1 and regulates p53-mediated transcription.
      and inhibits Wnt signalling by interacting with Frizzled family receptors.
      • Loregger A.
      • Grandl M.
      • Mejias-Luque R.
      • Allgauer M.
      • Degenhart K.
      • Haselmann V.
      • et al.
      The E3 ligase RNF43 inhibits Wnt signaling downstream of mutated beta-catenin by sequestering TCF4 to the nuclear membrane.
      RNF43 mutations may predict the sensitivity to porcupine inhibitors
      • Koo B.K.
      • van Es J.H.
      • van den Born M.
      • Clevers H.
      Porcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43;Znrf3-mutant neoplasia.
      and have been described in a subpopulation of patients with biliary tract cancers (<5%).
      • Valle J.W.
      • Lamarca A.
      • Goyal L.
      • Barriuso J.
      • Zhu A.X.
      New horizons for precision medicine in biliary tract cancers.
      The safety and activity of Wnt inhibitors in patients with previously treated advanced solid tumours harbouring RNF43 mutations is currently being investigated (NCT03447470).

       Targeting NTRK (neurotropic tyrosine kinase receptor) fusions

      The gene NTRK encodes for tropomyosin receptor kinase (TRK), a membrane-bound receptor linked to the MAPK pathway when activated.
      • Amatu A.
      • Sartore-Bianchi A.
      • Siena S.
      NTRK gene fusions as novel targets of cancer therapy across multiple tumour types.
      Fusions of the gene NTRK can be targeted and its use for tumour-agnostic strategies has already shown success. Multiple partners for such fusions have been described. NTRK fusions lead to a constitutively activated TRK, promoting differentiation, proliferation and survival. Two TRK inhibitors are currently under development: entrectinib (RXDX-101)
      • Drilon A.
      • Siena S.
      • Ou S.I.
      • Patel M.
      • Ahn M.J.
      • Lee J.
      • et al.
      Safety and antitumor activity of the multi-targeted pan-TRK, ROS1, and ALK inhibitor entrectinib (RXDX-101): combined results from two phase 1 trials (ALKA-372-001 and STARTRK-1).
      and larotrectinib (LOXO-101).
      • 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.
      The ORRs have been impressive (between 57–75%) in previously treated advanced solid tumours, supporting a tumour-agnostic approach.
      • 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.
      ,
      • Doebele R.C.
      • Drilon A.
      • Paz-Ares L.
      • Siena S.
      • Shaw A.T.
      • Farago A.F.
      • et al.
      Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials.
      NTRK fusions have been identified in 3.5% of patients with iCCA.
      • 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.
      TRK inhibitors have also shown activity against ROS1 and ALK fusions, which have been reported in 0–8.7% and 2.7% of CCA, respectively.
      • 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.
      ,
      • Gu T.L.
      • Deng X.
      • Huang F.
      • Tucker M.
      • Crosby K.
      • Rimkunas V.
      • et al.
      Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma.
      ,
      • Ruzzenente A.
      • Fassan M.
      • Conci S.
      • Simbolo M.
      • Lawlor R.T.
      • Pedrazzani C.
      • et al.
      Cholangiocarcinoma heterogeneity revealed by Multigene mutational profiling: clinical and prognostic relevance in surgically resected patients.

       BRAF

      BRAF mutations have been described in a small proportion of patients with biliary tract malignancies (<5%)
      • Javle M.
      • Bekaii-Saab T.
      • Jain A.
      • Wang Y.
      • Kelley R.K.
      • Wang K.
      • et al.
      Biliary cancer: utility of next-generation sequencing for clinical management.
      even though the percentage has been reported to be higher in other series.
      • Tannapfel A.
      • Sommerer F.
      • Benicke M.
      • Katalinic A.
      • Uhlmann D.
      • Witzigmann H.
      • et al.
      Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma.
      For patients harbouring BRAF V600E mutations, strategies involving dual inhibition of both BRAF (dabrafenib) and MEK (trametinib) have been tested as part of the ROAR basket clinical trial in solid tumours.
      • Wainberg Z.A.
      • Lassen U.N.
      • Elez E.
      • Italiano A.
      • Curigliano G.
      • De Braud F.G.
      • et al.
      Efficacy and safety of dabrafenib and trametinib in patients with BRAF V600E-mutated biliary tract cancer: a cohort of the ROAR basket trial.
      Within the biliary tract cancer subgroup (33 patients), partial response rates of 42% and 36% with investigator and independent assessment were achieved, respectively. Median PFS was 9.2 months.
      • Wainberg Z.A.
      • Lassen U.N.
      • Elez E.
      • Italiano A.
      • Curigliano G.
      • De Braud F.G.
      • et al.
      Efficacy and safety of dabrafenib and trametinib in patients with BRAF V600E-mutated biliary tract cancer: a cohort of the ROAR basket trial.

      Current caveats and future perspectives

      It is becoming clearer that specific patient subpopulations with biliary tract cancers can now access real “Precision Medicine” approaches, with IDH1 mutations and FGFR2 fusions being the main targets of interest (Fig. 4). However, these still only represent a small proportion of all patients diagnosed with biliary tract cancer. There is, therefore, an urgent need to identify new drivers and targetable alterations while the current approaches are being fully developed. In addition, further understanding of the role of these strategies in settings other than palliative treatment (i.e. adjuvant, neoadjuvant, liver-directed, etc.) and potential combinations with chemotherapy and immunotherapy, together with an in depth understanding of primary and acquired resistance mechanisms, and strategies to overcome them are still to be elucidated.
      Figure thumbnail gr4
      Fig. 4Current overview of “Precision Medicine” in biliary tract cancers.
      FGFR2 and IDH1 are the best understood targets to date. Other targets are being investigated, but are less prevalent. Size of spheres is proportional to number of patients with biliary tract cancer likely to harbour these targetable alterations (approximate percentages extracted and adapted from are provided). Empty spheres represent other potential targets with lower prevalence in biliary tract cancers. FGFR2, fibroblast growth factor receptor 2; HER2, human epidermal growth factor receptor 2; IDH1, isocitrate dehydrogenase 1; NTRK, neurotropic tyrosine kinase; MMR, mismatch repair deficiency (for the purpose of this figure, this also includes microsatellite instability).
      One of the main challenges for a “Precision Medicine” approach, especially in a disease group with cancer arising from non-easily biopsiable locations, is the access to tumour tissue.
      • Forner A.
      • Vidili G.
      • Rengo M.
      • Bujanda L.
      • Ponz-Sarvise M.
      • Lamarca A.
      Clinical presentation, diagnosis and staging of cholangiocarcinoma.