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Targeted Therapies in Advanced Cholangiocarcinoma: a Focus on FGFR Inhibitors

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Targeted Therapies in Advanced Cholangiocarcinoma: a Focus on FGFR Inhibitors medicina Review Targeted Therapies in Advanced Cholangiocarcinoma: A Focus on FGFR Inhibitors Alessandro Rizzo Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, 40138 Bologna, Italy; [email protected] Abstract: Despite advanced diseases continuing to be associated with grim prognoses, the past decade has witnessed the advent of several novel treatment options for cholangiocarcinoma (CCA) patients. In fact, CCA has emerged as a heterogeneous group of malignancies harboring potentially druggable mutations in approximately 50% of cases, and thus, molecularly targeted therapies have been actively explored in this setting. Among these, fibroblast growth factor receptor (FGFR) inhibitors have reported important results, as witnessed by the FDA approval of pemigatinib in previously treated metastatic CCA patients harboring FGFR2 fusion or other rearrangements. Herein, we provide an overview of available evidence on FGFR inhibitors in CCA, especially focusing on the development, pitfalls and challenges of emerging treatments in this setting. Keywords: FGFR; cholangiocarcinoma; targeted therapies; intrahepatic cholangiocarcinoma; pemi- gatinib 1. Introduction Citation: Rizzo, A. Targeted Cholangiocarcinoma (CCA) encompasses a group of heterogeneous, rare and aggres- Therapies in Advanced sive malignancies, including intrahepatic cholangiocarcinoma (iCCA) and extrahepatic Cholangiocarcinoma: A Focus on cholangiocarcinoma (eCCA), with the latter further subclassified into perihilar (pCCA) FGFR Inhibitors. Medicina 2021, 57, and distal (dCCA) cholangiocarcinoma [1–3]. CCAs account for approximately 3% of 458. https://doi.org/10.3390/ all gastrointestinal cancers worldwide and 10–15% of all primary liver tumors [4–6]. As medicina57050458 suggested by several studies, these subgroups of hepatobiliary tumors not only develop from different anatomical locations, but vary widely in terms of epidemiology, biology, Academic Editor: Zygmunt Warzecha prognosis, and etiology [7–9]. Although radical surgical resections with negative tumor margins is the standard Received: 27 March 2021 of care for early stages, for resectable diseases, only a small proportion of CCA patients Accepted: 4 May 2021 Published: 8 May 2021 are eligible for curative surgery at the time of diagnosis [10–12]. Adjuvant treatments have been actively explored in this setting, with the aim of lowering recurrence rates and Publisher’s Note: MDPI stays neutral improving the survival of patients [11]. In particular, adjuvant capecitabine has been with regard to jurisdictional claims in recently established as standard treatment following radical surgery; in fact, this agent published maps and institutional affil- has been suggested to improve survival, according to the results of the phase III BILCAP iations. trial [12–14]. Although the BILCAP failed to meet its primary endpoints according to an intention-to-treat analysis, in the prespecified per-protocol analysis (adjusted by nodal status, disease grade and gender) a statistically significant benefit in terms of median overall survival (OS) was reported (53 months versus 36 months; Hazard Ratio [HR] 0.75, 95% Confidence Interval [CI], 0.58–0.97; p = 0.028) [15]. Copyright: © 2021 by the author. Licensee MDPI, Basel, Switzerland. As regards metastatic disease, combination chemotherapy with cisplatin plus gem- This article is an open access article citabine (CisGem) represents the reference treatment for previously untreated patients distributed under the terms and with advanced CCA, following the landmark results of the ABC-02 and BT22 clinical conditions of the Creative Commons trials [16–18]. More recently, for metastatic CCA patients whose disease progresses on Attribution (CC BY) license (https:// front-line CisGem chemotherapy, second-line modified oxaliplatin plus 5-fluorouracil creativecommons.org/licenses/by/ (mFOLFOX) plus active symptom control (ASC) has provided a survival benefit compared 4.0/). to ASC alone, according to the ABC-06 phase III trial [19,20]. However, the overall benefit Medicina 2021, 57, 458. https://doi.org/10.3390/medicina57050458 https://www.mdpi.com/journal/medicina Medicina 2021, 57, x FOR PEER REVIEW 2 of 13 Medicina 2021, 57, 458 line CisGem chemotherapy, second-line modified oxaliplatin plus 5-fluorouracil (mFOL-2 of 13 FOX) plus active symptom control (ASC) has provided a survival benefit compared to ASC alone, according to the ABC-06 phase III trial [19,20]. However, the overall benefit provided by mFOLFOX is modest (median OS of 6.2 months in the ASC plus mFOLFOX providedgroup versus by mFOLFOX 5.3 months is in modest the ASC (median alone OSgroup), of 6.2 and months the overall in the ASCresponse plus rate mFOLFOX remains group versus 5.3 months in the ASC alone group), and the overall response rate remains disappointing. disappointing. In fact, the overall limited survival benefit provided by systemic therapies in this set- In fact, the overall limited survival benefit provided by systemic therapies in this ting, with most patients reporting a survival rate of less than a year from the moment of setting, with most patients reporting a survival rate of less than a year from the moment of diagnosis, has led to notable efforts towards the identification of novel targets and agents diagnosis, has led to notable efforts towards the identification of novel targets and agents that could modify the natural history of these aggressive hepatobiliary malignancies [20– that could modify the natural history of these aggressive hepatobiliary malignancies [20–24]. 24]. In fact, the massive use of next-generation sequencing (NGS) has led to the identifica- In fact, the massive use of next-generation sequencing (NGS) has led to the identification of tion of previously unknown molecular features of CCA, including the presence of specific previously unknown molecular features of CCA, including the presence of specific genetic genetic aberrations that have been suggested to be distinctive features of iCCA and eCCA aberrations that have been suggested to be distinctive features of iCCA and eCCA [25–28]. [25–28]. Among these druggable alterations, fibroblast growth factor receptor (FGFR)2 Among these druggable alterations, fibroblast growth factor receptor (FGFR)2 gene fusions andgene rearrangements, fusions and rearrangements, isocitrate dehydrogenase-1 isocitrate dehydrogenase-1 (IDH-1) mutations, (IDH-1) and BRAF mutations, mutations and haveBRAF been mutations widely have described been widely in CCA described patients, in reporting CCA patients, important reporting differences important between differ- iCCAences andbetween eCCA iCCA (Figure and1)[ eCCA29–32 (Figure]. 1) [29–32]. Figure 1. Schematic figure representing the main signaling pathways and selected targeted therapies currently under evaluationFigure 1. Schematic in cholangiocarcinoma. figure representing Abbreviations: the main AKT: signaling protein path kinaseways B; and EGFR: selected epidermal targeted growth therapies factor currently receptor; under FGF: fibroblastevaluation growth in cholangiocarcinoma. factor; HER2: epidermal Abbreviations: growth factor AKT: receptor protein 2; kinase HGF: hepatocyteB; EGFR: epidermal growth factor; growth IL-6: factor interleukin receptor; 6; IDH:FGF: isocitratefibroblast dehydrogenase; growth factor; HER2: JAK: Janus epidermal kinase; growth mTOR: factor mammalian receptor target 2; HGF: of rapamycin;hepatocyte PDGFR:growth factor; platelet IL-6: derived interleukin growth 6; factorIDH: receptor;isocitrate PDK1: dehydrogenase; phosphoinositide-dependent JAK: Janus kinase; kinase-1; mTOR: PI3K:mammalian phosphoinositide target of rapamycin; 3-kinase. PDGFR: platelet derived growth factor receptor; PDK1: phosphoinositide-dependent kinase-1; PI3K: phosphoinositide 3-kinase. In particular, FGFR-targeted treatments have entered into the clinical practice of CCA patients,In particular, since these FGFR-targeted agents have reported treatments promising have entered results into in athe number clinical of practice phase I of and CCA II clinicalpatients, studies since [these33–35 agents]. In fact, have in Aprilreported 2020, promising the US Food results and in Drug a number Administration of phase I (FDA) and II grantedclinical acceleratedstudies [33–35]. approval In fact, of in the April FGFR 2020, inhibitor the US pemigatinib, Food and Drug on theAdministration basis of the results (FDA) ofgranted the phase accelerated II FIGHT-202 approval trial—as of the we FGFR shall inhibitor see later pemigatinib, in more detail on [36 the]. Moreover,basis of the several results otherof the FGFR phase inhibitors II FIGHT-202 are beingtrial—as tested, we shall together see later with in studies more detail aimed [36]. at betterMoreover, identifying several mechanismsother FGFR involvedinhibitors in are secondary being tested, resistance togeth [37er –with42]. studies aimed at better identifying mechanismsHerein, weinvolved provide in secondary an overview resistance of current [37–42]. evidence on FGFR inhibitors in CCA patients, especially focusing on the development of these molecules, as well as future research avenues in this setting. We performed research on PubMed/Medline, Cochrane library, and Scopus using the keywords “cholangiocarcinoma”, “intrahepatic cholangio- carcinoma”, “extrahepatic cholangiocarcinoma”, “biliary tract cancer”, “FGFR”, “FGFR2”, Medicina 2021, 57, x FOR PEER REVIEW 3 of 13 Herein, we provide an overview of current evidence on FGFR inhibitors
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