Bridgewater, J

Khan, SA

Vithayathil, M

English

UCL Discovery

Medical therapies for intra-hepatic cholangiocarcinoma Mathew Vithayathil1,, John Bridegwater2, Shahid A Khan1 1. Liver Unit, Division of Digestive Diseases, Imperial College London and Imperial College Healthcare NHS Trust 2. Department of Medical Oncology, UCL Cancer Institute, London, UK  Corresponding author: Professor Shahid Khan Division of Digestive Diseases Imperial College London  Email: shahid.khan@imperial.ac.uk Tel: +44 (0)20 3312 6254  Keywords:  cholangiocarcinoma; intrahepatic bile ducts; biliary tract neoplasm; chemotherapy  Word Count: 600 Figures: 1 (to be created) Conflict of interest: J. Bridgewater declares consulting or advisory roles for Merck Serono, SERVIER, Roche, Bayer, AstraZeneca, Incyte and Basilea; travel support from MSD Oncology, Merck Serono, Servier and BMS. Financial support statement: No financial support was given for completion of the manuscript Author contributions: SK and JB conceived the article structure; MV drafted the manuscript. All authors reviewed and approved the final version of the manuscript.   Background Cholangiocarcinoma (CCA) is a heterogenous group of cancers arising from the biliary tree. Intrahepatic CCA (iCCA) arise from biliary ducts within the hepatic parenchyma, anatomically above second-order bile ducts[1], and have been increasing in global incidence over the last few decades. Less than 30% of patients with CCA have resectable disease at diagnosis and most patients require systemic therapy. Advancements in understanding the diverse genetic and molecular signatures of CCA has identified novel targets for cancer specific therapy. Systemic Chemotherapy Post surgical resection, the BILCAP study demonstrated adjuvant therapy with capecitabine improves relapse-free and overall survival[2]. In the palliative setting, systemic chemotherapy with gemcitabine and cisplatin remains standard first-line therapy, with a progression free survival (PFS) of 11.7 months demonstrated[3]. FOLFOX (folinic acid, 5-FU and oxaliplatin) is second-line therapy, demonstrating an increase in 12 month survival, though only modest increases in median survival[4].  Targeted Cancer Therapy iCCA carcinogenesis arises from an interplay of extracellular bile acids, growth factors and cytokines causing aberrant activation of cholangiocyte cell surface receptors. Deregulation of downstream intracellular signalling lead to genetic and epigenetic alterations, driving changes to cell proliferation, survival and migration/invasion. Multiple gene mutations have been identified and histological subtypes of iCCAs show distinct molecular profiles. Large-duct iCCA arising from peribiliary glands exhibit KRAS and TP53 gene mutations, whereas small-duct iCCA are characterised by mutations in isocitrate dehydrogensase (IDH) and fibroblast growth factor receptor 2 (FGFR2) gene fusions. Based on liquid or tissue-based biopsy DNA profiling, it is estimated at least 20-30% of advanced CCAs have somatic alterations targetable for novel therapies. FGFR Antagonists Fibroblast growth factor (FGF) signalling has a role in cell development and angiogenesis, with aberrant FGF receptor activation implicated in carcinogenesis. FGFR2 gene fusion with gene partners, most frequently BICC1, is highly enriched in iCCA. FGFR1-3 inhibitor Pemigatinib is the first FDA approved targeted agent for treatment of iCCA, with 82% of patients with FGF2 gene alterations responding to therapy in the FIGHT-202 trial[5]. A multi-centre randomised open-label study trialling first-line pemigatinib versus gemcitabine/cisplatin underway. Further oral FGFR antagonists including infigratinib, derazantinib and futibatinib show promising disease control responses in phase II trials.  IDH Antagonists IDH gene mutations lead to accumulation of pro-oncological metabolite 2-hydroxyglutarate, driving DNA hypermethylation. IDH1/2 mutations are found in 10-20% of iCCAs and inhibitors including ivosidenib (IDH1), AG221 (IDH2) and AG881 (pan-IDH1/2) have shown promising clinical results. Ivosidenib demonstrated an increase in PFS of 2.7 compared to 1.4 months with placebo in a phase III study[6].  Further targeted therapy HER2 overexpression is seen in 5% of iCCAs, with combination trastuzumab and pertuzumab inhibition demonstrating response[7]. Novel inhibitors, zanidalamab (HER2) and neratinib (pan-HER), have shown promising preliminary results. Mutations in the RAS-MAPK signalling pathway are implicated in multiple cancers and a basket study showed 47% of BRAFV600E-mutated iCCA patients responded to combination BRAF/MEK inhibition[8]. A randomised phase II trial of patients failing to respond to first-line chemotherapy showed protein kinase inhibition with regorafenib significantly improved PFS compared to placebo[9]. Preliminary results of two phase I/II trials evaluating arginase (INCB001158) and casein-kinase 2 (simitasertib) inhibitors in combination with first-line gemcitabine/cisplatin demonstrate promising response rates and tolerability, with full results awaited. Immunotherapy There is limited data for the role of immunotherapy in iCCA. A basket study showed mismatch repair-deficient iCCAs showed a 17% response to pembrolizumab[10], with future studies assessing immunotherapy in combination with other systemic therapies.   Future Directions The advent of tissue subtyping of iCCAs has increased potential targets for medical therapy. Current trials such as the SAFIR ABC-10 study will use molecular subtyping to deliver precision medicine and identify therapies to improve survival in advanced disease. References [1] Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol 2020. https://doi.org/10.1038/s41575-020-0310-z. [2] Primrose JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol 2019. https://doi.org/10.1016/S1470-2045(18)30915-X. [3] Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract Cancer. N Engl J Med 2010. https://doi.org/10.1056/nejmoa0908721. [4] Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, et al. ABC-06 | A randomised phase III, multi-centre, open-label study of active symptom control (ASC) alone or ASC with oxaliplatin / 5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers (ABC) previously-tr. J Clin Oncol 2019. https://doi.org/10.1200/jco.2019.37.15_suppl.4003. [5] Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol 2020. https://doi.org/10.1016/S1470-2045(20)30109-1. [6] Abou-Alfa GK, Macarulla Mercade T, Javle M, Kelley RK, Lubner S, Adeva J, et al. ClarIDHy: A global, phase III, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation. Ann Oncol 2019. https://doi.org/10.1093/annonc/mdz394.027. [7] Javle MM, Hainsworth JD, Swanton C, Burris HA, Kurzrock R, Sweeney C, et al. Pertuzumab + trastuzumab for HER2-positive metastatic biliary cancer: Preliminary data from MyPathway. J Clin Oncol 2017. https://doi.org/10.1200/jco.2017.35.4_suppl.402. [8] Subbiah V, Lassen U, Élez E, Italiano A, Curigliano G, Javle M, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol 2020. https://doi.org/10.1016/S1470-2045(20)30321-1. [9] Demols A, Borbath I, Van den Eynde M, Houbiers G, Peeters M, Marechal R, et al. Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced/metastatic biliary tumors: REACHIN, a randomized, double-blind, phase II trial. Ann Oncol  Off J Eur Soc Med Oncol 2020;31:1169–77. https://doi.org/10.1016/j.annonc.2020.05.018. [10] Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015. https://doi.org/10.1056/nejmoa1500596.  

Medical therapies for intra-hepatic cholangiocarcinoma

https://discovery.ucl.ac.uk/10137212/3/Bridgewater_2021_Jan_26%20Medical%20Treatment%20for%20iCCA_JHep.pdf

Medical therapies for intra-hepatic cholangiocarcinoma

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