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Targeted Therapy for Biliary Cancers

Picture of Champions Oncology   Champions Oncology  ·  4 minute read

3d rendered image, enhanced scanning electron micrograph (SEM) of cancer cell

Biliary tract cancers, which are also known as cholangiocarcinomas (CCA), describe malignancies that occur in the biliary tract and include the pancreas, gallbladder, and bile ducts. These are relatively rare cancers but are associated with a poor prognosis given that these cancers are difficult to detect and are usually diagnosed at later stages of the disease.

Current CCA classification and clinical care

 

CCAs are classified by growth pattern as mass forming, intraductal, or periductal, anatomical location as intrahepatic or extrahepatic (perihilar, or distal), and histology (predominantly adenocarcinomas with mixed hepatocellular CCAs are defined as a separate subtype of primary hepatic cancer) [1].

 

CCAs can arise de novo with no discernable risk factors, but a variety of genetic and nongenetic risk factors are associated with CCA, including liver cirrhosis, obesity, type 2 diabetes, chronic hepatitis B or C infection, or infection with hepatobiliary flukes [2]. Individuals with primary sclerosing cholangitis have higher levels of chronic liver inflammation and increased incidence of CCA [3] as well. CCAs are typically aggressive cancers with a median overall survival of < 24 months. The only treatment options have been surgical resection or liver transplantation for early-stage patients or aggressive chemotherapy for patients with advanced stages of the disease [4].

 

CCA molecular classification

 

Next-generation sequencing technology has allowed the identification of molecular subtypes associated with several gene mutations that are linked to increased CCA risk, including mutations in chromatin remodeling genes (ARID1A, BAP1, and PBRM1) [5,6]. IDH1 mutations have been linked to intrahepatic CCA and mutations in ERBB2 are more closely associated with extrahepatic CCA [7].

 

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Mutations in the fibroblast growth factor (FGF) signaling pathway, including mutations or translocations in FGF receptor (FGFR) genes, have also been identified in CCA, and an FGFR fusion has been linked specifically to intrahepatic CCA [8]. Moreover, patients with IDH1/2 mutations also exhibit elevated FGFR expression, even without FGFR mutations or fusions, further affirming a role for FGF/FGFR signaling in CCA progression[9]. In addition to tumor cell alterations, the tumor microenvironment is also being extensively explored and has led to the identification of an inflamed intrahepatic CCA subtype potentially treatable with checkpoint blockade immunotherapy [10].

 

 New CCA precision therapies

 

The FGF/FGFR pathway has become one of the most encouraging targets for novel

CCA therapeutics. As FGFRs are receptor tyrosine kinases, nonselective FGFR inhibitors that target the conserved ATP-binding domain were the first drugs to be tested in clinical trials. A recent trial exploring the use of the nonselective FGFR kinase inhibitor pazopanib combined with a MEK inhibitor showed little efficacy [11].

 

Pemagatinib is the first FDA-approved targeted therapy for advanced CCA with FGFR2 fusions or rearrangements. Pemagatinib is a selective inhibitor of FGFR1, 2, and 3 and was approved in 2020 and given breakthrough therapy designation as the first drug to specifically treat CCA [12].

 

In 2021, Ivosidenib (Tibsovo), a small molecule IDH1 inhibitor, was approved by the FDA for treating IDH1 mutated locally advanced or metastatic CCA [13].

 

Very recently, the FDA has granted accelerated approval to two FGFR inhibitors: Infigratinib (Truseltiq), for the treatment of previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusion (and a companion diagnostic to identify patients eligible to receive this treatment) [14,15]; and Futinatinib (TAS-120) for patients with previously treated, unresectable, locally advanced or metastatic intrahepatic CCA with FGFR2 gene fusions or other rearrangements [16,17].

 

Alternative FGF/FGFR inhibitors are also under development and target the extracellular domain or function as FGF ligand traps [18]. These alternative inhibitors can be used potentially in combination with FGFR kinase inhibitors that have lost efficacy due to the development of resistance [19].

 

In addition to mutation-driven therapeutic approaches, immune checkpoint inhibitors are currently tested in combination with chemotherapy to improve efficacy. A very recent study conducted on patients with advanced biliary tract cancer showed that Durvalumab, a PD-L1 inhibitor, significantly improves survival compared to chemotherapy alone [20].

New research on novel inhibitors and combination therapies will likely identify other therapeutic options for CCA, and these cancers will not be the terminal diagnoses they once were.

 

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  1. Razumilava N, Gores Cholangiocarcinoma. Lancet. 2014;383(9935):2168- 79.

  2. Yao KJ, Jabbour S, et al. Increasing mortality in the United States from cholangiocarcinoma: an analysis of the National Center for Health Statistics Database. BMC Gastroenterol. 2016;16(1):117.

  3. Hirschfield GM, Karlsen TH, et Primary sclerosing cholangitis. Lancet. 2013;382(9904):1587-99.

  4. Yazici C, Niemeyer DJ, et al. Hepatocellular carcinoma and cholangiocarcinoma: an Expert Rev Gastroenterol Hepatol. 2014;8(1):63-82.

  5. Jusakul A, Cutcutache I, et al. Whole‐genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov 2017;7:1116‐1135

  6. Jiao Y, Pawlik TM, et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A, and PBRM1 in intrahepatic Nat Genet. 2013;45:1470–3.

  7. Churi CR, Shroff R, et Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS One. 2014;9:e115383.

  8. Graham RP, Barr Fritcher EG, et al. Fibroblast growth factor receptor 2 translocations in intrahepatic Hum Pathol. 2014;45(8):1630- 1638.

  9. Wang P, Dong Q, et Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene. 2013;32(25):3091-3100.

  10. Job S, Rapoud D, et al.. Identification of Four Immune Subtypes Characterized by Distinct Composition and Functions of Tumor Microenvironment in Intrahepatic Cholangiocarcinoma. Hepatology. 2020 Sep;72(3):965-981

  11. Shroff RT, Yarchoan M, O’Connor A, et The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma. Br J Cancer. 2017;116(11):1402-1407.

  12. Patel TH, Marcus L, et al. FDA Approval Summary: Pemigatinib for Previously Treated, Unresectable Locally Advanced or Metastatic Cholangiocarcinoma with FGFR2 fusion or other rearrangements. Clin Cancer Res. 2022 Oct 7:CCR-22-2036.

  13. Sumbly V, Landry I, Rizzo V. Ivosidenib for IDH1 Mutant Cholangiocarcinoma: A Narrative Review. Cureus. 2022 Jan 7;14(1):e21018

  14. Javle M, Roychowdhury S, et al. Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study. Lancet Gastroenterol Hepatol. 2021 Oct;6(10):803-815.

  15. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-infigratinib-metastatic-cholangiocarcinoma

  16. Goyal L, Meric-Bernstam F, et al. Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma. N Engl J Med. 2023 Jan 19;388(3):228-239. doi: 10.1056/NEJMoa2206834. PMID: 36652354.

  17. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-futibatinib-cholangiocarcinoma

  18. Tolcher AW, Papadopoulos KP, Patnaik A, et A phase I, first in human study of FP-1039 (GSK3052230), a novel FGF ligand trap, in patients with advanced solid tumors. Ann Oncol. 2016;27(3):526-532.

  19. Touat M, Ileana E, et Targeting FGFR signaling in cancer. Clin Cancer Res. 2015;21(12):2684-2694.

  20. https://meetings.asco.org/abstracts-presentations/204876