Cholangiocarcinoma (CCA)


Cholangiocarcinoma (CCA) is a rare malignancy of the biliary tract.1 The development of more accurate diagnostic techniques and the improvement of tumor classification has contributed to the increase in CCA incidence.1 Overall 5 year survival in CCA patients is less than 10%.2

Surgery is the only option for a curative treatment. Liver transplant after neoadjuvant chemotherapy may also be an option for a small subset of patients with extrahepatic tumors.3 Patients that present as unresectable tumor or a metastatic disease can have indication for chemotherapy. The first-line option for the systemic treatment is represented by the combination of gemcitabine and cisplatin. The second-line treatment is typically performed with 5-fluorouracil with oxaliplatin.4

There are currently few approved standard therapies for CCA, however, there is a diversified number of therapeutics being developed aiming to improve the outcomes of CCA disease.

Targeted Therapies

The existence of potentially actionable mutations in CCA is paving the way to allow the development of antitumor drugs. Isocitrate dehydrogenase (IDH)-1 (AG120, IDH305), IDH2 (AG221) and pan-IDH1-IDH2 (AG881) inhibitors have been tested in patients with intrahepatic CCA (iCCA) with different trials targeting advanced malignancies ongoing (NCT02381886 and NCT02481154).5,6 IDH1 mutations are present in almost 13% of iCCA patients.7 

Mutations in fibroblast growth factor receptor (FGFR) pathway, in particular fusions of FGFR2, have been identified in about 20% of iCCA patients.4,7 Data from FGFR inhibitors has been made available through different trials. Pemigatinib is a targeted therapy that has been approved for CCA treatment. This drug is an ATP-competitive inhibitor of FGFR1, FGFR2 and FGFR3 with an objective response of 35.5% in a subset of patients with FGFR2 fusions.8 The activity of other FGFR inhibitors is being demonstrated in phase II clinical trials. These include the covalent pan-FGFR inhibitor, futibatinib (NCT02052778).7 Other phase 3 studies are evaluating the effect of targeted therapies in the early stages of the disease (FIGHT-302 and PROOF studies).9,10 The anticancer activity of derazantinib, a pan-FGFR inhibitor with important activity against FGFR1-3 kinases, is also currently under evaluation in patients with inoperable or advanced iCCA (NCT03230318).11 

There are additional mutations that may be important as therapeutic targets in CCA, such as BRAF V600E mutations, NTRK fusions, and activating ERBB2 mutations.12,13,14

Immune Checkpoint Inhibitors

There is limited data on immune-directed therapies for CCA treatment, however, immune checkpoint inhibition has been shown effective in different tumor types. In CCA studies, low objective response rates have been observed with this therapy. Patients with microsatellite instability (MSI) or presenting with high tumor mutational burden (TMB) may show a higher rate response.7

The programmed cell death protein 1 (PD-1) is a common immune checkpoint inhibitor (ICI) that has been explored for developing new immune-directed therapies. PD-1 expressed by tumor-infiltrating lymphocytes is associated with a poor prognosis. Studies show that PD-1 inhibitors may be able to recruit immune cells increasing the monitoring of tumor cells and the use of checkpoint molecule-specific monoclonal antibodies (mAbs) may benefit CCA patients.15 

Pembrolizumab is a humanized immunoglobulin G4 (IgG4) κ anti‑PD1 mAb that has been studied in different clinical trials for the treatment of different tumors.16 Trials KEYNOTE-158 (NCT02628067) and KEYNOTE-028 (NCT02054806) revealed pembrolizumab’s antitumor activity in about 6% to 13% of patients which presented with advanced disease.17,18

Nivolumab is a human IgG4 anti-PD-1 mAB approved for targeting different tumors, from melanoma to neck cancer.19 The objective response rate of the therapy with this mAB in a phase II clinical trial (NCT02829918) was 11% and the disease control rate 50%.20

Other studies are being performed to assess the increase of the patient’s immune response by combining immune checkpoint inhibition with chemotherapy or with locally ablative treatments.7 In addition to these investigations, other studies try to relate the total number of somatic mutations with the response to immune therapy.20,21

Chimeric Antigen Receptor (CAR) T Cells

Chimeric antigen receptor (CAR) T cells show efficacy in the treatment of refractory hematological cancers.3 Different CARs’ generations have been developed and have been explored against solid tumors in different clinical trials. The tolerability of the biological CT-0508 (anti-HER2 CAR macrophages) will be determined in a phase 1 clinical trial, currently recruiting (NCT04660929).22 However, the efficacy of CAR T-cell cocktail immunotherapy in CCA warrants further investigations considering the toxicity data observed until today.3

Cancer Vaccines

Dendritic cell (DC) vaccines were shown to be potentially efficient for tumor therapy.23 A non-randomized uncontrolled study of patients with biliary tract tumors treated with a DC-based immunotherapy supported safety of this treatment. Disease control rate and objective response rate in this study were 29% and 6%, respectively.24 A different study showed that the combination of a DC vaccine with activated T-cell transfer could allow managing recurrence and long-term survival in iCCA patients who underwent surgical resection.25

Combined therapies

Experimental treatments have been proposed as second or third-line treatment options for CCA, either alone or in combination with chemotherapy or developed targeted therapies.10

Immunotherapy treatment can be coupled with chemotherapy to improve the therapeutic response of CCA tumors with high TMB.26 Nivolumab has been combined with gemcitabine and cisplatin in a phase II trial (NCT03311789) that enrolled patients with biliary tract tumors, revealing an objective response rate of 55.6%. The results of the study point to the ability of nivolumab in resensitizing the tumor to the systemic therapy.27 It is also suggested that adding an ICI to the systemic treatment may result in a boost of the chemotherapeutic activity, increasing antigenicity of the tumor cells and reducing the immunosuppressant activity of chemotherapy.27 The combination of DCs with chemotherapy has also been explored in clinical trials, showing a prolonged median survival time (MST).24

More recently, data from a phase 3 clinical trial, TOPAZ-1 (NCT03875235), which included 685 patients with advanced biliary tract cancer, demonstrates that the pairing of the PD-L1 immune checkpoint inhibitor durvalumab with the standard first-line chemotherapy combination gemcitabine and cisplatin improved overall survival by 20% in patients, with better progression-free survival (PFS) and objective response rate, and without causing any additional adverse events.28,29 These positive outcomes could pave the way for durvalumab combination with cisplatin and gemcitabine to become the standard of care for first-line therapy for many patients.10

The combination of radiotherapy with immunotherapy can potentially lead to a synergistic effect when treating CCA. A case report has shown that the efficacy of the immunotherapy treatment may be increased in patients with recurrent iCCA and in advanced stages of the disease presenting with low TMB, MSI and negative PD-L1 expression.30

Other immunotherapeutic combinations have also been studied. The efficacy and safety of the combination of nivolumab and ipilimumab were evaluated in a phase II clinical trial that showed an objective response rate and disease control rate of 23% and 44%, respectively. Overall survival was 5.7 months. Patients that responded to the treatment had been previously treated with chemotherapy.31 Despite the effective drug combinations, only the percentage of objective response rate was different when compared to a single-drug regimen.

Other combinatorial strategies are currently under study. These include the association of pembrolizumab with lenvatinib, an anti-angiogenic multikinase inhibitor, to determine both its safety and efficacy in patients with solid tumors, including biliary tract cancers (NCT03797326).32 The IMbrave 151 phase 2 trial (NCT04677504) designed for reporting the effects of combining PD-L1 inhibition (with atezolimuab) with cisplatin and gemcitabine and with an anti-VEGF monoclonal antibody (bevacizumab) in patients with advanced biliary tract cancer is still ongoing.33


1. Ntanasis-Stathopoulos I, Tsilimigras DI, Gavriatopoulou M, Schizas D, Pawlik TM. Cholangiocarcinoma: investigations into pathway-targeted therapies. Expert Rev Anticancer Ther. 2020 Sep;20(9):765-773. doi:10.1080/14737140.2020.1807333

2. Everhart JE, Ruhl CE. Burden of digestive diseases in the united states Part III: Lver, biliary tract, and pancreas. Gastroenterology. 2009 Apr;136(4):1134-44. doi:10.1053/j.gastro.2009.02.038

3. Guo X, Shen W. Latest evidence on immunotherapy for cholangiocarcinoma. Oncol Lett. 2020 Dec;20(6):381. doi:10.3892/ol.2020.12244.

4. Simile MM, Bagella P, Vidili G, et al.  Targeted therapies in cholangiocarcinoma: emerging evidence from clinical trials. Medicina (Kaunas). 2019 Feb 8;55(2):42. doi: 10.3390/medicina55020042

5. Keenan BP, Kelley RKK. Key challenges for drugs in clinical development for cholangiocarcinoma. Expert Opin Investig Drugs. 2021 Apr;30(4):285-290. doi:10.1080/13543784.2021.1880565

6. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Jun;21(6):796-807. doi:10.1016/S1470-2045(20)30157-1

7. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020 May;21(5):671-684. doi:10.1016/S1470-2045(20)30109-1

8. Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020 Sep;17(9):557-588. doi:10.1038/s41575-020-0310-z

9. Lowery MA, Ptashkin R, Jordan E, et al. Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: potential targets for intervention. Clin Cancer Res. 2018 Sep 1;24(17):4154-4161. doi:10.1158/1078-0432.CCR-18-0078

10. Subbiah V, Puzanov I, Blay JY, et al. Pan-cancer efficacy of vemurafenib in BRAFV600-mutant non-melanoma cancers. Cancer Discov. 2020 May;10(5):657-663. doi:10.1158/2159-8290.CD-19-1265

11. Kheder ES, Hong DS. Emerging targeted therapy for tumors with NTRK fusion proteins. Clin Cancer Res. 2018 Dec 1;24(23):5807-5814. doi:10.1158/1078-0432.CCR-18-1156

12. Sabbatino F, Villani V, Yearley JH, et al. PD-L1 and HLA class I antigen expression and clinical course of the disease in intrahepatic cholangiocarcinoma. Clin Cancer Res. 2016 Jan 15;22(2):470-8. doi:10.1158/1078-0432.CCR-15-0715

13. Kwok G, Yau TC, Chiu JW, Tse E, Kwong YL. Pembrolizumab (keytruda). Hum Vaccin Immunother. 2016 Nov;12(11):2777-2789. doi:10.1080/21645515.2016.1199310

14. Kim RD, Chung V, Alese OB, El-Rayes BF, Li D, Al-Toubah TE et al. A Phase 2 Multi-institutional Study of Nivolumab for Patients With Advanced Refractory Biliary Tract Cancer. JAMA Oncol. 2020 Jun 1;6(6):888-894. doi:10.1001/jamaoncol.2020.0930

15. Piha-Paul SA, Oh DY, Ueno M, Malka D, Chung HC, Nagrial A et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: results from the KEYNOTE-158 and KEYNOTE-028 studies. Int J Cancer. 2020 Oct 15;147(8):2190-2198. doi:10.1002/ijc.33013

16. Finkelmeier F, Waidmann O, Trojan J. Nivolumab for the treatment of hepatocellular carcinoma. Expert Rev Anticancer Ther. 2018 Dec;18(12):1169-1175. doi:10.1080/14737140.2018.1535315

17. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014 Dec 4;371(23):2189-2199. doi:10.1056/NEJMoa1406498

18. Zhu B, Tang L, Chen S, Yin C, Peng S, Li X et al. Targeting the upstream transcriptional activator of PD-L1 as an alternative strategy in melanoma therapy. Oncogene. 2018 Sep;37(36):4941-4954. doi:10.1038/s41388-018-0314-0

19. Yi M, Jiao D, Xu H, et al. Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors. Mol Cancer. 2018 Aug 23;17(1):129. doi:10.1186/s12943-018-0864-3

20. Kobayashi M, Sakabe T, Abe H, et al. DC-vaccine study group at the japan Society of Innovative cell therapy (J-SICT). Dendritic cell-based immunotherapy targeting synthesized peptides for advanced biliary tract cancer. J Gastrointest Surg. 2013 Sep;17(9):1609-17. doi:10.1007/s11605-013-2286-2

21. Shimizu K, Kotera Y, Aruga A, Takeshita N, Takasaki K, Yamamoto M. Clinical utilization of postoperative dendritic cell vaccine plus activated T-cell transfer in patients with intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2012 Mar;19(2):171-8. doi:10.1007/s00534-011-0437-y

22. Mou H, Yu L, Liao Q, et al. Successful response to the combination of immunotherapy and chemotherapy in cholangiocarcinoma with high tumour mutational burden and PD-L1 expression: a case report. BMC Cancer. 2018 Nov 12;18(1):1105. doi:10.1186/s12885-018-5021-2

23. Feng K, Liu Y, Zhao Y, et al. Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: results from a phase II study. J Immunother Cancer. 2020 Jun;8(1):e000367. doi:10.1136/jitc-2019-000367

24. Liu X, Yao J, Song L, Zhang S, Huang T, Li Y. Local and abscopal responses in advanced intrahepatic cholangiocarcinoma with low TMB, MSS, pMMR and negative PD-L1 expression following combined therapy of SBRT with PD-1 blockade. J Immunother Cancer. 2019 Aug 5;7(1):204. doi:10.1186/s40425-019-0692-z

25. Klein O, Kee D, Nagrial A, Markman B, Underhill C, Michael M et al. Evaluation of combination nivolumab and ipilimumab immunotherapy in patients with advanced biliary tract cancers: subgroup analysis of a phase 2 nonrandomized clinical trial. JAMA Oncol. 2020 Sep;6(9):1405-1409. doi:10.1001/jamaoncol.2020.2814

Reviewed by Harshi Dhingra, MD, on 8/3/2022.