Partner Perspectives: Moving Cholangiocarcinoma Into the Age of Targeted Therapy

OncologyLive, Vol. 22/No. 08, Volume 22, Issue 08

In Partnership With:

Partner | Cancer Centers | <b>Dana-Farber Cancer Institute</b>

The plethora of actionable targets in intrahepatic cholangiocarcinoma has created opportunities for these patients to be treated with targeted therapy.

Biliary tract cancers are an aggressive group of malignancies that historically have been very challenging to treat because of their anatomical location and limited responsiveness to systemic therapy.1-3 Biliary cancers arise from the epithelial lining of the intrahepatic bile ducts known as intrahepatic cholangiocarcinoma (IHCC), extrahepatic bile ducts known as extrahepatic cholangiocarcinoma (EHCC), and the gallbladder (GBC).3 Risk factors associated with the development of biliary tract cancers include liver flukes (Opisthorchis viverrini and Clonorchis sinensis), hepatitis B and C, nonalcoholic steatohepatitis, alcoholism, cholelithiasis, primary sclerosing cholangitis, and choledochal cysts.3,4 Although biliary tract cancers are rare, recent studies suggest that the incidence of IHCC is rising in the United States and that the mortality from IHCC is increasing worldwide.5,6

For patients with biliary tract cancers, as with most solid tumors, surgical resection is the only therapeutic modality that offers a chance at a cure. However, because of the challenging anatomical location and the tendency of patients to present with advanced disease, only approximately 35% of patients with biliary tract cancer have resectable disease.1 For patients with advanced disease, the landmark ABC-02 trial (NCT00262769) established first-line cisplatin and gemcitabine chemotherapy as the standard of care.7 This trial, which randomized 410 patients to gemcitabine alone or cisplatin/gemcitabine, demonstrated that cisplatin/gemcitabine, compared with gemcitabine monotherapy prolongs overall survival (OS) by 3.6 months (11.7 months vs 8.1 months, respectively).7

After progression on first-line chemotherapy, the benefit of second-line treatment has been unclear because it had not been explored by large randomized trials until recently. The phase 3 ABC06 trial (NCT01926236) randomized 162 patients with advanced biliary tract cancer who progressed on first-line cisplatin/gemcitabine chemotherapy to either leucovorin, fluorouracil, and oxaliplatin (FOLFOX) or best supportive care.8 Results of the trial showed a modest 0.9 month survival benefit in patients treated with FOLFOX, highlighting the need for more effective systemic therapies.

Molecular Targeted Therapy

In recent years, molecular profiling has demonstrated that approximately 45% of patients with IHCC have actionable alterations.9-13 The plethora of actionable targets in IHCC has created opportunities for these patients to be treated with targeted therapy. However, actionable alterations in EHCC and GBC are rarer, and targeted therapies for patients with these malignancies are urgently needed.12,13 For the remainder of this review, we focus on the targetable alterations found in IHCC.

FGFR Inhibitors

Approximately 15% of patients with IHCC have tumors with FGFR2 rearrangements.2,9,12,13 Several reversible FGFR inhibitors in clinical development, such as Debio 1347, erdafitinib (Balversa), infigratinib, and derazantinib, have shown encouraging activity against IHCCs with FGFR2 rearrangments.14-17 Recently, a reversible adenosine triphosphate–competitive FGFR kinase inhibitor, pemigatinib (Pemazyre), became the first FDA-approved targeted therapy for cholangiocarcinoma based on the results of the FIGHT-202 trial (NCT02924376). In that trial, 107 patients with cholangiocarcinoma harboring FGFR2 rearrangements who were previously treated with chemotherapy were treated with 13.5 mg of oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off).18 The trial demonstrated an impressive 36% objective response rate and a median progression-free survival (PFS) of 6.9 months in patients with IHCC tumors with FGFR2 rearrangements.

An irreversible FGFR inhibitor, futibatinib, has also shown impressive activity in FGFR2-rearranged IHCC. In results from the single-arm phase 1/2 FOENIX-CCA2 trial (NCT02052778), the agent elicited an objective response rate of 34% and a median PFS of 7.2 months.19 Notably, investigators have reported several cases in which futibatinib has overcome acquired resistance to reversible FGFR inhibitors.20 For example, Goyal et al described an extraordinary case of a patient with IHCC harboring an FGFR2 translocation who responded to the FGFR inhibitor infigratinib for 12.6 months and then, after developing acquired resistance to infigratinib, responded for 15.8 months to futibatinib.20 This finding has generated great optimism because of the potential of sequential FGFR inhibitor therapy to offer prolonged benefit, such as the 28.4-month improvement in the case above.

FGFR inhibitors are well tolerated overall but do cause some significant toxicities.21 Hyperphosphatemia, caused by inhibition of FGFR1-mediated regulation of renal phosphate transport, is very common and can be managed with a low-phosphate diet, phosphate binders such as sevelamer (Renagel), and dose modifications.21,22 Cutaneous toxicities are the other major adverse effects caused by these agents.21 Patients frequently complain of dry skin and eyes. They may experience nail changes and discoloration. Ophthalmological toxicities, including corneal abrasions and central serous retinopathy, can also occur.21

IDH1 Inhibitors

Pathogenic mutations in IDH1, a metabolic enzyme involved in the conversion of isocitrate to α-ketoglutarate, are present in approximately 20% of patients with IHCC.2,9,12,13,23 Ivosidenib (Tibsovo), an oral IDH1 inhibitor approved by the FDA for the treatment of IDH1-mutated acute myeloid leukemia, was evaluated in the phase 3 ClarIDHy trial (NCT02989857).24 In that trial, 185 patients (91% IHCC) with IDH1-mutated cholangiocarcinoma who had received 1 or 2 lines of prior therapy were randomly assigned to ivosidenib or placebo.24 Similar to the results of the phase 1 trial of ivosidenib in patients with cholangiocarcinoma, results of the ClarIDHy trial showed that ivosidenib appears to be cytostatic because the objective response rate with ivosidenib was similar to that with the placebo control (2.4% vs 0%, respectively).24,25 However, ivosidenib showed a modest benefit, with a median PFS of 2.7 months compared with 1.4 months for patients treated with placebo. Formally, no OS benefit with ivosidenib compared with placebo was observed in the trial (median OS, 10.3 vs 7.5 months; P = .09).24

The ClarIDHy trial allowed for crossover from placebo to ivosidenib; a prespecified statistical analysis called rank-preserving structural failure time (RPSFT) was performed to statistically account for the crossover.26 The RPSFT statistical analysis suggested an OS benefit with ivosidenib compared with placebo (median OS, 10.3 vs 5.1 months; P < .0001).26 Notably, the toxicity profile of ivosidenib was very favorable, and no difference was observed in the number of patients who discontinued therapy for toxicity with ivosidenib vs placebo.26 Dose reductions for patients treated with ivosidenib were also rare (3%).

In light of the encouraging data from the ClarIDHy trial, the developer of the drug, Agios Pharmaceuticals, Inc, has submitted a supplemental new drug application to the FDA for patients with previously treated, IDH1-mutated cholangiocarcinoma.27

BRAF-Directed Therapy

BRAF V600E mutations are relatively rare and are present in approximately 3% of IHCC.2,9,12,13 Because combined BRAF/MEK inhibition has been effective in treating some BRAF-mutated malignancies, such as non–small cell lung cancer and melanoma, but not colorectal cancer, an important question has been whether BRAF-targeted therapy might be effective in IHCC.28 Investigators of the single-arm, multicenter phase 2 ROAR trial (NCT02034110) sought to answer this question by evaluating the BRAF inhibitor dabrafenib (Tafinlar) combined with the MEK inhibitor trametinib (Mekinist).29 Impressively, results of the ROAR trial demonstrated that the dabrafenib/trametinib combination had a 47% objective response in patients with BRAF V600E–mutated cholangiocarcinoma29 (Table17-19,24,26,29). Patients with cholangiocarcinoma enrolled in this trial had a median PFS of 9.2 months and median OS of 11.7 months.29

Other Molecular Targets

Several other targetable molecular abnormalities occur with low prevalence in IHCC. PD-1–directed immunotherapy is an effective option for patients with microsatellite instability–high cholangiocarcinomas, but unfortunately mismatch repair deficiency is rare in cholangiocarcinoma and found only in approximately 1% of patients.30 Similarly, targetable translocations such as ALK, ROS1, and NTRK are also present at low frequencies in IHCC, but when these abnormalities are present, targeted therapy can be effective.1,31,32 HER2 amplification and mutation are also present.9,12,13 Data suggest that targetable HER2 amplification may occur more frequently in patients with liver fluke–associated cholangiocarcinoma.33

IHCC has several actionable genomic alterations, and molecular profiling is helpful in identifying systemic treatment options. The high prevalence (approximately 45%) of these actionable alterations underscores the importance of performing next-generation sequencing for patients with IHCC. However, even with the initial success of targeting several molecular subtypes of IHCC, identifying additional druggable alterations remains an important goal. Furthermore, in the coming years, increased emphasis must be placed on finding additional therapeutic options for patients with EHCC and GBC.

Disclosures: James M. Cleary, MD, PhD, received research funding to his institution from AbbVie, Merus NV, Roche, and Bristol Myers Squibb. He received research funding from Merck, AstraZeneca, Esperas Pharma, Bayer, and Tesaro; and travel funding and consulting fees from Bristol Myers Squibb.


  1. Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma - evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018;15(2):95-111. doi:10.1038/nrclinonc.2017.157
  2. Valle JW, Lamarca A, Goyal L, Barriuso J, Zhu AX. New horizons for precision medicine in biliary tract cancers. Cancer Discov. 2017;7(9):943-962. doi:10.1158/2159-8290.CD-17-0245
  3. Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17(9):557-588. doi:10.1038/s41575-020-0310-z
  4. Søreide K, Søreide JA. Bile duct cyst as precursor to biliary tract cancer. Ann Surg Oncol. 2007;14(3):1200-1211. doi:10.1245/s10434-006-9294-3
  5. Saha SK, Zhu AX, Fuchs CS, Brooks GA. Forty-year trends in cholangiocarcinoma incidence in the U.S.: intrahepatic disease on the rise. Oncologist. 2016;21(5):594-599. doi:10.1634/theoncologist.2015-0446
  6. Bertuccio P, Malvezzi M, Carioli G, et al. Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma. J Hepatol. 2019;71(1):104-114. doi:10.1016/j.jhep.2019.03.013 
  7. Valle J, Wasan H, Palmer DH, et al; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273-1281. doi:10.1056/NEJMoa0908721
  8. Lamarca A, Palmer DH, Wasan HS, 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-treated with cisplatin/gemcitabine (CisGem) chemotherapy. J Clin Oncol. 2019;37(suppl 15):4003. doi:10.1200/JCO.2019.37.15_suppl.4003
  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;24(17):4154-4161. doi:10.1158/1078-0432.CCR-18-0078
  10. Jiao Y, Pawlik TM, Anders RA, et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet. 2013;45(12):1470-1473. doi:10.1038/ng.2813
  11. Farshidfar F, Zheng S, Gingras MC, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep. 2017;19(13):2878-2880. doi:10.1016/j.celrep.2017.06.008
  12. Nakamura H, Arai Y, Totoki Y, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47(9):1003-1010. doi:10.1038/ng.3375
  13. Jusakul A, Cutcutache I, Yong CH, et al. Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov. 2017;7(10):1116-1135. doi:10.1158/2159-8290.CD-17-0368
  14. Voss MH, Hierro C, Heist RS, et al. A phase I, open-label, multicenter, dose-escalation study of the oral selective FGFR inhibitor Debio 1347 in patients with advanced solid tumors harboring FGFR gene alterations. Clin Cancer Res. 2019;25(9):2699-2707. doi:10.1158/1078-0432.CCR-18-1959
  15. Bahleda R, Italiano A, Hierro C, 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. Clin Cancer Res. 2019;25(16):4888-4897. doi:10.1158/1078-0432.CCR-18-3334
  16. Mazzaferro V, El-Rayes BF, Droz Dit Busset M, et al. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. Br J Cancer. 2019;120(2):165-171. doi:10.1038/s41416-018-0334-0 
  17. Javle M, Kelley RK, Roychowdhury S, 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. Ann Oncol. 2018;29(suppl 8):viii720. doi:10.1093/annonc/mdy424.030
  18. 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;21(5):671-684. doi:10.1016/S1470-2045(20)30109-1
  19. Goyal L, Meric-Bernstam F, Hollebecque A, et al. FOENIX-CCA2: a phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements. J Clin Oncol. 2020;38(suppl 15):108. doi:10.1200/JCO.2020.38.15_suppl.108 
  20. Goyal L, Shi L, Liu LY, et al. TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma. Cancer Discov. 2019;9(8):1064-1079. doi:10.1158/2159-8290.CD-19-0182
  21. Mahipal A, Tella SH, Kommalapati A, Yu J, Kim R. Prevention and treatment of FGFR inhibitor-associated toxicities. Crit Rev Oncol Hematol. 2020;155:103091. doi:10.1016/j.critrevonc.2020.103091
  22. Gattineni J, Alphonse P, Zhang Q, Mathews N, Bates CM, Baum M. Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4. Am J Physiol Renal Physiol. 2014;306(3):F351-F358. doi:10.1152/ajprenal.00232.2013
  23. Molenaar RJ, Maciejewski JP, Wilmink JW, van Noorden CJF. Wild-type and mutated IDH1/2 enzymes and therapy responses. Oncogene. 2018;37(15):1949-1960. doi:10.1038/s41388-017-0077-z
  24. 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;21(6):796-807. doi:10.1016/S1470-2045(20)30157-1
  25. Lowery MA, Burris HA 3rd, Janku F, et al. Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study. Lancet Gastroenterol Hepatol. 2019;4(9):711-720. doi:10.1016/S2468-1253(19)30189-X
  26. Zhu AX, Macarulla T, Javle MM, et al. Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. J Clin Oncol. 2021;39(suppl 3):266. doi:10.1200/JCO.2021.39.3_suppl.266
  27. Agios submits supplemental new drug application to FDA for Tibsovo (ivosidenib tablets) for patients with previously treated IDH1-mutant cholangiocarcinoma. News release. Agios Pharmaceuticals Inc. March 1, 2021. Accessed April 1, 2021. 
  28. Dankner M, Rose AAN, Rajkumar S, Siegel PM, Watson IR. Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations. Oncogene. 2018;37(24):3183-3199. doi:10.1038/s41388-018-0171-x
  29. Subbiah V, Lassen U, Élez E, 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;21(9):1234-1243. doi:10.1016/S1470-2045(20)30321-1
  30. Winkelmann R, Schneider M, Hartmann S, et al. Microsatellite instability occurs rarely in patients with cholangiocarcinoma: a retrospective study from a German tertiary care hospital. Int J Mol Sci. 2018;19(5):1421. doi:10.3390/ijms19051421
  31. Jakubowski CD, Mohan AA, Kamel IR, Yarchoan M. Response to crizotinib in ROS1 fusion-positive intrahepatic cholangiocarcinoma. JCO Prec Oncol. 2020;4:825-828. doi:10.1200/PO.20.00116
  32. Kheder ES, Hong DS. Emerging targeted therapy for tumors with NTRK fusion proteins. Clin Cancer Res. 2018;24(23):5807-5814. doi:10.1158/1078-0432.CCR-18-1156
  33. Albrecht T, Rausch M, Rössler S, et al. HER2 gene (ERBB2) amplification is a rare event in non-liver-fluke associated cholangiocarcinogenesis. BMC Cancer. 2019;19(1):1191. doi:10.1186/s12885-019-6320-y