Recent Developments in Genomic-Driven Therapies for Cholangiocarcinoma

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Personalized medicine has expanded the treatment options for patients with cholangiocarcinoma (CCA). At the 2021 Annual Meeting of the Cholangiocarcinoma Foundation (CCF), Ghassan K. Abou-Alfa, MD, MBA, Professor of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, discussed recent developments in personalized therapies, highlighting genomic alterations that are informing the new therapies for patients with CCA.

Look for the next issue of CCA News for additional key presentations from the CCF meeting.

Several CCA driver genes and actionable targets are being identified and are in various stages of clinical development. To date, isocitrate dehydrogenase (IDH) and fibroblast growth factor receptor 2 (FGFR2) are the best understood molecular targets in CCA.

Dr Abou-Alfa focused on data about FGFR alterations in CCA. Currently, he noted, 2 FGFR2 inhibitors have been approved by the FDA—pemigatinib (Pemazyre) and infigratinib (Truseltiq), and other agents are being investigated in CCA. In addition, in April 2021, the FDA granted a breakthrough therapy for futibatinib; and derazantinib is another investigational agent.

Dr Abou-Alfa discussed results of a final analysis of a phase 2 clinical trial of infigratinib in 108 patients with advanced or metastatic CCA and FGFR2 alterations whose disease progressed during ≥1 lines of systemic therapies. At a median follow-up of 11.3 months, infigratinib therapy led to an objective response rate (ORR) of 23%; the median progression-free survival (PFS) was 7.3 months, and the median overall survival (OS) was 12.2 months.1

Pemigatinib received FDA approval based on results from a phase 2 clinical trial in patients with advanced, unresectable CCA and FGFR2 fusion or other alteration; treatment with pemigatinib yielded an ORR of 35% and a median OS of 21.1 months.

And in a first-in-human phase 1 dose-escalation clinical trial, futibatinib showed robust response in patients with heavily pretreated advanced solid tumors.2

Other FGFR inhibitors showing promising activity in biliary tract cancers are derazantinib and Debio 1347.3,4 Polyclonal secondary FGFR2 mutations were reported to drive acquired resistance to FGFR2 inhibition in CCA.5 Several phase 3 clinical trials investigating these FGFR inhibitors are ongoing; however, accrual of patients is challenging. Dr Abou-Alfa noted that the PFS and duration of response may be more realistic end points than OS in these investigations.

Finally, IDH1 mutations represent the most common targetable driver alterations in CCA, particularly in intrahepatic CCA, which accounts for 20% of CCA cases.6 IDH1-mutated CCA is characterized by poor differentiation, dysregulation of hypermethylation, and has poor prognosis.7

IDH1-targeted small-molecule inhibitors have completed pivotal studies and exhibit promising benefits. In the double-blind, placebo-controlled phase 3 ClarIDHy study, the IDH1 inhibitor ivosidenib (Tibsovo) led to modest, but significant, PFS improvement in patients with CCA (hazard ratio, 0.37).8 A high proportion of crossover masked the significant OS benefit, but a trend for OS benefit was observed.8

Mechanisms of primary and acquired resistance are poorly understood thus far. Future research efforts need to focus on identifying patient subsets who benefit from IDH inhibitors.


  1. Javle MM, Roychowdhury S, Kelley RK, et al. Final results from a phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement. J Clin Oncol. 2021;39(3_suppl):Abstract 265.
  2. Bahleda R, Meric-Bernstam F, Goyal L, et al. Phase I, first-in-human study of futibatinib, a highly selective, irreversible FGFR1-4 inhibitor in patients with advanced solid tumors. Ann Oncol. 2020;31:1405-1412.
  3. 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;120:165-171.
  4. 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;25:2699-2707.
  5. Goyal L, Saha SK, Liu LY, et al. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion–positive cholangiocarcinoma. Cancer Discov. 2017;7:252-263.
  6. Javle M, Bekaii-Saab T, Jain A, et al. Biliary cancer: utility of next-generation sequencing for clinical management. Cancer. 2016;122:3838-3847.
  7. Kipp BR, Voss JS, Kerr SE, et al. Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma. Hum Pathol. 2012;43:1552-1558.
  8. 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;21:796-807. Erratum in: Lancet Oncol. 2020;21:e462.

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