The Oncology Pipeline Offers Hope for Patients with Cholangiocarcinoma

December 2020, Vol 1, No 3

Despite the onslaught of the COVID-19 pandemic, researchers are hard at work to develop innovative therapies that will make a difference in the lives of patients with cancer.

At the 2020 Cholangiocarcinoma Summit, Filip Janku, MD, Associate Professor of Medicine, Investigational Cancer Therapeutics, Center Medical Director, Clinical and Translational Research Center, and Associate Member, Graduate School of Biomedical Sciences, the University of Texas M.D. Anderson Cancer Center, Houston, TX, delivered the keynote address, discussing drugs in the pipeline that may also be used for the treatment of patients with cholangiocarcinoma (CCA).

Multiple oncogenic molecular alterations have been identified in patients with CCA, Dr Janku said, and many of these mutations can effectively be targeted with cancer therapies. “Cholangiocarcinoma is…from the genomic standpoint, an extremely interesting disease,” Dr Janku suggested.

FGFR Inhibitors

Patients with advanced CCA whose disease progresses during or after first-line chemotherapy have few treatment options for second-line therapy. A major advance in the management of patients with CCA and FGFR2 fusions or other rearrangements was the FDA approval of pemigatinib (Pemazyre) in April 2020.

“Probably all of us noticed the pemigatinib approval for FGFR fusion cholangiocarcinoma. It was actually the first molecularly targeted therapy approved in cholangiocarcinoma,” said Dr Janku.

Other FGFR inhibitors that are in the advanced stage of development for CCA include infigratinib and futibatinib. These 2 investigational agents have exhibited efficacy in the second-line treatment, demonstrating safety profiles consistent with other drugs in this class.

In one study, the frequency of drug-resistant clones was lower with futibatinib, an inhibitor of several drug-resistant FGFR2 mutations, including the FGFR2 V565I/L gatekeeper mutations, with greater potency than any of the reversible FGFR inhibitors that were tested.1

Phase 3 clinical trials with infigratinib as well as with futibatinib are ongoing.

IDH Inhibitors

IDH1 or IDH2 mutations have been identified in 25% of patients diagnosed with CCA.2

Ivosidenib (Tibsovo), an oral targeted IDH1 inhibitor, was added to the National Comprehensive Cancer Network (NCCN) Guidelines for Hepatobiliary Cancers in June 2020 based on the strength of the clinical data that led to its FDA approval in 2020. Ivosidenib is indicated for the treatment of patients with acute myeloid leukemia (AML) and a susceptible IDH1 mutation, but it has not yet been approved by the FDA for the treatment of CCA.

Several other promising IDH inhibitors are in development. Vorasidenib is a pan-IDH inhibitor that inhibits the 2 isoforms IDH1 and IDH2 and is being studied in clinical trials for the treatment of glioma with IDH1 or IDH2 mutations.

HMPL306, another pan-IDH inhibitor, is being tested in a phase 1 clinical trial for relapsed or refractory AML with IDH mutations.

Another IDH1 inhibitor, LY3410738, is being investigated in a phase 1 clinical trial in patients with solid tumors, including CCA.

IDH inhibitors have a little bit more of a difficult development pathway. They are drugs that are arguably more cytostatic than cytotoxic, but at the same time, they have a very favorable safety profile. They definitely have a future, if not as a single agent, definitely as an agent for combinations with other therapies for cholangiocarcinoma,” Dr Janku said regarding the IDH inhibitors in development.

HER2 Inhibitors

HER2 amplifications have been observed in 11% to 20% of patients with CCA.2 Several clinical trials are investigating HER2-amplified gastrointestinal cancers, including CCA.

HER2 seems to be a very promising target, especially HER2 amplifications,” Dr Janku noted. “There are multiple studies led by companies, investigator-initiated groups, which essentially look at HER2 beyond gastric cancer and beyond breast cancer. They show interesting data, and cholangiocarcinoma is not an exception.”

BRCA, MEK, BRAF Mutations

Other molecular alterations that have been seen in patients with CCA are BRCA, MEK, and BRAF mutations.

“We found that quite a lot of patients with cholangiocarcinoma and IDH1 mutations had some simultaneous major alterations which were in multiple anchor genes,” Dr Janku said. These were “often associated with major pathways, such as MEK kinase pathways, such as KRAS or BRAF, or…DDR pathways, such as RN1A, APM, and BRCA,” he added.

The MEK and BRAF “inhibitors are extremely interesting. There are some very promising data from the basket trial, which was focusing on rare cancers with BRAF and MEK mutations,” Dr Janku said.

In this basket study reported in 2020, the FGFR inhibitors futibatinib, erdafitinib (Balversa), and infigratinib were evaluated in patients with CCA and BRAF V600 mutations. The data were very encouraging, demonstrating an overall response rate of 51% and overall survival of 14 months in patients who had received previous treatment with at least 1 line of therapy. Many of the patients had a response on the first restaging.

Cold Tumors

A predominant focus in oncology in general has been the development of immunotherapy strategies that increase the immunoresponsiveness of cold tumors. To address CCA that displays an immune desert phenotype or an immune-excluded phenotype, both of which are characteristically nonresponsive to treatment with immune checkpoint inhibitors, efforts are now underway to render cold tumors more sensitive to immunotherapies, Dr Janku said.


  1. Sootome H, Fujita H, Ito K, et al. Futibatinib is a novel irreversible FGFR1-4 inhibitor that shows selective antitumor activity against FGFR-deregulated tumors. Cancer Res. 2020;80:4986-4997.
  2. Pellino A, Loupakis F, Cadamuro M, et al. Precision medicine in cholangiocarcinoma. Transl Gastroenterol Hepatol. 2018;3:40.

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