Aiwu Ruth He, MD
Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC

Key Takeaways

  • Biliary tract cancers (BTCs), a heterogeneous group of malignancies that make up about 3% of all gastrointestinal tumors, are notably aggressive and difficult to treat.
  • Gemcitabine plus cisplatin is the most commonly used front-line regimen for BTCs, and folinic acid and fluorouracil plus oxaliplatin (FOLFOX) is the typical second-line treatment in the United States.
  • Survival of patients with advanced BTCs remains abysmal, with a median overall survival of less than 1 year with traditional chemotherapy.
  • Over the past decade, breakthrough therapies in BTCs have revolved around targeted therapies and immunotherapies.
  • Recently-approved molecularly targeted agents include ivosidenib, pemigatinib, and infigratinib.

Aiwu Ruth He, MD, is a gastrointestinal oncologist and associate professor of medicine at the Georgetown-Lombardi Comprehensive Cancer Center in Washington, District of Columbia.

What are the unmet treatment needs for patients with advanced cholangiocarcinoma?

BTCs are a heterogeneous group of aggressive and difficult-to-treat malignancies that make up about 3% of all gastrointestinal tumors.1 More than 70% of patients are diagnosed with late-stage disease with tumors that cannot be resected or that has metastasized.2 For these patients, gemcitabine plus cisplatin is still the most commonly used front-line regimen in the United States, and folinic acid and fluorouracil plus oxaliplatin (FOLFOX) is the typical second-line treatment, supported by the phase 3 ABC-02 ( Identifier: NCT00262769) and ABC-06 ( Identifier: NCT01926236) trials, respectively.3,4 Nonetheless, survival of patients with advanced BTC remains abysmal, with a median overall survival of less than 1 year with traditional chemotherapy.5 As such, more treatment options for advanced cholangiocarcinoma are needed.

Can you describe the current treatment landscape regarding cholangiocarcinoma and the role of targeted therapies?

The increased use of molecular profiling in cancer has shown that BTCs have some of the highest rates of genetic aberration. Some of these aberrations include mutations in IDH1, FGFR2, and NTRK.2 As a result, breakthrough therapies in BTCs revolve around targeted therapies and immunotherapies. Targeted agents recently approved by the Food and Drug Administration (FDA) include ivosidenib, an inhibitor of isocitrate dehydrogenase 1 (IDH1), and pemigatinib and infigratinib, which are inhibitors of fibroblast growth factor receptor 1 (FGFR1), FGFR2, and FGFR3.6,7 Phase 2 studies have shown early promising data targeting BRAF mutation and HER2 amplifications.8

What is the current role of immunotherapy in advanced cholangiocarcinoma and where do you see it going in the future as new targeted therapies become available?

Immunotherapy has been evaluated in advanced cholangiocarcinoma. The TOPAZ-1 study ( Identifier: NCT03875235) established the role of durvalumab, an anti-programmed death ligand 1 (anti-PD-L1) antibody, in combination with cisplatin and gemcitabine in advanced cholangiocarcinoma.9 Additional immune checkpoint inhibitors, with or without chemotherapy, are also being evaluated in advanced cholangiocarcinoma.10 Currently, all targeted therapies are approved by the FDA in patients with targetable mutations who have progressed on first-line therapy. The targeted therapies are being tested in the first-line setting.
All tumors should be profiled to identify targeted genetic alterations. When the safety and efficacy data from randomized phase 3 studies become available, I expect that either targeted therapy or immunotherapy options will be recommended as first-line therapy in patients with certain tumor genetic profiles. In patients with primary or secondary resistance to first-line therapy, I expect that additional targeted therapy or immunotherapy will be recommended as second-line therapy. The availability of multiple lines of therapy may prolong survival in patients with advanced cholangiocarcinoma.

The positive data from the global randomized phase 3 TOPAZ-1 study established a new standard first-line therapy. In addition, TOPAZ-1 is the first phase 3 study supporting the role of the immune checkpoint inhibitor durvalumab, an anti-PD-L1 antibody, in biliary cancer treatment.

Futibatinib, an irreversible FGFR1 through 4 inhibitor, has shown promise in the treatment of patients with intrahepatic cholangiocarcinoma harboring FGFR2 fusions and is currently undergoing phase 3 investigation. Can you elaborate on this investigational agent, including the available data and what this could mean if ultimately approved for cholangiocarcinoma?

The ligand-independent activation of FGFR2 is a known oncogenic event that predominantly occurs in intrahepatic cholangiocarcinoma with a prevalence of approximately 10% to 15%.11 Infigratinib and pemigatinib, reversible adenosine triphosphate (ATP)-competitive and selective inhibitors of FGFR1 through 3, were approved by FDA for patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 fusion or other rearrangement on the basis of promising data from phase 2 studies.7 Infigratinib ( Identifier: NCT03773302) and pemigatinib ( Identifier: NCT03656536) are being evaluated in phase 3 studies. 
Futibatinib is an oral investigational agent that is a potent, selective, and irreversible tyrosine kinase inhibitor (TKI) of FGFR1 through 4. In the phase 2b FOENIX-CCA2 trial ( Identifier: NCT02052778), futibatinib produced an objective response rate of 41.7% per independent central review with a median duration of response of 9.7 months. Among patients who responded to treatment, 72% continued to respond for 6 months or longer. The median overall survival from enrolled patients was reported at 21.7 months.12 On the basis of this result, the FDA has granted priority review to a New Drug Application for futibatinib in the treatment of patients with previously-treated locally advanced or metastatic cholangiocarcinoma harboring FGFR2 gene rearrangements, including gene fusions.13 Futibatinib is being tested in the phase 3 FOENIX-CCA3 trial ( Identifier: NCT04093362).

The PD-L1 inhibitor durvalumab, when combined with chemotherapy, significantly improved survival compared with chemotherapy alone in patients with BTCs in the phase 3 TOPAZ-1 trial. Can you touch on this trial and the data in terms of potential impacts on future clinical care and outcomes?

TOPAZ-1 is a randomized, double-blind, multicenter, global, phase 3 study. Patients with locally-advanced or metastatic BTCs were randomly assigned 1:1 to receive either durvalumab plus gemcitabine and cisplatin or placebo plus gemcitabine and cisplatin for 8 cycles, followed by durvalumab or placebo monotherapy until disease progression or unacceptable toxicity. Randomization was stratified by disease status (initially unresectable vs recurrent) and primary tumor location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer). The primary endpoint of the TOPAZ-1 study was met at the pre-planned interim analysis. As previously mentioned, a statistically significant improvement in overall survival was observed in patients who received durvalumab vs placebo (hazard ratio, 0.80). There is often a delayed separation of immunotherapy plus chemotherapy vs chemotherapy alone. To explore this further, a piece-wise hazard ratio was calculated. The hazard ratio for durvalumab vs placebo from 0 to 6 months was 0.91 and after 6 months was 0.74, demonstrating the long-term survival benefit with durvalumab plus gemcitabine plus cisplatin.9
In the subgroup analysis of the TOPAZ-1 study, the addition of durvalumab to gemcitabine plus cisplatin was associated with improved overall survival in patients with advanced BTCs, irrespective of primary tumor location or geographic area.9 The secondary endpoint, progression-free survival, was statistically significant in the full analysis set with a hazard ratio for durvalumab vs placebo of 0.75.9 The combination of durvalumab, cisplatin, and gemcitabine was well tolerated and did not show a significant difference in treatment-related adverse effects compared with the cisplatin plus gemcitabine combination. Consistent with the mechanism of action, the incidence of immune-mediated adverse events was higher in the durvalumab arm.

What did the TOPAZ-1 study find?
Improved overall survival in patients with advanced BTCs with the addition of durvalumab to gemcitabine plus cisplatin.

Gemcitabine plus cisplatin was the first-line standard of care for patients with advanced BTC worldwide for over a decade until the TOPAZ-1 study. The positive data from the global randomized phase 3 TOPAZ-1 study established a new standard first-line therapy. In addition, TOPAZ-1 is the first phase 3 study supporting the role of the immune checkpoint inhibitor durvalumab in biliary cancer treatment.

What other emerging therapies are in the late stages of the pipeline for cholangiocarcinoma and what is the impact they may have on treatment decisions?

For targeted therapy, FGFR inhibitors and IDH1 inhibitors are being tested in first-line treatment of cholangiocarcinoma. The benefit of therapies targeting BRAF mutation and HER2 amplification will be validated in cholangiocarcinoma. Targeted therapies to other driving mutations will also be tested. Additional targeted therapies will be tested in patients who develop resistance to first-generation targeted therapy.
For immunotherapy, additional immune checkpoint inhibitors alone or in combination, with or without chemotherapy, will be evaluated in advanced cholangiocarcinoma. 
Targeted therapy and immunotherapy will be tested in earlier stages of cholangiocarcinoma to improve the survival and cure rate in patients who have resectable cholangiocarcinoma.

This Q&A was edited for clarity and length.


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Reviewed October 2022