Global Cholangiocarcinoma Clinical Trials Update

August 2020, Vol 1, No 1

Rachna T. Shroff, MD, MS, Chief, Section of GI Medical Oncology, University of Arizona Cancer Center, Tucson, and Co-Chair of the 2020 Cholangiocarcinoma Foundation Annual Conference, provided an update of important global clinical trial developments since the last conference of the foundation. Dr Shroff reminded the audience that the ABC-02 clinical trial established the use of gemcitabine and cisplatin chemotherapy as the standard of care for patients with metastatic or unresectable cholangiocarcinoma (CCA) since 2010.

Until recently, one of the greatest unmet needs in the treatment of patients with CCA was the lack of a standard of care in the second-line treatment after a patient’s lack of response to first-line therapy. The ABC-06 clinical trial, which was published in 2019, established FOLFOX (folinic acid, fluorouracil, and oxaliplatin) as the preferred regimen choice for patients whose CCA has progressed after first-line treatment.

Longer Survival

Looking forward to future developments, Dr Shroff highlighted some important clinical trials that may give hope to patients with this rare disease. A group at M.D. Anderson Cancer Center investigated the 3-drug combination of gemcitabine, cisplatin, and nab-paclitaxel in a single-arm study of newly diagnosed patients with biliary tract cancers, including CCA.

The data were published in 2019, and the results look promising. The results show an improvement in median progression-free survival (PFS), and an impressive increase in median survival compared with the historical data from the ABC-02 clinical trial.

The majority of patients in the study had some tumor shrinkage. Of the patients who had unresectable disease, 20% converted to resectable disease with this 3-drug regimen and were taken to the operating room for curative surgery.

The National Cancer Institute is sponsoring an ongoing study known as S1815, which compares the potential benefit of the 3-drug combination of gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin in a randomized clinical trial. The primary end point is overall survival, and the simple question that this study is trying to answer is, “Can we do better than the standard of care?” The S1815 clinical trial has successfully accrued more than 400 patients to date.

Molecular Profiling in CCA

Although chemotherapy regimens have prolonged the lives of some patients with CCA, many researchers and clinicians are looking to the exciting discipline of molecular profiling to take a step beyond chemotherapy. The discovery of the FGFR2 fusions, IDH1 and IDH2, as well as BRAF mutations and HER2 amplifications in CCA has encouraged researchers to investigate the possibility of developing drugs that target these and other molecular aberrations in this rare malignancy. Dr Shroff reviewed recent progress in drug therapy based on results from global clinical trials.

Recently, ivosidenib (Tibsovo), an IDH1 inhibitor that that targets IDH1 mutations, demonstrated statistically significant improvement in PFS, as well as good tolerability, in phase 2 and 3 clinical trials. Ivosidenib was included as a treatment option in the June 2020 version of the National Comprehensive Cancer Network hepatobiliary guidelines for the treatment of patients with biliary tract cancers and IDH1 mutation, after disease progression.

In the past year, the US Food and Drug Administration (FDA) considered the data from a phase 2 clinical trial for the investigational drug infigratinib, which targets the FGFR2 fusion. In January 2020, infigratinib received a fast track designation by the FDA as a first-line therapy for adults with advanced or metastatic CCA, as well as an orphan drug designation for CCA.

In April 2020, the CCA community had a huge win when the FDA approved pemigatinib (Pemazyre) as the first targeted agent indicated for adults with previously treated, unresectable, locally advanced or metastatic CCA.

Other drugs are being investigated for the treatment of CCA with FGFR2 fusions, including futibatinib, TAS-120, and ARQ187.

On the Horizon

Now that it is possible to identify molecular aberrations associated with CCA, and that treatments have been approved that target or are on the horizon to target some of these aberrations, what else could oncologists potentially offer their patients in the future?

Liquid biopsies, which use circulating tumor-cell DNA, could conceivably be used to monitor the response to therapy or track the development of resistance to drugs.

Emerging data, according to Dr Shroff, are supporting the contention that with the use of circulating tumor-cell DNA, we can see the disappearance of pathological mutations as drug therapy progresses, but it can also identify the evolution of resistance clones. More work needs to be done, but the stage has been set for progress in the treatment of CCA, she said.

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