Cholangiocarcinoma: shedding light on the most promising drugs in clinical development

ABSTRACT

Introduction: Cholangiocarcinoma (CCA) is a diverse group of fatal malignancies arising from the biliary tract. Surgical resection with negative margin offers the only potentially curative option. The majority of patients present at locally advanced or metastatic stages, when surgical resection is not feasible, highlighting the significance of systemic therapy. Given the limited effectiveness of traditional chemotherapy regimens in CCA, many investigators have focused on developing novel molecular therapies targeting key aberrant signaling pathways.

Areas covered: We present the main genomic aberrations known to play a key role in cholangiocarcinogenesis and discuss promising targeted therapies in clinical development.

In October of 2020, a review of the English literature was performed utilizing PubMed and Web of Science databases for the keywords of ‘cholangiocarcinoma’, ‘biliary tract cancer’, and ‘targeted therapy’.

Expert opinion: Unfortunately, despite encouraging results in preclinical studies, the outcome of clinical trials with established targeted therapies like anti-EGFR medications have been discouraging. Currently, agents targeting FGFR2 fusion and IDH1/2 mutations hold great promise for improving the management of CCA. Future studies focused on enhancing our understanding of key aberrant signaling pathways of cholangiocarcinogenesis and the design of homogeneous and biomarker-driven cohorts are key elements of establishing precision medicine in CCA.

KEYWORDS:

• Cholangiocarcinoma
• biliary tract cancer
• targeted therapy
• precision medicine
• genomic aberrations
• signaling pathways

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose

Article Highlights

• CCA is the second most common primary liver and biliary tract malignancy after hepatocellular carcinoma and gallbladder cancer, respectively. The incidence and mortality rates of CCA are increasing globally.

• Surgical resection with negative microscopic margins remains as the only potentially curative option. The majority of patients is not amenable to surgical resection at the time of diagnosis due to presentation at advanced stages.

• Data on systemic therapy for CCA are scarce and are typically derived from studies that examine ‘all comer’ advanced biliary tract and pancreatic cancers with variable clinical application due to the heterogeneity of patients included in trials.

• Combination of Gemcitabine plus Cisplatin has been recommended as a first-line chemotherapy by several investigators, although with limited efficacy, thus highlighting the urgent need for novel systemic therapies.

• New advances in genomic profiling have shed light on a better understanding of cholangiocarcinogenesis and its key aberrant signaling pathways with hope for development of novel diagnostic biomarkers and targeted therapies.

• Despite promising results in preclinical studies, the outcome of clinical trials with established targeted therapies have been discouraging.

• Lack of large homogenous CCA specific studies due to low incidence of the disease, high grade of inter- and intra-tumoral heterogeneity, and paucity of biomarker-driven clinical trials are the major limitations of current studies.

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Additional information

Funding

This paper was not funded.