Recent Progress in the Systemic Treatment of Advanced/Metastatic Cholangiocarcinoma

Abstract

Cholangiocarcinomas (CCAs) comprise of a heterogeneous group of cancers arising in the biliary tract (intrahepatic or iCCA, perihilar or pCCA and distal or dCCA; the latter are known under the collective term of eCCA), each subtype having its own particularities in carcinogenesis, management and prognosis. The increasing incidence in recent decades, limited treatment options and high mortality rates, even in the early stages, have led to an imperious need for more in-depth understanding and development of tailored treatments for this type of aggressive tumour. The wide use of molecular profiling has increased the understanding of biology and identified key molecular drivers, for example, IDH1 mutations or FGFR2 fusions for iCCA, or BRAF mutations in eCCA. Most recently, the FDA approved pemigatinib, an FGFR inhibitor and ivosidenib, an IDH1 inhibitor, but even though progress has been made to better understand the mechanisms of tumorigenesis, genetic make-up, and tumour resistance to standard chemotherapy and targeted therapies, cholangiocarcinomas still represent an important challenge in the daily clinical practice of oncology. The purpose of this review is to highlight the recent progress in the systemic treatment of advanced/metastatic CCAs with a focus on targeted drugs and their biomarkers currently evaluated in early-phase clinical trials.

Molecular Pathogenesis and Regulation of the miR-29-3p-Family: Involvement of ITGA6 and ITGB1 in Intra-Hepatic Cholangiocarcinoma

“…Cholangiocarcinoma is anatomically divided into intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma. From cancer genomic analysis, each cancer contains characteristic gene mutations, suggesting molecular biological differences [ 1 , 2 , 3 ]. ICC is the second most common cancer of the liver after hepatocellular carcinoma (HCC).…”

Surgical Treatment of Intrahepatic Cholangiocarcinoma: Current and Emerging Principles

“…The 7th edition of the American Joint Committee on Cancer (AJCC) Staging Manual introduced a distinct staging system for ICC, and the 8th edition provided further refinement of this staging system, leading to more accurate stratification of prognosis [ 3 ]. An improved understanding of the genetic underpinnings of ICC has led to identification of new molecular biomarkers and increased opportunities for targeted therapies [ 4 , 5 ]. Refinement of liver-directed therapies have expanded treatment options for patients with locally advanced disease and improved local control [ 6 , 7 , 8 ].…”

Targeted Therapies in Advanced Cholangiocarcinoma: A Focus on FGFR Inhibitors

“…In particular, several attempts have been made in order to develop targeted treatments in this setting, including the use of small molecule inhibitors (such as ATP competitive small molecule FGFR inhibitors and covalent small molecule inhibitors), recombinant peptides, monoclonal antibodies, and antibody drug conjugates [ 57 ]. Early studies on FGFR inhibition in CCA patients were mainly focused on non-selective inhibitors, such as lenvatinib, pazopanib, regorafenib, and dovitinib [ 58 , 59 , 60 , 61 ]. In particular, following case reports and case series showing the promising activity of the non-selective tyrosine kinase inhibitors ponatinib and pazopanib, these agents have been tested in preclinical and clinical trials.…”