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Review
. 2023 Jan;78(1):217-228.
doi: 10.1016/j.jhep.2022.09.004. Epub 2022 Sep 20.

Rational development of combination therapies for biliary tract cancers

James J Harding  1 , Danny N Khalil  1 , Luca Fabris  2 , Ghassan K Abou-Alfa  3
Affiliations
Review

Rational development of combination therapies for biliary tract cancers

James J Harding et al. J Hepatol. 2023 Jan.

Abstract

Biliary tract cancers are an uncommon set of gastrointestinal malignancies that are associated with high morbidity and mortality rates. Most patients present with incurable locally advanced or metastatic disease. The pathophysiology of biliary tract cancer can be exploited for direct therapeutic benefit, and indeed, chemotherapy, precision medicine, immunotherapy and combination treatments are now applied as both standard-of-care and investigational therapies. In the first-line setting, the immune-based chemotherapy combination of durvalumab plus gemcitabine and cisplatin has recently been shown to improve survival compared to chemotherapy alone. In the second-line, precision medicine can be employed in those with select genetic alterations in IDH1/2 (isocitrate dehydrogenase 1/2), FGFR2 (fibroblast growth factor receptor 2), KRAS, BRAF, ERBB2, NTRK (neurotrophic receptor tyrosine kinase), ROS, RET, and/or deficiencies in mismatch repair enzymes. In those patients without targetable genetic alterations, fluoropyridine doublets lead to modest improvements in outcomes. Next-generation sequencing is critical for direct patient care and to help elucidate genomic mechanisms of resistance in a research context. Currently, multiple clinical trials are ongoing - hence, this review seeks to provide an update on evolving standards of care and ongoing investigational agents, limitations to current treatments, and a framework for effective combination drug development for the future.

Keywords: Cholangiocarcinoma; Drug Development; Gallbladder Cancer; Immunotherapy; Precision Medicine.

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Conflict of interest statement

Conflict of interest James J. Harding reports grant research support from BI, Bristol Myers Squibb, Calithera, CytomX, Eli Lilly, Genoscience, Incyte, Novartis, Polaris, Yiviam and Zymeworks; consulting supprot from Adaptimmune, Bristol Myers Squibb, Eisai, Elevar, Exelixis, Hepion, Medivir, and Merck; and honoraria from HCC Connect, and NCCN. Danny N. Khalil reports royalty for intellectual property rights associated with Merck Sharp & Dohme; consulting fees from AbbVie and Psioxus; and patents EP3331612A1, CA3042867A1 for which he holds intellectual property interests related to CD40, nanoparticle therapeutics, and in situ vaccination. Luca Fabris reports consulting fees from L.E.K. Consulting and MedPanel; spport for attending European Association for the Study of the Liver (EASL) Liver Cancer Summit (2020), Prague, CZE, and European Network for the Study of Cholangiocarcinoma (ENS-CCA) Biennal Meeting (2022), Edinburgh, Scotland, ledership fiudicary role in International PSC Study Group, Working Group Malignancy (ongoing) (unpaid), Member Expert Panel, National Science Centre, Poland - Narodowe Centrum Nauki (NCN), Life Science section NZ5, Krakow (2019 e 2020), and external Reviewer of Doctoral Thesis for International Assessment. Invited by the Rabdoud University, The Netherlands (2022). Ghassan K. Abou-Alfa reports grant research support from Arcus, Astra Zeneca, BioNtech, BMS, Celgene, Flatiron, Genentech/Roche, Genoscience, Incyte, Polaris, Puma, QED, Silenseed, Yiviva, and consulting supprot from Adicet, Alnylam, Astra Zeneca, Autem, Beigene, Berry Genomics, Boehringer Ingelheim, Celgene, Cend, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech/Roche, Genoscience, Helio, Helsinn, Incyte, Ipsen, Merck, Nerviano, Newbridge, Novartis, QED, Redhill, Rafael, Servier, Silenseed, Sobi, Vector, Yiviva. Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

Fig. 1.
Fig. 1.. Timeline of drug development in biliary tract cancers.
FGFR2, fibroblast growth factor receptor 2; FOLFOX, 5-FU and oxaliplatin; IDH1, isocitrate dehydrogenase 1; MSI, microsatellite instability; NTRK, neurotrophic receptor tyrosine kinase; TMB, tumour mutational burden.
Fig. 2.
Fig. 2.. Drug targets in biliary tract cancer based on oncogenesis.
FGFR, fibroblast growth factor receptor; IDH, isocitrate dehydrogenase; NTRK, neurotrophic receptor tyrosine kinase.
See this image and copyright information in PMC

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