Druggable molecular alterations in bile duct cancer: potential and current therapeutic applications in clinical trials

ABSTRACT

Introduction: Cholangiocarcinomas (CCA) are rare tumors that are associated with a variety of molecular alterations. Many of these alterations are now actionable using drugs currently in development, and CCA may be a perfect example of application of a precision oncology approach. However, development of drugs in CCA faces the challenge of targeting rare alterations in a rare disease.

Areas covered: In this review, we present the current data on targeted therapies in development for CCA, focusing on IDH1, FGFR2, BRAF, and HER2 alterations. We also discuss rationale for targeting other alterations, currently without specific development in CCA. We searched PubMed and google scholar in February 2021 for relevant articles and presentation in recent congress regarding the literature on molecular alterations, drugs in cholangiocarcinomas and biliary tract cancers.

Expert opinion: Despite a strong rationale and promising early results, applying a precision oncology approach in CCA for everyday patients is still exposed to significant challenges: obtaining the molecular portrait of these tumors due to difficulties with biopsy access, complexities of drug development in subgroups of these relatively rare tumors, and sub-optimal access to drugs outside clinical trials.

KEYWORDS:

• Cholangiocarcinoma
• molecular alterations
• precision oncology
• targeted therapies
• biliary tract cancers

Article highlights

• Cholangiocarcinomas are tumors with a large variety of targetable alterations.

• Drugs targeting IDH1, FGFR2, BRAF and HER2 showed activity in clinical trials dedicated to cholangiocarcinoma, and these alterations should now be tested in clinical practice.

• The relative rarity of these tumors leads to specific difficulties for drug development and drug access: molecular testing might be difficult to achieve, and running randomized trial in such rare populations might prove very delicate. Platform trials might help future development.

Declaration of interest

A Lamarca has received travel and educational support from Ipsen, Pfizer, Bayer, AAA, Sirtex, Novartis, Mylan, and Delcath; speaker honoraria from Merck, Pfizer, Ipsen, and Incyte; advisory honoraria from EISAI, Nutricia Ipsen, QED, and Roche; and is a member of the Knowledge Network and NETConnect Initiatives funded by Ipsen. The salary of Dr Angela Lamarca is part funded by The Christie Charity and the European Union’s Horizon 2020 Research and Innovation Programme [grant number 825,510, ESCALON]. M McNamara has received research grant support from Servier, Ipsen, and NuCana; travel and accommodation support from Bayer and Ipsen; speaker honoraria from Pfizer, Ipsen, NuCana, and Mylan and has served on advisory boards for Incyte, Celgene, Ipsen, Sirtex, and Baxalta. R Hubner has served on the advisory board for Roche, BMS, Eisai, Celgene, Beigene, Ipsen, BTG; has received speaker fees from Eisai, Ipsen, Mylan, PrimeOncology; and has received travel and educational support from Bayer, BMS, and Roche (all outside of the scope of this work). JW Valle has received consulting or advisory role for Agios, AstraZeneca, Delcath Systems, Keocyt, Genoscience Pharma, Incyte, Ipsen, Merck, Mundipharma EDO, Novartis, PCI Biotech, Pfizer, Pieris Pharmaceuticals, QED, and Wren Laboratories; Speakers’ Bureau for Imaging Equipment Limited, Ipsen, Novartis, Nucana; and received Travel Grants from Celgene and Nucana. J Edeline has acted in an advisory role for Roche, AstraZeneca, BMS, MSD, Bayer, Ipsen, Eisai, Merck Serono; received travel grants from Amgen, Novartis; research grant from Beigene, BMS. The authors have no other 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 apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper is not funded.