Rare cancer, rare alteration: the case of NTRK fusions in biliary tract cancers

ABSTRACT

Introduction: For patients with advanced/unresectable biliary tract cancers, cisplatin–gemcitabine combination is the standard first-line treatment. Beyond the first line, the therapeutic arsenal is limited with minimal benefit. Biliary tract cancers exhibit one of the highest frequencies of targetable molecular alterations across cancer types, and several targeted therapies are emerging as treatment options.

Areas covered:We discuss neurotrophic tyrosine kinase receptor gene (NTRK) fusions in biliary tract cancers and the use of NTRK inhibitors (now approved in a ‘cancer-agnostic’ way), mechanisms of resistance, and emerging second-generation NTRK inhibitors.

Expert opinion: Despite their rarity in biliary tract cancers, NTRK fusions are promising molecular targets because i) NTRK inhibitors have proven highly effective in NTRK-rearranged cancers and are now approved in a ‘cancer-agnostic’ way; ii) emerging second-generation NTRK inhibitors may overcome secondary resistance; iii) NTRK rearrangements will be readily detectable with the generalization of next-generation-sequencing in biliary tract cancers, including the detection of other frequent gene rearrangements, such as those involving the fibroblast growth factor receptor 2 gene (FGFR2). However, more data are necessary regarding the prevalence and characteristics of NTRK fusions in biliary tract cancers and the efficacy of NTRK inhibitors in these patients.

KEYWORDS:

• Biliary tract cancer
• tumor agnostic
• NTRK fusions
• investigational drugs
• larotrectinib
• entrectinib
• rare cancers
• precision medicine
• precision oncology

Article Highlights

• Among the rich molecular landscape of biliary tract cancers, neurotrophic tyrosine kinase receptor gene (NTRK) fusions seem rare (<1% of the cases)

• NTRK inhibitors are highly effective and well tolerated in NTRK-rearranged tumors

• Because NTRK inhibitors are validated across multiple tumor types and molecular profiling is becoming standard in biliary tract cancers, physicians should know how to utilize these drugs even in this ‘rare-alteration-in-a-rare-disease’ setting

• More studies are necessary to clarify the position of NTRK inhibitors in the management of biliary tract cancers

This box summarizes key points contained in the article.

Declarations of interest

D Malka received honoraria and non-financial support from Amgen, Bayer, Ipsen, Incyte, MSD, Merck Serono, Roche, Sanofi and Servier and received honoraria from Shire, HalioDx and Agios.

L Verlingue reports personal fees from Adaptherapy, grants from Bristol-Myers Squibb, and consulting fees from Pierre-Fabre and Servier, all outside the submitted work.

V Boigereceived honoraria for advisory boards and as a presenter in a symposium from Bayer, Merck Serono and Ipsen.

M Ducreux received honoraria for advisory boards and as a presenter in symposium from Merck Serono, MSD, AMGEN, Roche, Bayer, Ipsen, Pfizer, Servier, Pierre Fabre, HalioDx, Lilly, Sanofi and BMS.

A Hollebecque has a Consultant/Advisory role for Amgen, Spectrum Pharmaceuticals and Lilly and received Invitations to national or international congresses from Servier, Amgen, Lilly Courses, training for Bayer. He is Principal/sub-Investigator of Clinical Trials for AbbVie, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Chugai Pharmaceutical Co., Clovis Oncology, Daiichi Sankyo and Debiopharm

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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded