Immunotherapies in clinical development for biliary tract cancer

ABSTRACT

Introduction: Cancers of the biliary tract (BTC) are aggressive malignancies with limited treatment options and an overall dismal prognosis. In recent years, two concepts, namely precision oncology and immune oncology (IO) have profoundly influenced and, in some cancers, even revolutionized tumor treatments. While positive data from randomized trials have led to the incorporation of targeted concepts for genetically select BTC patients, IO is not yet implemented in clinical practice.

Areas covered: We discuss published results from completed, as well as from ongoing studies on IO in BTC, based on a literature search on Pubmed and information provided by clinicaltrials.gov in October 2020. Apart from monotherapy, we outline IO-based combination approaches and highlight pivotal studies whose results will likely influence the future development of relevant concepts in BTC.

Expert opinion: Despite partially positive signals, IO thus far disappointed in unselected BTC populations and should currently not be considered as a preferred systemic treatment in patients with microsatellite stable disease outside of clinical trials. In the coming years, a better understanding of the molecular mechanisms underlying resistance to checkpoint inhibition, and the identification of positive predictive biomarkers will be important for the successful integration of IO into treatment concepts for BTC patients.

KEYWORDS:

• Cholangiocarcinoma
• chemotherapy
• PD-1/PD-L1
• CTLA-4
• targeted therapies

Article highlights

• Cancers of the biliary system (BTC) are highly aggressive tumors with a dismal prognosis and only a few established options for systemic therapy.

• In recent years, treatment concepts for BTC were genuinely influenced by two novel ‘approaches’ to anti-cancer therapy, namely precision oncology and immune oncology (IO).

• The initial enthusiasm about immunotherapy in BTC was dampened by the observation that only few patients derive a durable clinical benefit from checkpoint inhibition. However, there is a clear signal that a subgroup of BTC patients benefits from IO-based systemic therapies.

• The most promising data on IO in BTC have been reported in phase-II trials in combination with chemotherapy.

• MSI and TMBhigh, as well as high PD-L1 expression, might serve as valuable biomarkers, but their prevalence is very low in BTC.

• Inclusion of BTC patients into ongoing clinical trials is strongly encouraged.

This box summarizes key points contained in the article.

Reviewer disclosures

One reviewer has received honoraria from Ono Pharmaceutical.

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

Declaration of interest

Honoraria for speaker, consultancy, and advisory roles was awarded to A Vogel from Roche, Bayer, Sanofi, BMS, Lilly, Novartis, EISAI, AstraZeneca, Merck, Medac, Ipsen, PierreFabre and MSD.

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.

Additional information

Funding

A Vogel and A Saborowski have received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – [SFB/TRR 209 - 314905040, and Vo959/9-1 (to AV)]. A Vogel is supported by the European-Latin- American ESCALON consortium, funded by the EU Horizon2020 program. A Saborowski is supported by Deutsche Krebshilfe (DK) −70114101.