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. 2025 Sep;21(21):2713-2721.
doi: 10.1080/14796694.2025.2539018. Epub 2025 Jul 29.

ABC-12: exploring the microbiome in patients with advanced biliary tract cancer in a first-line study of durvalumab (MEDI4736) in combination with cisplatin/gemcitabine

Eleni Vrana  1 , Hayley Timmins  2 , Ashley Osborne  1 , Rebecca Cox  1 , Harpreet Wasan  3 , Yuk Ting Ma  4 , Arvind Arora  5 , Olusola Faluyi  6 , Roopinder Gillmore  7 , Pippa Corrie  8 , Paul Miller  9 , Seema Arif  10 , Joanna Canham  2 , Charlotte Martin  2 , Muhammad Riaz  2 , Tongtong Shi  2 , Melissa Frizziero  1 , Victoria Foy  1 , Richard A Hubner  1 , Helen Morement  11 , John Bridgewater  12 , Richard Adams  2 , Juan W Valle  13   14 , Mairéad G McNamara  15
Affiliations

ABC-12: exploring the microbiome in patients with advanced biliary tract cancer in a first-line study of durvalumab (MEDI4736) in combination with cisplatin/gemcitabine

Eleni Vrana et al. Future Oncol. 2025 Sep.

Abstract

Until recently, cisplatin/gemcitabine was standard of care for the first-line treatment of patients with advanced biliary tract cancer (BTC). The addition of durvalumab, an immune checkpoint inhibitor, to the combination of cisplatin/gemcitabine has demonstrated an overall survival (OS) benefit and is now a standard of care first-line treatment option. BTCs exhibit immunogenic features may develop through an accumulation of genetic and epigenetic alterations, and can be influenced by microbial exposure. Microbiota can influence inflammation and immunity, and its disruption may impair tumor response to immunotherapy and chemotherapy. Here, the rationale and design of the multi-center, single-arm ABC-12 trial (ISRCTN11210442) is described, which investigates the role of the microbiome in patients with advanced BTC in a first-line study of durvalumab (MEDI4736) in combination with cisplatin/gemcitabine. The primary objective is to determine the difference in baseline alpha diversity between "responders" (partial or complete response) and "non-responders" at 18 weeks (RECIST 1.1) in patients treated with cisplatin/gemcitabine/durvalumab. Secondary objectives include investigating the association between microbiome parameters and objective response rate, tumor control (partial, complete response, and stable disease), progression-free and OS, and investigating the interaction between treatment effect and microbiome parameters on clinical outcomes.

Keywords: Advanced biliary tract cancer; cisplatin; durvalumab; first-line treatment; gemcitabine; microbiome.

Plain language summary

Biliary tract cancers (BTCs) are highly lethal cancers. Until recently, cisplatin plus gemcitabine was the standard chemotherapy regimen for patients with BTC where surgery was not possible. Durvalumab is an immunotherapy which works by assisting the immune system to recognize and attack cancer cells. The addition of durvalumab to cisplatin and gemcitabine has shown a survival benefit.Thousands of bacteria live in the human digestive system, which are called the microbiota. Each person has an individual community of microorganisms, and the microbiome is a collection of genomes (genetic material) from all the microorganisms in the environment, and this varies greatly from one person to the other. This is responsible for the breakdown of food, changing food into energy for the body, and protecting against infections. It also helps in developing the immune system. Research shows that its disruption can cause disease, including cancer, and can affect response to chemotherapy and immunotherapy. The aim of this trial is to assess whether the number and types of bacteria that live naturally in saliva and the bowel impact the response to the combination of immunotherapy with cisplatin and gemcitabine in patients with biliary tract cancer, where cure is not possible.

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Conflict of interest statement

YTM has received consultancy fees from AstraZeneca, Taiho and Astellas and personal fees from Faron, Incyte and Roche.

RG has received speaker honoraria from AstraZeneca and has served on advisory boards for Astellas.

PC has received institutional research funding from AstraZeneca, MSD and Microbiotica and has received consultancy fees from Microbiotica. She has served on advisory boards for BMS, Astellas, MSD and SUN Pharma and received speaker fees from MSD, Novartis, and Pierre Fabre.

PM has served on an advisory board for Jazz Pharmaceuticals.

MF has received travel and accommodation support from Ipsen and speaker honoraria from AAA.

RAH has served on trial steering committees for Ipsen and Beigene and has received personal honoraria for consulting role from Novartis. He has received travel and accommodation support from Roche, BMS and Bayer and speaker honoraria from AstraZeneca and Sirtex.

JWV has received personal honoraria for consulting/advisory role from AstraZeneca, Incyte, Taiho Oncology, Servier, Jazz Pharmaceuticals; and honoraria to institution from RedX Pharma, Cogent Biosciences, Owkin, Jazz Pharmaceuticals and Oncosil.

MMN has received research grant support from AstraZeneca, Servier, Ipsen and NuCana. She has received travel and accommodation support from Bayer and Ipsen and speaker honoraria from Pfizer, Ipsen, NuCana, Mylan and AAA. She has served on advisory boards for Celgene, Ipsen, Sirtex, Baxalta, Incyte and Astra Zeneca.

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.

No writing assistance was utilized in the production of this manuscript.

References

    1. Vogel A, Bridgewater J, Edeline J, et al. Biliary tract cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up ☆. Ann Oncol. 2023;34(2):127–140. doi: 10.1016/j.annonc.2022.10.506 - DOI - PubMed

    2. • This reference is important as it represents the current ESMO guidelines regarding management of patients with biliary tract cancers (BTCs).

    1. Siegel RL, Kratzer TB, Giaquinto AN, et al. Cancer statistics, 2025. CA Cancer J Clin. 75(1):10–45. doi: 10.3322/caac.21871 - DOI - PMC - PubMed
    1. Primrose JN, Neoptolemos J, Palmer DH, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019;20(5):663–673. doi: 10.1016/S1470-2045(18)30915-X - DOI - PubMed
    1. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273–1281. doi: 10.1056/nejmoa0908721 - DOI - PubMed

    2. • Valle et al showed the benefit of cisplatin addition to single agent gemcitabine in the 1st line setting of patients with BTCs back in 2010.

    1. Valle JW, Vogel A, Denlinger CS, et al. Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study. Lancet Oncol. 2021;22(10):1468–1482. doi: 10.1016/S1470-2045(21)00409-5 - DOI - PubMed

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