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Clinical Studies

Primary resistance to immunotherapy in patients with a dMMR/MSI metastatic gastrointestinal cancer: who is at risk? An AGEO real-world study

British Journal of Cancer volume 130, pages 442–449 (2024)Cite this article

Subjects

Abstract

Background

The outstanding efficacy of immunotherapy in metastatic dMMR/MSI gastro-intestinal (GI) cancers has led to a rapid increase in the number of patients treated. However, 20-30% of patients experience primary resistance to immune checkpoint inhibitors (ICIPR) and need better characterization.

Methods

This AGEO real-world study retrospectively analyzed the efficacy and safety of ICIs and identified clinical variables associated with ICIPR in patients with metastatic dMMR/MSI GI cancers treated with immunotherapy between 2015 and 2022.

Results

399 patients were included, 284 with colorectal cancer (CRC) and 115 with non-CRC, mostly treated by an anti-PD(L)1 (88.0%). PFS at 24 months was 55.8% (95CI [50.8–61.2]) and OS at 48 months was 59.1% (95CI [53.0–65.9]). ORR was 51.0%, and 25.1% of patients were ICIPR. There was no statistical difference in ORR, DCR, PFS, or OS between CRC and non-CRC groups. In multivariable analysis, ICIPR was associated with ECOG-PS ≥ 2 (OR = 3.36), liver metastases (OR = 2.19), peritoneal metastases (OR = 2.00), ≥1 previous line of treatment (OR = 1.83), and age≤50 years old (OR = 1.76).

Conclusion

These five clinical factors associated with primary resistance to ICIs should be considered by physicians to guide treatment choice in GI dMMR/MSI metastatic cancer patients.

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Fig. 1: Distribution of the cohort population according to the number of risk factors for ICIPR and outcomes after ICI treatment.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank AGEO and David Marsh for supporting the study and English language correction, respectively. We thank the study staff for their contributions as well as Prof Frederic Di Fiore and Prof Stefano Kim.

Author information

Authors and Affiliations

  1. Department of Digestive Oncology, Georges Pompidou European Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Université Paris Cité, Paris, France

    Clémence Flecchia & Julien Taieb

  2. CARPEM, SIRIC, Université Paris Cité, Georges Pompidou European Hospital, Paris, France

    Edouard Auclin & Claire Gallois

  3. Digestive Oncology Department, Rangueil Hospital, University Hospital of Toulouse, Toulouse, France

    Emily Alouani & Rosine Guimbaud

  4. Gastroenterology and Hepatology Department, Poitiers University Hospital, Poitiers, France

    Mathilde Mercier & David Tougeron

  5. Drug Development Department (DITEP), Gustave Roussy Institute, Saclay University, 94800, Villejuif, France

    Antoine Hollebecque

  6. Department of Medical Oncology, CNRS UMR9020, Inserm UMR-S 1277-Canther-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, CHU Lille, Lille, France

    Anthony Turpin

  7. Department of Medical Oncology, Institut de Recherche en Cancérologie de Montpellier, INSERM, University of Montpellier, ICM, Montpellier, France

    Thibault Mazard

  8. Department of Digestive Oncology, Institut Bergonié, Bordeaux, France

    Simon Pernot

  9. Department of Medical Oncology, Henri Becquerel Centre, Rouen, France

    Marie Dutherage

  10. Department of Medical Oncology, Sorbonne University, Hôpital Saint-Antoine, AP-HP, and INSERM UMRS 938, Équipe Instabilité des Microsatellites et Cancer, Équipe Labellisée par la Ligue Nationale Contre le Cancer, SIRIC CURAMUS, Centre de recherche Saint Antoine, Paris, France

    Romain Cohen

  11. Department of Medical Oncology, University Hospital of Besançon, Besançon, France

    Christophe Borg

  12. Department of Hepato-Gastroenterology and Digestive Oncology, CHU Amiens Picardie, Amiens, France

    Vincent Hautefeuille

  13. Department of Digestive Oncology, Institut Jules Bordet, The Brussels University Hospital, Université Libre de Bruxelles, 1070, Anderlecht, Belgium

    Francesco Sclafani

  14. Medical Oncology Department, ICANS, Strasbourg, France

    Meher Ben-Abdelghani

  15. Gastroenterology Department, Saint Louis Hospital, APHP, Paris, France

    Thomas Aparicio

  16. Medical Oncology Department, Léon Bérard Center, Lyon, France

    Christelle De La Fouchardière

  17. Department of Medical Oncology, GHM, Grenoble, France

    Camille Herve

  18. Department of Gastroenterology, CHU Rennes, Rennes, France

    Geraldine Perkins

  19. Department of Medicine III and Comprehensive Cancer Center (CCC Munich LMU), University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany

    Kathrin Heinrich

  20. Department of Internal Medicine II, University Hospital Würzburg, Germany on behalf of the WERA Comprehensive Cancer Center Alliance, Würzburg, Germany

    Volker Kunzmann

Authors
  1. Clémence Flecchia
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  2. Edouard Auclin
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Contributions

Conceptualization: JT, DT and RG. Data curation: CF, EAl and MM. Formal analysis: CF, EAu and JT. Methodology: CF, EAu, and JT. Validation: JT. Writing, review, and editing: CF, JT, EAu, DT and RG. Validation of final manuscript: all authors.

Corresponding author

Correspondence to Julien Taieb.

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Competing interests

TM has received honoraria as a speaker or in an advisory role from Servier, Pierre Fabre, Merck Serono, AAA, Sanofi, and research funding from Amgen; and travel grants from Pierre Fabre, Merck Serono, and Sanofi. RC has received honoraria from AstraZeneca, Bristol-Myers Squibb, MSD Oncology, Mylan Medical, Pierre Fabre, Servier, and travel/accommodation fees from Amgen, Bristol-Myers Squibb, Mylan Medical, and Servier. CB has received honoraria from Bayer, Pierre Fabre, and MSD and research grants from Bayer and Roche. FS has received honoraria for consultancy, advisory roles, or speeches from AMAL Therapeutics, Amgen, Bayer, BMS, Dragonfly Therapeutics, Merck, Nordic Pharma, Roche, and Servier, research funding (institute) from Amgen, Astra Zeneca, Bayer, BMS, Roche, and Sanofi, support for travel/accommodation from Amgen, Bayer, Lilly, and Servier, and serves as Co-Chair of the EORTC Task Force Colon, Rectum, Anal Canal. TA has received honoraria as a speaker or in an advisory role from Amgen, Servier, Pierre Fabre, BMS, SIRTEC, and MSD. CG has participated in consulting and/or advisory boards for Servier, Sanofi, Merck, and Pierre Fabre, and has received support for travel to meetings from Amgen and Pierre Fabre. DT has received honoraria as a speaker or in an advisory role from Sanofi, Roche, Merck Serono, Amgen, Servier, Pierre Fabre, BMS, Astra Zeneca, and MSD. JT has received honoraria as a speaker or in an advisory role from Sanofi, Roche, Merck Serono, Amgen, Servier, Pierre Fabre, Lilly, Astra Zeneca, and MSD. Other authors do not report any competing interest.

Ethics approval and consent to participate

This study was approved by the French Data Protection Authority (CNIL) (2222018v0) and by the APHP (Assistance Publique des Hopitaux de Paris) ethics and research committee. It complies with the Declaration of Helsinki and is registered on the Health Data Hub site No. F20210315164546 within the framework of the MR-004 methodology. An information memo was given to all centers to be sent to patients. No patient objected to the use of their data.

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Flecchia, C., Auclin, E., Alouani, E. et al. Primary resistance to immunotherapy in patients with a dMMR/MSI metastatic gastrointestinal cancer: who is at risk? An AGEO real-world study. Br J Cancer 130, 442–449 (2024). https://doi.org/10.1038/s41416-023-02524-3

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