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. 2024 Feb;130(3):442-449.
doi: 10.1038/s41416-023-02524-3. Epub 2023 Dec 15.

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

Clémence Flecchia  1 , Edouard Auclin  2 , Emily Alouani  3 , Mathilde Mercier  4 , Antoine Hollebecque  5 , Anthony Turpin  6 , Thibault Mazard  7 , Simon Pernot  8 , Marie Dutherage  9 , Romain Cohen  10 , Christophe Borg  11 , Vincent Hautefeuille  12 , Francesco Sclafani  13 , Meher Ben-Abdelghani  14 , Thomas Aparicio  15 , Christelle De La Fouchardière  16 , Camille Herve  17 , Geraldine Perkins  18 , Kathrin Heinrich  19 , Volker Kunzmann  20 , Claire Gallois  2 , Rosine Guimbaud  3 , David Tougeron  4 , Julien Taieb  21
Affiliations

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

Clémence Flecchia et al. Br J Cancer. 2024 Feb.

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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Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1. Distribution of the cohort population according to the number of risk factors for ICIPR and outcomes after ICI treatment.
a OR and b radar plot of oncological outcomes (*p-value < 0.001; **p-value = 0.03). Data concerning risk factors were not available in 3 patients.
See this image and copyright information in PMC

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