Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jan;11(1):e005493.
doi: 10.1136/jitc-2022-005493.

Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer

Vincenzo Nasca  1 , Francesco Barretta  2 , Francesca Corti  1 , Sara Lonardi  3 , Monica Niger  1 , Maria Elena Elez  4 , Marwan Fakih  5 , Priya Jayachandran  6 , Aakash Tushar Shah  7 , Massimiliano Salati  8 , Elisabetta Fenocchio  9 , Lisa Salvatore  10   11 , Chiara Cremolini  12 , Javier Ros  13   14 , Margherita Ambrosini  1 , Giacomo Mazzoli  1 , Rossana Intini  15 , Michael J Overman  16 , Rosalba Miceli  2 , Filippo Pietrantonio  17
Affiliations

Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer

Vincenzo Nasca et al. J Immunother Cancer. 2023 Jan.

Abstract

Background: Immune checkpoint inhibitors (ICIs) show a tremendous activity in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but a consistent fraction of patients does not respond. Prognostic/predictive markers are needed. Despite previous investigations in other tumor types, immune-related adverse events (irAEs) have not been well evaluated in patients with MSI-H cancers treated with ICIs.

Methods: We conducted an international cohort study at tertiary cancer centers collecting clinic-pathological features from 331 patients with MSI-H mCRC treated with ICIs. Of note, the irAEs were summarized using a 'burden score' constructed in a way that the same score value could be obtained by cumulating many low-grade irAEs or few high-grade irAEs; as a result, the lower the burden the better. Clearly, the irAE burden is not a baseline information, thus it was modeled as a time-dependent variable in univariable and multivariable Cox models.

Results: Among 331 patients, irAEs were reported in 144 (43.5%) patients. After a median follow-up time of 29.7 months, patients with higher burden of skin, endocrine and musculoskeletal irAEs (the latter two's effect was confirmed at multivariable analysis) had longer overall survival (OS), as opposed to gastrointestinal, pneumonitis, neurological, liver, renal and other irAEs, which showed an harmful effect. Similar results were observed for progression-free survival (PFS). Based on the results retrieved from organ-specific irAEs, 'aggregated' burden scores were developed to distinguish 'protective' (endocrine and musculoskeletal) and 'harmful' (gastrointestinal, pneumonitis, neurological, hepatic) irAEs showing prognostic effects on OS and PFS.

Conclusions: Our results demonstrate that not all irAEs could exert a protective effect on oncologic outcome. An easy-to-use model for ICIs toxicity (burden score of protective and harmful irAEs) may be used as surrogate marker of response.

Keywords: Gastrointestinal Neoplasms; Immunotherapy; Translational Medical Research; Tumor Biomarkers.

PubMed Disclaimer

Conflict of interest statement

Competing interests: LS: Speakers’ and consultant’s fees from MSD, Astra-Zeneca, Servier, Bayer, Merck, Amgen, Pierre-FabreMJO: Consulting fees from Pfizer, Merck, Glaxosmithkline, 3D Medicine, Nouscom, Roche. Research fees from Roche, Takeda, Merck, BMS, Astra-Zeneca, Nouscom. FP: Honoraria: Servier, Bayer, AstraZeneca/MedImmune, Lilly, MSD Oncology, Amgen, Pierre-Fabre, Merck-Serono, BMS. Consulting or Advisory Role: Merck-Serono, Amgen, Servier, MSD Oncology, Organon. Research Funding: Bristol Myers Squibb (Inst), AstraZeneca (Inst), Incyte. All other authors declare no specific conflicts of interest(s).

Figures

Figure 1
Figure 1
Summary of incidence and severity of immune-related adverse events recorded in the study population.
Figure 2
Figure 2
Timeline with median onset-timing (in months, mo.) (IQR) of the different organ-specific irAEs. ICI, immune checkpoint inhibitor; irAEs, immune-related adverse events.
See this image and copyright information in PMC

References

    1. Lemery S, Keegan P, Pazdur R. First FDA Approval Agnostic of Cancer Site - When a Biomarker Defines the Indication. N Engl J Med 2017;377:1409–12. 10.1056/NEJMp1709968 - DOI - PubMed
    1. Overman MJ, McDermott R, Leach JL, et al. . Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017;18:1182–91. 10.1016/S1470-2045(17)30422-9 - DOI - PMC - PubMed
    1. Le DT, Uram JN, Wang H, et al. . PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509–20. 10.1056/NEJMoa1500596 - DOI - PMC - PubMed
    1. Le DT, Durham JN, Smith KN, et al. . Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409–13. 10.1126/science.aan6733 - DOI - PMC - PubMed
    1. Llosa NJ, Cruise M, Tam A, et al. . The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 2015;5:43–51. 10.1158/2159-8290.CD-14-0863 - DOI - PMC - PubMed

Supplementary concepts

LinkOut - more resources