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    Interleukin-1 receptor antagonist levels predict favorable outcome after bermekimab, a first-in-class true human interleukin-1alpha antibody, in a phase III randomized study of advanced colorectal cancer

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    Authors
    Kurzrock, R
    Hickish, T
    Wyrwicz, L
    Saunders, Mark P
    Wu, Q
    Stecher, M
    Mohanty, P
    Dinarello, CA
    Simard, J
    Affiliation
    Center for Personalized Cancer Therapy, Division of Hematology/Oncology, Department of Medicine, Moores Cancer Center, University of California, San Diego, CA, USA
    Issue Date
    2019
    
    Metadata
    Show full item record
    Abstract
    Bermekimab is a true human monoclonal antibody that targets interleukin-1alpa (IL-1?), an inflammation-mediating alarmin. IL-1 receptor antagonist (IL-1Ra) is a natural molecule that blocks IL-1? activity by occupying the IL-1 receptor. The effect of endogenous IL-1Ra levels on the effectiveness of bermekimab is unknown. We investigated whether pre-treatment levels of circulating IL-1Ra, assessed by an enzyme-linked immunoassay, correlated with achievement of the primary outcome endpoint (effect on lean body mass and symptoms at week 8) in a Phase III study (2:1 randomization) of bermekimab versus placebo (each with best supportive care) in advanced colorectal cancer. Patients who responded to bermekimab in terms of achieving the primary endpoint had lower levels of IL-1Ra than non-responders (N = 204 patients; median = 843 vs. 1035 pg/ml, p=0.0092); no such relationship was observed in the placebo arm (N = 100 patients; 901 vs. 984 pg/ml, p = 0.55). Multivariate analysis corroborated that, in the bermekimab group, patients with lower baseline IL-1Ra levels were more likely to achieve the primary endpoint (odds ratio (OR) 1.7 (95% confidence interval (CI), 1.1 to 2.6), p = 0.017); in contrast, in the placebo arm, pre-treatment plasma IL-1Ra levels were not associated with outcome (OR 1.2 (95% CI 0.6 to 2.5), p = 0.57). The current findings demonstrate that, in a randomized phase III trial, patients with advanced colorectal cancer and lower levels of circulating IL-1Ra are more responsive to treatment with the IL-1?-targeting antibody bermekimab and these observations define a potential biomarker for anti-IL-1? therapy.
    Citation
    Kurzrock R, Hickish T, Wyrwicz L, Saunders M, Wu Q, Stecher M, et al. Interleukin-1 receptor antagonist levels predict favorable outcome after bermekimab, a first-in-class true human interleukin-1alpha antibody, in a phase III randomized study of advanced colorectal cancer. Oncoimmunology. 2019;8(3):1551651.
    Journal
    Oncoimmunology
    URI
    http://hdl.handle.net/10541/621629
    DOI
    10.1080/2162402X.2018.1551651
    PubMed ID
    30723583
    Additional Links
    https://dx.doi.org/10.1080/2162402X.2018.1551651
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1080/2162402X.2018.1551651
    Scopus Count
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    All Christie Publications

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