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
Saunders, Mark P
AffiliationCenter for Personalized Cancer Therapy, Division of Hematology/Oncology, Department of Medicine, Moores Cancer Center, University of California, San Diego, CA, USA
MetadataShow full item record
AbstractBermekimab 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.
CitationKurzrock 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.
- SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke): A Randomized Controlled Phase 2 Trial.
- Authors: Smith CJ, Hulme S, Vail A, Heal C, Parry-Jones AR, Scarth S, Hopkins K, Hoadley M, Allan SM, Rothwell NJ, Hopkins SJ, Tyrrell PJ
- Issue date: 2018 May
- Reduction of inflammation after administration of interleukin-1 receptor antagonist following aneurysmal subarachnoid hemorrhage: results of the Subcutaneous Interleukin-1Ra in SAH (SCIL-SAH) study.
- Authors: Galea J, Ogungbenro K, Hulme S, Patel H, Scarth S, Hoadley M, Illingworth K, McMahon CJ, Tzerakis N, King AT, Vail A, Hopkins SJ, Rothwell N, Tyrrell P
- Issue date: 2018 Feb
- Inflammation in human brain injury: intracerebral concentrations of IL-1alpha, IL-1beta, and their endogenous inhibitor IL-1ra.
- Authors: Hutchinson PJ, O'Connell MT, Rothwell NJ, Hopkins SJ, Nortje J, Carpenter KL, Timofeev I, Al-Rawi PG, Menon DK, Pickard JD
- Issue date: 2007 Oct
- Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial.
- Authors: Fisher CJ Jr, Slotman GJ, Opal SM, Pribble JP, Bone RC, Emmanuel G, Ng D, Bloedow DC, Catalano MA, IL-1RA Sepsis Syndrome Study Group
- Issue date: 1994 Jan
- The safety and efficacy of interleukin-1 receptor antagonist in the treatment of rheumatoid arthritis.
- Authors: Bresnihan B
- Issue date: 2001 Apr