Kurzrock Razelle, Hickish Tamas, Wyrwicz Lucjan, Saunders Mark, Wu Qian, Stecher Michael, Mohanty Prasant, Dinarello Charles A, Simard John
Center for Personalized Cancer Therapy, Division of Hematology/Oncology, Department of Medicine, Moores Cancer Center, University of California, San Diego, CA, USA.
Department of Oncology, Poole Hospital NHS Foundation Trust, Poole, UK.
Oncoimmunology. 2018 Dec 12;8(3):1551651. doi: 10.1080/2162402X.2018.1551651. eCollection 2019.
Bermekimab is a true human monoclonal antibody that targets interleukin-1alpa (IL-1α), an inflammation-mediating alarmin. IL-1 receptor antagonist (IL-1Ra) is a natural molecule that blocks IL-1α 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-1α-targeting antibody bermekimab and these observations define a potential biomarker for anti-IL-1α therapy.
伯美吉单抗是一种真正的人源单克隆抗体，其靶向白细胞介素-1α（IL-1α），一种炎症介导的警报素。白细胞介素-1受体拮抗剂（IL-1Ra）是一种天然分子，通过占据IL-1受体来阻断IL-1α的活性。内源性IL-1Ra水平对伯美吉单抗疗效的影响尚不清楚。在一项伯美吉单抗与安慰剂（均采用最佳支持治疗）对比的晚期结直肠癌III期研究（2:1随机分组）中，我们调查了通过酶联免疫吸附测定评估的循环IL-1Ra预处理水平是否与主要结局终点（第8周时对瘦体重和症状的影响）的达成相关。在主要终点方面对伯美吉单抗有反应的患者，其IL-1Ra水平低于无反应者（N = 204例患者；中位数 = 843 vs. 1035 pg/ml，p = 0.0092）；在安慰剂组未观察到这种关系（N = 100例患者；901 vs. 984 pg/ml，p = 0.55）。多变量分析证实，在伯美吉单抗组中，基线IL-1Ra水平较低的患者更有可能达成主要终点（比值比（OR）1.7（95%置信区间（CI），1.1至2.6），p = 0.017）；相反，在安慰剂组中，预处理血浆IL-1Ra水平与结局无关（OR 1.2（95%CI 0.6至2.5），p = 0.57）。目前的研究结果表明，在一项随机III期试验中，晚期结直肠癌且循环IL-1Ra水平较低的患者对靶向IL-1α的抗体伯美吉单抗治疗反应更强，这些观察结果确定了抗IL-1α治疗的一种潜在生物标志物。
