Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Lancet. 2017 Oct 21;390(10105):1833-1842. doi: 10.1016/S0140-6736(17)32247-X. Epub 2017 Aug 27.
Inflammation in the tumour microenvironment mediated by interleukin 1β is hypothesised to have a major role in cancer invasiveness, progression, and metastases. We did an additional analysis in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), a randomised trial of the role of interleukin-1β inhibition in atherosclerosis, with the aim of establishing whether inhibition of a major product of the Nod-like receptor protein 3 (NLRP3) inflammasome with canakinumab might alter cancer incidence.
We did a randomised, double-blind, placebo-controlled trial of canakinumab in 10 061 patients with atherosclerosis who had had a myocardial infarction, were free of previously diagnosed cancer, and had concentrations of high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater. To assess dose-response effects, patients were randomly assigned by computer-generated codes to three canakinumab doses (50 mg, 150 mg, and 300 mg, subcutaneously every 3 months) or placebo. Participants were followed up for incident cancer diagnoses, which were adjudicated by an oncology endpoint committee masked to drug or dose allocation. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, NCT01327846. The trial is closed (the last patient visit was in June, 2017).
Baseline concentrations of hsCRP (median 6·0 mg/L vs 4·2 mg/L; p<0·0001) and interleukin 6 (3·2 vs 2·6 ng/L; p<0·0001) were significantly higher among participants subsequently diagnosed with lung cancer than among those not diagnosed with cancer. During median follow-up of 3·7 years, compared with placebo, canakinumab was associated with dose-dependent reductions in concentrations of hsCRP of 26-41% and of interleukin 6 of 25-43% (p<0·0001 for all comparisons). Total cancer mortality (n=196) was significantly lower in the pooled canakinumab group than in the placebo group (p=0·0007 for trend across groups), but was significantly lower than placebo only in the 300 mg group individually (hazard ratio [HR] 0·49 [95% CI 0·31-0·75]; p=0·0009). Incident lung cancer (n=129) was significantly less frequent in the 150 mg (HR 0·61 [95% CI 0·39-0·97]; p=0·034) and 300 mg groups (HR 0·33 [95% CI 0·18-0·59]; p<0·0001; p<0·0001 for trend across groups). Lung cancer mortality was significantly less common in the canakinumab 300 mg group than in the placebo group (HR 0·23 [95% CI 0·10-0·54]; p=0·0002) and in the pooled canakinumab population than in the placebo group (p=0·0002 for trend across groups). Fatal infections or sepsis were significantly more common in the canakinumab groups than in the placebo group. All-cause mortality did not differ significantly between the canakinumab and placebo groups (HR 0·94 [95% CI 0·83-1·06]; p=0·31).
Our hypothesis-generating data suggest the possibility that anti-inflammatory therapy with canakinumab targeting the interleukin-1β innate immunity pathway could significantly reduce incident lung cancer and lung cancer mortality. Replication of these data in formal settings of cancer screening and treatment is required.
Novartis Pharmaceuticals.
在肿瘤微环境中，白细胞介素 1β介导的炎症被认为在癌症侵袭、进展和转移中起着重要作用。我们在 Canakinumab Anti-inflammatory Thrombosis Outcomes Study（CANTOS）中进行了一项额外分析，这是一项关于白细胞介素-1β抑制在动脉粥样硬化中的作用的随机试验，目的是确定使用 Canakinumab 抑制 Nod-like receptor protein 3（NLRP3）炎症小体的主要产物是否会改变癌症的发病率。
我们对 10061 名患有动脉粥样硬化且曾发生过心肌梗死、无先前诊断出的癌症且高敏 C 反应蛋白（hsCRP）浓度≥2mg/L 的患者进行了一项随机、双盲、安慰剂对照的 Canakinumab 试验。为了评估剂量反应效应，患者通过计算机生成的代码随机分配至三个 Canakinumab 剂量组（50mg、150mg 和 300mg，每 3 个月皮下注射一次）或安慰剂组。参与者接受了新诊断癌症的随访，由肿瘤终点委员会进行裁决，该委员会对药物或剂量分配进行了盲法评估。分析按意向治疗进行。该试验在 ClinicalTrials.gov 上注册，编号为 NCT01327846。该试验已关闭（最后一次患者访视于 2017 年 6 月）。
与未诊断出癌症的参与者相比，随后被诊断为肺癌的参与者的 hsCRP（中位数 6.0mg/L 比 4.2mg/L；p<0.0001）和白细胞介素 6（3.2ng/L 比 2.6ng/L；p<0.0001）基线浓度显著更高。在中位随访 3.7 年期间，与安慰剂相比，Canakinumab 与 hsCRP 浓度降低 26-41%和白细胞介素 6 降低 25-43%相关（所有比较的 p<0.0001）。在总癌症死亡率（n=196）方面，联合用药组显著低于安慰剂组（p=0.0007 组间趋势），但仅在 300mg 组中显著低于安慰剂组（风险比 [HR] 0.49[95%CI 0.31-0.75]；p=0.0009）。在 150mg 组（HR 0.61[95%CI 0.39-0.97]；p=0.034）和 300mg 组（HR 0.33[95%CI 0.18-0.59]；p<0.0001 组间趋势）中，新发肺癌（n=129）的发生率显著降低。与安慰剂组相比，Canakinumab 300mg 组的肺癌死亡率显著降低（HR 0.23[95%CI 0.10-0.54]；p=0.0002），联合用药组的肺癌死亡率也显著降低（p=0.0002 组间趋势）。Canakinumab 组的致命感染或脓毒症的发生率显著高于安慰剂组。Canakinumab 组和安慰剂组的全因死亡率无显著差异（HR 0.94[95%CI 0.83-1.06]；p=0.31）。
我们的假设生成数据表明，使用 Canakinumab 靶向白细胞介素-1β先天免疫途径的抗炎治疗可能显著降低肺癌的发病率和肺癌死亡率。需要在癌症筛查和治疗的正式环境中对这些数据进行复制。
诺华制药公司。
