Elsevier

The Lancet

Volume 390, Issue 10105, 21–27 October 2017, Pages 1833-1842
The Lancet

Articles
Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(17)32247-XGet rights and content

Summary

Background

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.

Methods

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).

Findings

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).

Interpretation

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.

Funding

Novartis Pharmaceuticals.

Introduction

Many malignancies arise in areas of chronic inflammation,1, 2 and inadequate resolution of inflammation could have a major role in tumour invasion, progression, and metastases.3, 4, 5 Inflammation is of particular pathophysiological relevance in lung cancer, in that chronic bronchitis, triggered by asbestos, silica, smoking, and other external inhaled toxins, results in a persistent inflammatory response.6, 7 Inflammatory activation in the lung is partly mediated through activation of the Nod-like receptor protein 3 (NLRP3) inflammasome, with consequent local generation of active interleukin 1β, a process that can lead to both chronic fibrosis and cancer.8, 9 In mice, inflammasome activation and pro-interleukin-1β processing accelerates tumour invasiveness, growth, and metastatic spread.3 For example, in interleukin 1β−/− mice, neither local tumours nor lung metastases developed after localised or intravenous inoculation with melanoma cell lines, which suggests that interleukin 1β participates in the invasiveness of already existing malignancies.10 Thus, inhibition of interleukin 1β might have an adjunctive role in the treatment of cancers that have at least a partial inflammatory basis.11, 12, 13, 14

Research in context

Evidence before this study

During protocol development in 2010, and intermittently through trial completion in 2017, we searched MEDLINE with the terms “inflammation”, “cancer”, “lung cancer”, “canakinumab”, “interleukin-1β”, and “anakinra” for articles published in English. We also included major review articles from noted experts. We identified previous evidence from animal models suggesting a potential role for interleukin-1β inhibition in cancer invasiveness, growth, and metastasis, but little data from human studies.

Added value of this study

CANTOS provides the first evidence from a randomised trial in human beings that inhibition of interleukin 1β with the monoclonal antibody canakinumab is associated with reduced incidences of fatal cancer, lung cancer, and fatal lung cancer. Our data should be interpreted in the context that the primary aim of the trial was to investigate cardiac events rather than cancer events (the trial also showed a significant reduction in cardiovascular events with canakinumab compared with placebo).

Implications of all the available evidence

Our exploratory data should be replicated and extended in settings directly related to early cancer screening and initial treatment of cancers, particularly lung cancer.

The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) was a randomised, double-blind, placebo-controlled trial of 10 061 patients who were stable after a myocardial infarction. It was designed primarily to assess whether canakinumab, a human monoclonal antibody targeting interleukin 1β, can prevent recurrent vascular events among men and women who have a persistent proinflammatory response defined by the presence of high-sensitivity C-reactive protein (hsCRP) concentrations of 2 mg/L or higher.15, 16 The primary endpoints were non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death.17 By design, however, all participants had to be free of previously diagnosed cancer (other than basal cell skin carcinoma) at trial entry and were followed up prospectively for incident medical events for 3–5 years. Individuals with increased hsCRP concentrations have increased risk of several inflammatory cancers, most prominently lung cancer.18, 19, 20 Furthermore, patients with atherosclerosis commonly smoke, which is a major risk factor for cancer. By enrolling such patients, CANTOS afforded the additional opportunity to address in a high-risk population and within the context of a prospective, randomised, placebo-controlled trial whether interleukin-1β inhibition with canakinumab could be associated with reduced incidence of site-specific cancers.

Section snippets

Trial population

We did a secondary analysis of the randomised controlled CANTOS trial to assess the effect of interleukin-1β inhibition with canakinumab on incident cancer. Screening for inclusion in CANTOS began on April 11, 2011. People were eligible for enrolment if they had a history of myocardial infarction and blood concentrations of hsCRP of 2 mg/L or higher at entry despite use of aggressive secondary prevention strategies. People with a history of chronic or recurrent infections, previous malignancy

Results

Of 17 482 patients screened for CANTOS, 10 061 were randomly assigned, 3344 to placebo, 2170 to the canakinumab 50 mg group, 2284 to the canakinumab 150mg group, and 2263 to the canakinumab 300 mg group (figure 1). The most common reasons for pre-randomisation exclusion were hsCRP concentration of less than 2 mg/L, active tuberculosis or tuberculosis risk factors, and exclusionary concomitant disorders (figure 1). Baseline clinical characteristics and cancer risk factors were well matched

Discussion

Our exploratory data from the randomised, double-blind, placebo-controlled CANTOS trial suggest that inhibition of interleukin 1β with canakinumab over a median period of 3·7 years was associated with a reduction in the occurrence of fatal and non-fatal lung cancers among patients with atherosclerosis who had increased hsCRP concentrations and who did not have previous diagnoses of cancer. Effects were dose dependent, with relative hazard reductions of 67% (p<0·0001) for total lung cancer and

References (33)

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These authors contributed equally

CANTOS Trial Group listed in the apendix

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