Does Targeted Inflammation Therapy Reduce Risk of CV Events, Lung Cancer?

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Further investigation is needed to find anti-inflammatory agents that do not increase patients' risk of death from infection.
Further investigation is needed to find anti-inflammatory agents that do not increase patients' risk of death from infection.

The anti-inflammatory drug canakinumab is associated with a significantly lower rate of recurrent cardiovascular events compared with placebo, a finding that was independent of lipid-level lowering, according to research published in the New England Journal of Medicine.

Paul M. Ridker, MD, from the Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital in Boston, and colleagues conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody that targets interleukin-1β. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS; ClinicalTrials.gov Identifier NCT01327846) included 10,061 patients who had a previous myocardial infarction and a high-sensitivity C-reactive protein (hsCRP) level of 2 mg/L or greater. The researchers compared 3 doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. Canakinumab is approved for systemic juvenile idiopathic arthritis and multiple periodic fever syndromes.

The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. A key secondary end point included the components of the primary end point, in addition to hospitalization for unstable angina that led to urgent revascularization. Another key secondary end point was the incidence of new-onset type 2 diabetes among patients with prediabetes at randomization, which was not included in the published findings.

Trial enrollment was conducted between April 2011 and March 2014, and the last trial visit was in June 2017. Of the 17,482 patients who previously had a myocardial infarction and had undergone screening in the central laboratory, 10,061 (57.6%) underwent randomization and had received at least 1 dose of canakinumab or placebo. Participants had a mean age of 61 years, 25.7% were women, and 40.0% had diabetes. Most participants had undergone previous revascularization procedures — 66.7% had had percutaneous coronary intervention, and 14.0% had undergone coronary-artery bypass grafting. 

At 48 months, the researchers found that the median reduction from baseline in the hsCRP level was 26 percentage points greater in the group who received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Lipid levels from baseline were not reduced with use of canakinumab.

At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. Compared with placebo, the hazard ratios were 0.93 in the 50-mg group, 0.85 in the 150-mg group, and 0.86 in the 300-mg group.

According to the investigators, the 150-mg dose met the prespecified threshold for statistical significance regarding the primary end point and the secondary end point that also included hospitalization for unstable angina leading to urgent revascularization (hazard ratio vs placebo, 0.83).

Among adverse events, neutropenia was more common in participants who received canakinumab than in those in the placebo group, and significantly more deaths were attributed to infection or sepsis in the pooled canakinumab groups than in the placebo group (incidence rate, 0.31 vs 0.18 events per 100 person-years).

“CANTOS was designed to test directly the inflammatory hypothesis of atherothrombosis,” stated the study authors. “In this trial, in patients with a history of myocardial infarction, the levels of high-sensitivity C-reactive protein and interleukin-6 were significantly reduced from baseline by canakinumab, as compared with placebo, with no significant reduction in lipid levels from baseline.”

Canakinumab's effect on lung cancer

An exploratory analysis of the CANTOS data, which was published in The Lancet, also showed that canakinumab reduced the rates of total cancer death, particularly death due to lung cancer, and the incidence of lung cancer.

During a median follow-up of 3.7 years, canakinumab was associated with dose-dependent reductions in concentrations of hsCRP of 26% to 41% and of interleukin 6 of 25% to 43%, compared with placebo. Total cancer mortality (n=196) was significantly lower in the pooled canakinumab group than in the placebo group, but individually was significantly lower than placebo only in the 300-mg group (hazard ratio [HR], 0.49). Incident lung cancer (n=129) was significantly less common in the 150-mg group (HR, 0.61) and 300-mg groups (HR, 0.33). Lung cancer mortality was significantly less frequent in the canakinumab 300-mg group than in the placebo group (HR, 0.23) and in the pooled canakinumab group than in the placebo group.

“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,” stated Dr Ridker and colleagues. “Replication of these data in formal settings of cancer screening and treatment is required.”

A step forward, but caution urged

In an accompanying editorial published in the New England Journal of Medicine, Robert A. Harrington, MD, from the Department of Medicine at Stanford University, noted that although the CANTOS trial has helped move the inflammatory hypothesis of coronary artery disease forward, barriers remain before canakinumab can be used routinely for this purpose.

“Despite the scientific and clinical excitement associated with having a new mechanism of action to attack in the treatment of coronary artery disease, a better understanding of the risks and benefits of this form of therapy is needed,” stated Dr Harrington. “Any discussion of the use of canakinumab in patients with a previous myocardial infarction must consider cost. Given monthly for approved indications, canakinumab is priced at approximately $200,000 per year in the United States. Such pricing may be suitable for rare diseases, but not for a common indication such as coronary artery disease, even if given every 3 months.

“Now that an agent targeting inflammation and autoimmunity has been shown to provide clinical benefit, the field is opened to further investigation to find agents that exert more substantial benefit than was seen in CANTOS and perhaps to find agents that do not increase the risk of death from infection as was seen with canakinumab,” Dr Harrington concluded.

References

  1. Harrington RA. Targeting inflammation in coronary artery disease [published online August 27, 2017]. N Engl J Med.  doi:10.1056/NEJMe1709904
  2. Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ,  on behalf of the CANTOS Trial Group. 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 [published online August 27, 2017]. Lancet. doi:10.1016/S0140-6736(17)32247-X
  3. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease [published online August 27, 2017]. N Engl J Med. doi:10.1056/NEJMoa1707914

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