CANTOS: Is Canakinumab Associated With Fewer CV Events, Less Cancer?

The first evidence from a randomized clinical trial in human beings suggest that inhibition of interleukin (IL-)1β with the monoclonal antibody canakinumab is associated with reduced incidences of fatal cancer, lung cancer and fatal lung cancer. The evidence was part of the CANTOS study presented on Aug. 27 during the ESC Congress 2017 in Barcelona.

Researchers randomized 10,061 patients with atherosclerosis and who had suffered a myocardial infarction (MI) to either canakinumab (50 mg, 150 mg or 300 mg, subcutaneously ever three months) or placebo. All patients were free of previously diagnosed cancer and had concentrations of high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater. Patients were followed for incident cancer diagnoses over a median of 3.7 years.

Cardiovascular outcomes from the trial, which were published in the New England Journal of Medicine, showed at 48 months the median reduction from baseline in hsCRP levels was 26 percentage points greater in patients who received 50 mg of canakinumab, 37 percentage points greater in patients who received 150 mg and 41 percentage points greater in patients receiving 300 mg, compared with the placebo group. Canakinumab did not reduce lipid levels from baseline.

The incidence rate for the primary end point of the first occurrence of nonfatal MI, any nonfatal stroke and cardiovascular death in a time-to-event analysis during the follow-up period 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. There were no significant differences in all-cause mortality. Researchers noted that only the 150 mg dose group met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point.

Researchers also highlighted cancer outcomes. Data, presented at the ESC Congress and published in The Lancet, showed significantly higher baseline concentrations of hsCRP (median 6.0 mg/L vs. 4.2 mg/L; p < 0.0001) and IL-6 (3.2 vs. 2.6 ng/L; p < 0.0001) in participants subsequently diagnosed with lung cancer than among those not diagnosed with lung cancer. Additionally, compared with placebo, canakinumab was associated with dose-dependent reductions in concentrations of hsCRP of 26-41 percent and of IL-6 of 25-43 percent (p < 0.0001 for all comparisons) during the follow-up period. Other results of note:

  • Total mortality from cancer (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 (p = 0.0009).
  • Incident lung cancer (n = 129) was significantly less frequent in the 150 mg (p = 0.034) and 300 mg groups (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 (p = 0.0002), as well as the pooled canakinumab group than in the placebo group (p = 0.0002).

“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),” the authors wrote. They note further studies are required and suggest their exploratory data be “replicated and extended in settings directly related to early cancer screening and initial treatment of cancers, particularly lung cancer.”

“CANTOS has helped move the inflammatory hypothesis of coronary artery disease forward scientifically,” writes Robert A. Harrington, MD, FACC, in an associated editorial comment. “However, the modest absolute clinical benefit of canakinumab cannot justify its routine use in patients with myocardial infarction until we understand more about the efficacy and safety trade-offs and unless a price restructuring and formal cost-effectiveness evaluation supports it.”

Keywords: ESC Congress, ESC2017, Coronary Artery Disease, C-Reactive Protein, Interleukin 1 Receptor Antagonist Protein, Incidence, Interleukin-6, Early Detection of Cancer, Antibodies, Monoclonal, Myocardial Infarction, Atherosclerosis, Stroke, Lung Neoplasms, Lipids

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