A secondary finding from a large clinical trial in patients with atherosclerosis has shown that reducing systemic inflammation with an interleukin-1beta inhibitor drug significantly reduced lung cancer incidence, as well as total cancer and lung cancer mortality.
The drug, canakinumab (Ilaris, Novartis), is already marketed for the treatment of rare autoimmune disease.
The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) has been making headlines for the past few days, after results from the trial were presented at the European Society of Cardiology (ESC) Congress 2017 and were simultaneously published in the New England Journal of Medicine.
The primary finding was a reduction in major cardiovascular events, despite there being no effect on cholesterol. One eminent cardiologist hailed the results were hailed as a “historic moment…as it shows a new direction,” as reported by Medscape Medical News.
But there was another remarkable finding – an exploratory analysis showed a marked reduction in the incidence of lung cancer, as well as lung cancer mortality and total cancer mortality.
The cancer findings have been published online in the Lancet.
After a median follow-up of 3.7 years, there was a 67% reduction in incident lung cancer (P = .00008) and a clear dose-dependent risk reduction in cancer mortality, which reached 51% with the highest dose of the drug (P = .0009).
“The data are exciting because they point to the possibility of slowing the progression of certain cancers,” lead author Paul M. Ridker, MD, from Brigham and Women’s Hospital, Boston, Massachusetts, commented in a statement.
This work represents a stepping stone toward what we hope will be a new treatment approach.
“Our work builds on the idea that cancer and inflammation are intimately linked, and gives novel insights regarding how inhibiting inflammation may slow cancer progression and invasiveness,” said Dr Ridker. “While confirmatory work in formal cancer studies are needed…this work represents a stepping stone toward what we hope will be a new treatment approach.”
It has previously been shown that the use of aspirin to reduce inflammation lowers the risk for cancer death, although these effects are seen after a decade or more of long-term use. The effects with canakinumab occurred over a much shorter time course, the authors note.
“These are fascinating, human findings that open a potential new class of therapies for cancer,” commented Laurie H. Glimcher, MD, president and CEO of the Dana-Farber Cancer Institute, Boston, who was not involved in the study.
High levels of Inflammation
CANTOS was conducted in 10,061 patients with atherosclerosis who had previously experienced a myocardial infarction and who had a high level of systemic inflammation, as indicated by concentrations of high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater.
Participants were assigned to receive either placebo or canakinumab at one of three doses (50 mg, 150 mg, or 300 mg) and were followed for 3 to 5 years.
All participants were free of cancer at baseline. About one quarter (24%) were current smokers, and about half (47%) were former smokers.
Because of the smoking history and also because of the high level of inflammation (the median hsCRP concentration was 4.2 mg/L), which is an indicator of cancer, the investigators had anticipated finding cancer, and lung cancer in particular, and so involved oncologists in the trial from the beginning.
“Although primarily designed as a cardiovascular outcomes trial, the CANTOS investigators planned this exploratory analysis and had an ‘endpoints committee’ of oncologists set up from the outset,” notes Brendan J. Jenkins, PhD, from the Hudson Institute of Medical Research in Clayton, Australia, in an accompanying editorial.
Canakimumab effectively suppressed inflammation, showing a dose-dependent effect on reducing levels of hsCRP and interleukin-6.
The trial met its primary cardiovascular endpoint, reducing risk for a composite of heart attack, stroke, and cardiovascular death by 15%. The results also showed significant reductions in arthritis, gout, and osteoarthritis, owing to the drug’s anti-inflammatory properties, but there was an increased risk for fatal infections (in approximately 1 of every 1000 patients treated).
All-cause mortality did not differ significantly between the canakinumab and placebo groups (hazard ratio [HR], 0.94; P = .31).
There was a decrease in total cancer mortality (n = 196) among the patients taking canakimumab compared to those taking placebo (P = .0007 for trend across groups), although the difference between drug and placebo reached statistical significance only at the highest dose (300 mg).
There was a clear dose-response effect ― total cancer mortality HRs were 0.86 for the 50-mg group, 0.78 for the 150-mg group, and 4.9 (P = .0009) for the 300-mg group.
Expressed another way, the incidence rate of cancer mortality per 100 person-years was 0.64 in the placebo group, 0.55 in the 50-mg group, 0.50 in the 150-mg, and 0.31 in the 300-mg group (P = .0007 for trend across active dose groups compared with placebo).
Lung cancer mortality (n = 77) was also reduced in patients taking canakimumab compared to those taking placebo (P = .0002 for trend across groups). This too reached statistical significance for the highest dose (HR, 0.23; 95% CI, 0.10 – 0.54; P = .0002) .
The incidence rate of lung cancer mortality per 100 person-years was 0.30 in the placebo group, 0.20 in the 50-mg group, 0.19 in the 150-mg group, and 0.07 in the 300-mg group (P = .0002 for trend across active dose groups compared with placebo).
There was no significant reduction in cancer mortality of any specific type other than lung cancer.
In addition, there was a reduction in the incidence of lung cancer.
Incident lung cancer (n = 129) was significantly less frequent among patients taking canakimumab than those taking placebo in both the 150-mg dose group (HR, 0.61; P = .034) and the 300-mg group (HR, 0.33; P < .0001).
The incidence rate of lung cancer per 100 person-years was 0.49 in the placebo group, 0.35 in the 50-mg group, 0.30 in the 150-mg group, and 0.16 in the 300-mg group (P < .0001 for trend across active dose groups compared with placebo).
“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,” the researchers conclude.
Mechanisms Involved
They also speculate as to the mechanism involved.
“Canakinumab seems unlikely to have had direct effects on oncogenesis and the development of new lung cancers (although this possibility cannot be ruled out),” the authors write.
“Patients who developed lung cancer during follow-up were on average 65 years old at study entry, and more than 90% were current or former smokers. Furthermore, the median follow-up time (3.7 years) was unlikely to have been adequate to show a reduction in new cancers. A more biologically plausible explanation is that canakinumab reduced the rate of progression, invasiveness, and metastatic spread of lung cancers that were prevalent but undiagnosed at trial entry,” they write.
In his editorial, Dr Jenkins writes that although “the findings from CANTOS are unlikely to directly inform treatment in lung cancer, they do nonetheless shed light on interleukin 1β as a potential therapeutic target in lung cancer,” and he calls for further studies.
CANTOS was funded by Novartis, which manufactures canakinumab. Dr Ridker has served as a consultant to Novartis.
Lancet. Published online August 27, 2017. Abstract, Editorial
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