ESC Congress 2017 In Review – Focus on CAD&ACS - 12

Late-Breaking Clinical Trials

The 150-mg dose of canakinumab was also associated
with significant (P = .005) reductions in the key secondary CV endpoint (the components of the primary endpoint plus hospitalisation for unstable angina that led to
urgent revascularisation; Figure 3).
Figure 3. Key Secondary Endpoint With Canakinumab, 150 mg vs Placebo
25

HR, 0.83 (95% CI, 0.73-0.95)
P = .005

Placebo
Canakinumab, 150 mg

Cumulative Incidence of
Secondary Endpoint (%)

100

15
10

5
40
0

Years

From The New England Journal of Medicine, Ridker PM et al, Antiinflammatory
Therapy with Canakinumab for Atherosclerotic Disease, EPub 27 August 2017.
Copyright © 2017 Massachusetts Medical Society. Reprinted with permission
from Massachusetts Medical Society.

In addition to the primary and secondary endpoints,
there were consistent and significant HR reductions in
MI, unstable angina leading to urgent revascularisation,
and any coronary revascularisation for the 150 mg dose
(all P ≤ .02). There was no significant effect on stroke
(HR, 0.98; 95% CI, 0.71 to 1.35; P = .91), CV death (HR,
95% CI, 0.70 to 1.12; P = .30) or all-cause mortality (HR,
0.92; 95% CI, 0.80 to 1.11; P = .33). Leukopenia and fatal
infections were more common with canakinumab, while
fatal malignancy and arthritis (including osteoarthritis
and gout) were less common.
In an exploratory analysis stratified by on-treatment
hsCRP, patients with an hsCRP less than the median
achieved value of 1.8mg/L at 3 months appeared to have a
greater benefit (HR, 0.73; 95% CI, 0.63 to 0.83; P = .0001)
compared with those above the median achieved hsCRP
(HR, 0.95; 95% CI, 0.84 to 1.08; P = .47); however, formal statistical testing for effect modification by achieved
hsCRP was not presented.
Tumor initiation, promotion, malignant conversion,
invasion, and metastasis can all be impacted by inflammation [Grivennikov SI et al. Cell. 2010]. IL-1 is abundant
at tumour sites, where it may affect the process of carcinogenesis, tumour growth, and invasiveness and the patterns of tumour-host interactions [Apte RN et al. Cancer
Metastasis Rev. 2006]. Sub-clinical chronic inflammation, as defined by an elevated hsCRP, is associated with
an increased risk of inflammatory cancers, including
lung cancer [Chaturvedi AK et al. J Clin Oncol. 2010].
As a result of these observations, it has been suggested

October 2017

that blocking IL-1β might be a good treatment approach
for human metastatic disease [Dinarrello CA. Cancer
Metastasis Rev. 2010]. Therefore, a clinical events committee of oncologists was established at trial initiation
to adjudicate incident cancer in CANTOS.
Notably, patients in the CANTOS study were at unusually high risk for certain inflammatory cancers, such as
lung cancer, due to older age, high rates of past and current smoking and chronic inflammation as evidenced
by an elevated hsCRP. Canakinumab (300 mg) reduced
death from any cancer by 51% (HR, 0.49; 95% CI, 0.31 to
0.75; P = .0009) and fatal lung cancer by 77% (HR, 0.23;
95% CI, 0.10 to 0.54; P = .0002) [Ridker PM et al. Lancet.
2017]. The effect appeared to be dose-dependent for
both endpoints where the P value for trend with increasing canakinumab doses were .0007 and .0002, respectively. These findings are exploratory and will need to be
replicated in future studies.
CANTOS was designed to directly test the inflammatory hypothesis of atherothrombosis. In this study, SC
canakinumab administered once every 3 months lowered the inflammatory biomarkers hsCRP and IL-6 but
did not reduce atherogenic lipids in patients with stable
CAD and an elevated hsCRP at baseline. In summary,
during the average 3.7-year follow-up period, the 150 mg
dose of canakinumab showed significant reductions in
the primary and secondary study endpoints, as well as
the individual endpoints of MI, unstable angina requiring urgent coronary revascularisation and any coronary
revascularisation. Stroke, CV death, and all-cause mortality were not significantly reduced with canakinumab.
Leukopenia and fatal infections were increased with
canakinumab, while fatal malignancies and arthritis
were reduced.
As a consequence, patients being treated with
canakinumab will require monitoring for early signs
and symptoms of infection as is the current policy for
individuals taking other biologic anti-inflammatory
agents. Exploratory analyses suggested that residual
inflammatory risk, defined by an elevated on-treatment
hsCRP, may be associated with greater benefit. Another
exploratory analysis suggests that patients at high risk
for inflammatory cancers may experience a reduction in
incident fatal malignancies, including lung cancer.
In Dr Ridker's opinion, the CANTOS trial demonstrates
that targeting the IL-1β to IL-6 pathway with canakinumab reduces CV event rates and potentially reduces rates
of incident lung cancer and lung cancer mortality. These
data provide proof that inflammation inhibition, even in
the absence of lipid lowering, can improve atherothrombotic outcomes and potentially alter the progression
of some fatal cancers. Furthermore, the exploratory
analyses with acheived hsCRP levels and malignancy
may provide a framework for a personalised approach
to initiating or continuing canakinumab in patients with
stable CAD and elevated hsCRP.
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