Practice Update: Oncology

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Effect of Interleukin-1β InhibitionWith
Canakinumab on Incident Lung Cancer in
Patients With Atherosclerosis
The Lancet
Take-home message
• This randomized, double-blind placebo-controlled trial was designed to evaluate the effect of inhibition of interleukin 1b via
canakinumab on recurrent vascular events in 10,061 patients with established coronary artery disease and high levels of hsCRP,
with incident lung cancer assessed as a secondary endpoint. Total cancer mortality was significantly lower in patients taking
canakinumab vs those taking placebo. Significantly less frequent incident lung cancer and lung cancer mortality were also
reported in patients receiving canakinumab compared with those receiving placebo. Patients receiving canakinumab experienced
significantly more fatal infections and sepsis than patients receiving placebo.
• No difference in all-cause mortality was reported between groups.
COMMENT
By Peter Libby MD The Canakinumab Anti-Inflammatory
Thrombosis Outcomes Study (CAN-
TOS) enrolled over 10,000 survivors
of myocardial infarction at least 30 days
following the index event who were equil-
ibrated on a full panel of standard-of-care
medications including highly effective sta-
tin, aspirin, and beta blocking agent and
angiotensin-converting enzyme inhibitor
or angiotensin receptor blocker therapy,
as appropriate and tolerated. The investi-
gators also selected a population that had
residual inflammation despite this back-
ground therapy as gauged by an elevation
in C-reactive proteinmeasuredwith a highly
sensitive assay (hsCRP) above median for
the general population, i.e. 2 mg/L. Indi-
viduals who met these entrance criteria
received randomly allocated placebo or
canakinumab, a monoclonal antibody that
selectively neutralizes the pro-inflammatory
cytokine interleukin-1 beta (IL-1 beta) admin-
istered by subcutaneous injection four times
yearly. The trial met its primary endpoint of
producing major adverse cardiovascular
events at the middle dose tested (150 mg
every three months). The major unwanted
action of canakinumab was a slight but sig-
nificant increase in fatal infection, an excess
on the order of one per thousand patient
years exposed in the canakinumab-treated
groups. A paper published in the New Eng-
land Journal of Medicine reports details of
the cardiovascular endpoints.1
As certain anti-inflammatory biological ther-
apies associate with a risk for lymphoma
(e.g. anti-tumor necrosis factor strategies),
an expert panel carefullymonitored incident
malignancies in the study participants, none
of whom had no known cancer at the time
of enrollment (save for cutaneous basal cell
carcinoma). In addition to the reduction in
cardiovascular endpoints, canakinumab
reduced total cancer mortality, incident lung
cancer, and fatalities due to lung cancer.
At the highest dose tested, canakinumab
(300 mg four times yearly) reduced lung
cancer fatalities by a remarkable 77%.2 The
enrolled population, as they were selected
for an elevated inflammatory status, likely
had enriched risk for lung cancer, given
that chronic lung disease and lung cancer
associate with increased C-reactive protein
concentrations.
A large body of prior evidence provides bio-
logical plausibility for an anti-cancer effect of
blockade of IL-1. 3 During the 3.7 year mean
follow-up period of CANTOS, the reduction
in cancer fatality probably did not result from
de novo oncogenesis inhibition. Rather, a
reduction in the invasiveness and metas-
tasis of tumors likely accounted for the
reductions in death. Considerable evidence
supports the role of the enzyme matrix
metalloproteinase 2 (MMP-2), a type IV col-
lagenase, in the ability of cells in cancers to
breach basement membrane barriers and
become invasive and give rise to metasta-
ses.4 IL-1 augments the activation of MMP-2,
providing one possible mechanistic expla-
nation for the results found.5 In addition,
IL-1 can promote epithelial to mesenchy-
mal transition, another process considered
important in cancer development.6
These exploratory results, although pre-
liminary and by no means ready for clinical
application, have important implications for
understanding tumor spread. The results
indicate that in addition to the exciting novel
checkpoint inhibitor approaches to cancer
therapy that target adaptive, T-cell-medi-
ated immunity, the innate immune response
may also contribute to the evolution of
cancers. The results on cancer incidence
from CANTOS have immediate scientific
implications, mandate prospective replica-
tion in independent clinical studies, andmay
point the way to novel therapies for manag-
ing individuals with markers for risk of lung
and other cancers in the future. Given the
highly exploratory nature of the analyses
of cancer in CANTOS, the cancer findings
should not change practice today, but may
open new doors for immune modulation
and anti-inflammatory interventions in oncol-
ogy going forward.
Dr. Libby is Mallinckrodt
Professor of Medicine,
Harvard Medical School,
Boston, Massachusetts.
References
1. 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.
2. Ridker PM, MacFadyen JG, Thuren T, et
al. 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:
S0140-6736(17)32247-X.
3. Dinarello CA. Why not treat human cancer with
interleukin-1 blockade? Cancer Metastasis Rev
2010;29(2):317-329.
4. Stetler-Stevenson WG, Aznavoorian S, Liotta
LA. Tumor cell interactions with the extracellular
matrix during invasion and metastasis. Annu Rev
Cell Biol 1993;9:541-573.
5. Galis Z, Muszynski M, Sukhova G, et al.
Cytokine-stimulated human vascular smooth
muscle cells synthesize a complement of
enzymes required for extracellular matrix
digestion. Circ Res 1994;75(1):181-189.
6. Li HJ, Reinhardt F, Herschman HR, Weinberg
RA. Cancer-stimulated mesenchymal stem
cells create a carcinoma stem cell niche via
prostaglandin E2 signaling. Cancer Discov
2012;2(9):840-855.
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