Practice Update: Oncology

EDITOR’S PICKS 10

Effect of Interleukin-1 β 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 T he Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CAN- TOS) enrolled over 10,000 survivors

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. 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: http://dx.doi.org/10.1016/ 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. Dr. Libby is Mallinckrodt Professor of Medicine, Harvard Medical School, Boston, Massachusetts.

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

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

PRACTICEUPDATE ONCOLOGY