Targeting the interleukin-1β innate immunity pathway through the use of the anti-inflammatory drug canakinumab (ACZ885) led to a significant reduction in lung cancer and lung cancer mortality, new study shows.
The study, “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,” was published in The Lancet.
Inflammation is a very common characteristic of lung cancer because bronchitis, which is triggered by toxins such as smoking or asbestos, leads to an ongoing inflammatory response.
Inflammation of the lung develops when the Nod-like receptor protein 3 (NLRP3) inflammasome is activated, which leads to the production of active interleukin-1β, which in turn contributes to both fibrosis and lung cancer. Preclinical experiments in mice have demonstrated that interleukin-1β increases tumor growth, invasiveness and metastasis. But a depletion in interleukin-1β has led to a decrease in tumor production and metastasis, suggesting that inhibiting this pathway could be a mechanism through which lung cancer can be treated.
Novartis, a biopharmaceutical company, has developed a drug called canakinumab, which is a selective, high-affinity antibody that inhibits interleukin-1β. In the CANTOS Phase 3 trial (NCT01327846), the company set out to determine whether canakinumab could prevent recurrent vascular events in patients who have a high inflammatory response in cardiovascular disease.
These patients are at an increased risk of developing several types of inflammatory cancers, predominantly lung cancer. Therefore, by conducting the trial in this population, Novartis was able to analyze the effect of interleukin-1β in preventing lung cancer in a high-risk population.
Patients in the CANTOS study were assigned one of three canakinumab doses — 50 mg, 150 mg, or 300 mg — or placebo and then followed for any subsequent cancer diagnosis.
Results from the study showed that in patients who subsequently developed lung cancer, baseline inflammatory markers were significantly higher. After years of follow-up (median 3.7 years) patients on canakinumab had a dose-dependent decrease in these inflammatory markers, compared to the placebo group.
More significantly, total cancer mortality was significantly lower in the pooled (including all dosages) canakinumab group than those in the placebo group. However, when looking at the individual dosages, only the 300 mg dose was statistically significant in its effect on total cancer mortality.
Furthermore, both the 150 mg and 300 mg groups had significantly less frequent incidents of lung cancer when compared to the placebo group. Additionally, lung cancer mortality was significantly less frequent in the 300 mg group and the pooled canakinumab group compared to the placebo. All-cause mortality was not significantly different between any of the canakinumab groups or the placebo group.
So, canakinumab therapy could be beneficial in reducing incident lung cancer and lung cancer-associated mortality by targeting the interleukin-1β pathway.
“These data are a significant milestone because they show that selectively targeting inflammation with [canakinumab] reduces cardiovascular risk and that [canakinumab] may also be an important immuno-oncology therapy targeting IL-1ß for lung cancer,” Vas Narasimhan, Novartis’ global head, Drug Development, and chief medical officer, said in a press release. “We look forward to submitting the CANTOS data to regulatory authorities for approval in cardiovascular and initiating additional phase III studies in lung cancer.”
“The results of CANTOS are exciting because we now have clear evidence that in addition to lowering cholesterol, targeting inflammation reduces patients’ risk of cardiovascular disease, and perhaps even lung cancer,” added Paul Ridker, MD, CANTOS study chairman. “On behalf of the entire study team, I would like to thank all of the clinical trial site physicians and healthcare providers, and of course the thousands of patients who participated in this trial over the years, for their passion and dedication to advancing this important research.”