Meeting NewsPerspective

CANTOS: Canakinumab reduces recurrent CV event rates in MI, inflammation

Paul Ridker
Paul M. Ridker

Patients with a history of MI and an elevated high-sensitivity C-reactive protein level treated with canakinumab had a lower rate of recurrent CV events compared with placebo, according to results of the CANTOS trial presented at the European Society of Cardiology Congress.

Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention and the Eugene Braunwald Professor of Medicine at Brigham and Women’s Hospital, and colleagues analyzed data from 10,061 patients (mean age, 61 years; 26% women, median CRP level: 4.2 mg/L; median LDL: 82.4 mg/dL) with a history of MI and a high-sensitivity C-reactive protein level of at least 2 mg/L with aggressive secondary prevention strategies.

Canakinumab vs. placebo

Patients were assigned doses of canakinumab at 50 mg, 150 mg or 300 mg or placebo, which were administered subcutaneously once every 3 months. In the 300-mg canakinumab group, the first two doses were administered every 2 weeks, then once every 3 months. Follow-up was conducted for a median of 3.7 years.

The primary efficacy endpoint was the first occurrence of any nonfatal stroke, nonfatal MI or CV death. The key secondary efficacy endpoint was any component of the primary endpoint in addition to hospitalization for unstable angina that resulted in urgent revascularization. Other secondary endpoints included death from any cause and a composite of any nonfatal stroke, nonfatal MI or all-cause death.

The main results were simultaneously published in The New England Journal of Medicine.

At 48 months, compared with those assigned placebo, CRP level reductions were 26% greater in patients assigned 50 mg of canakinumab, 37% in those assigned the 150 mg-dose and 41% in those assigned the 300-mg dose (P < .001 for all comparisons). HDL and LDL did not decrease in any of the canakinumab groups.

The incidence rate for the primary endpoint at follow-up was 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, 3.9 events per 100 person-years in the 300-mg group and 4.5 events per 100 person-years in the placebo group, according to the researchers.

Ridker and colleagues found that the 150-mg dose of canakinumab had a significant effect on the primary endpoint compared with placebo (HR = 0.85; 95% CI, 0.75-0.98). The 300-mg group had a similar HR vs. placebo to the 150-mg group (HR = 0.86; 95% CI, 0.75-0.99), but its P value (.0314) did not reach the threshold for significance. Patients assigned 50 mg of canakinumab did not experience a significant effect compared with placebo (HR = 0.93; 95% CI, 0.8-1.07).

The 150-mg dose of canakinumab also met the threshold for statistical significance regarding the secondary CV endpoint (HR = 0.83; 95% CI, 0.73-0.95).

Compared with the placebo group, more deaths in the canakinumab groups were caused by infection or sepsis (incidence rate, 0.31 events per 100 person-years vs. 0.18 events per 100 person-years; P = .02). There was no difference across groups in all-cause mortality (HR = 0.94; 95% CI, 0.83-1.06). 

“Despite the fact that no significant reduction in cholesterol levels occurred in this trial, the magnitude of effect on [CV] events with canakinumab (given every 3 months) was similar to that associated with monoclonal antibodies targeting [PCSK9] (given every 2 to 4 weeks),” Ridker and colleagues wrote in NEJM. “Yet, inhibition of interleukin-1β is a narrowly focused intervention that represents only one of many potential anti-inflammatory pathways that might serve as targets for atheroprotection. Thus, our data suggest that other anti-inflammatory interventions, such as those that directly inhibit NLRP3 function or that alter downstream interleukin-6 signaling, may also be beneficial in reducing [CV] risk.”

Robert Harrington
Robert A. Harrington

“CANTOS has helped move the inflammatory hypothesis of [CAD] forward scientifically,” Robert A. Harrington, MD, interventional cardiologist, Arthur L. Bloomfield Professor of Medicine and chairman of the department of medicine at Stanford University, wrote in a related editorial. “However, the modest absolute clinical benefit of canakinumab cannot justify its routine use in patients with previous [MI] until we understand more about the efficacy and safety trade-offs and unless a price restructuring and formal cost-effectiveness evaluation supports it.”

Canakinumab and lung cancer

Ridker and colleagues published a secondary analysis of the results from the CANTOS trial in The Lancet, which showed that patients free from previously diagnosed cancer who were treated with canakinumab had reduced risk for incident lung cancer and lung cancer mortality.

Increased high-sensitivity CRP levels have been previously linked to an increased risk for inflammatory cancers, especially lung cancer, according to the analysis’ background.  

Patients who developed incident lung cancer had higher concentrations of high-sensitivity CRP and interleukin 6 at baseline compared with those who did not have a cancer diagnosis.

During follow-up, patients in the canakinumab groups had fewer cases of total cancer mortality vs. the placebo group (P = .0158). Those assigned 300 mg of canakinumab had significantly lower rates of total cancer mortality (HR = 0.49; 95% CI, 0.31-0.75) compared with placebo.

Incident lung cancer was diagnosed in 129 patients, and was less frequent in the 150-mg (HR = 0.61; 95% CI, 0.39-0.97) and 300-mg groups (HR = 0.33; 95% CI, 0.18-0.59) compared with the other groups (P for trend across all groups < .0001).

Compared with the placebo group, patients assigned 300 mg of canakinumab had fewer lung cancer deaths (HR = 0.23; 95% CI, 0.1-0.54).

“We think that our data warrant prospective assessment of canakinumab as a potential therapy for early lung cancers or after imaging-based lung-cancer screening, perhaps in combination with debulking procedures, radiation and other immunomodulating treatments,” Ridker and colleagues wrote. “There is precedent for such an interleukin-1-targeted cytokine approach for other cancer types.” – by Darlene Dobkowski

References:

Ridker PM, et al. Hot Line: Late Breaking Clinical Trials 1. Presented at: European Society of Cardiology Congress; August 26-30, 2017; Barcelona, Spain.

Harrington RA. N Engl J Med. 2017;doi:10.1056/NEJMe1709904.

Ridker PM, et al. Lancet. 2017;doi:10.1016/S0140-6736(17)32247-X.

Ridker PM, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1707914.

Disclosures: The study was funded by Novartis. Ridker reports he receives grants from Kowa, Novartis and Pfizer, personal fees from AstraZeneca, CSL-Behring, Eisai, Janssen, Novartis, Sanofi and Teva and has patents with royalties paid to AstraZeneca and Siemens. Harrington reports he receives grants from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Merck, Novartis, Regado, Sanofi Aventis and The Medicines Company, receives personal fees from Amgen, Gilead, The Medicines Company, Merck, MyoKardia and WebMD, receives other support from Element Science and MyoKardia, and serves on the board of directors for Scanadu and SignalPath. Please see the full studies for a list of the other authors’ relevant financial disclosures.

Paul Ridker
Paul M. Ridker

Patients with a history of MI and an elevated high-sensitivity C-reactive protein level treated with canakinumab had a lower rate of recurrent CV events compared with placebo, according to results of the CANTOS trial presented at the European Society of Cardiology Congress.

Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention and the Eugene Braunwald Professor of Medicine at Brigham and Women’s Hospital, and colleagues analyzed data from 10,061 patients (mean age, 61 years; 26% women, median CRP level: 4.2 mg/L; median LDL: 82.4 mg/dL) with a history of MI and a high-sensitivity C-reactive protein level of at least 2 mg/L with aggressive secondary prevention strategies.

Canakinumab vs. placebo

Patients were assigned doses of canakinumab at 50 mg, 150 mg or 300 mg or placebo, which were administered subcutaneously once every 3 months. In the 300-mg canakinumab group, the first two doses were administered every 2 weeks, then once every 3 months. Follow-up was conducted for a median of 3.7 years.

The primary efficacy endpoint was the first occurrence of any nonfatal stroke, nonfatal MI or CV death. The key secondary efficacy endpoint was any component of the primary endpoint in addition to hospitalization for unstable angina that resulted in urgent revascularization. Other secondary endpoints included death from any cause and a composite of any nonfatal stroke, nonfatal MI or all-cause death.

The main results were simultaneously published in The New England Journal of Medicine.

At 48 months, compared with those assigned placebo, CRP level reductions were 26% greater in patients assigned 50 mg of canakinumab, 37% in those assigned the 150 mg-dose and 41% in those assigned the 300-mg dose (P < .001 for all comparisons). HDL and LDL did not decrease in any of the canakinumab groups.

The incidence rate for the primary endpoint at follow-up was 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, 3.9 events per 100 person-years in the 300-mg group and 4.5 events per 100 person-years in the placebo group, according to the researchers.

Ridker and colleagues found that the 150-mg dose of canakinumab had a significant effect on the primary endpoint compared with placebo (HR = 0.85; 95% CI, 0.75-0.98). The 300-mg group had a similar HR vs. placebo to the 150-mg group (HR = 0.86; 95% CI, 0.75-0.99), but its P value (.0314) did not reach the threshold for significance. Patients assigned 50 mg of canakinumab did not experience a significant effect compared with placebo (HR = 0.93; 95% CI, 0.8-1.07).

The 150-mg dose of canakinumab also met the threshold for statistical significance regarding the secondary CV endpoint (HR = 0.83; 95% CI, 0.73-0.95).

Compared with the placebo group, more deaths in the canakinumab groups were caused by infection or sepsis (incidence rate, 0.31 events per 100 person-years vs. 0.18 events per 100 person-years; P = .02). There was no difference across groups in all-cause mortality (HR = 0.94; 95% CI, 0.83-1.06). 

“Despite the fact that no significant reduction in cholesterol levels occurred in this trial, the magnitude of effect on [CV] events with canakinumab (given every 3 months) was similar to that associated with monoclonal antibodies targeting [PCSK9] (given every 2 to 4 weeks),” Ridker and colleagues wrote in NEJM. “Yet, inhibition of interleukin-1β is a narrowly focused intervention that represents only one of many potential anti-inflammatory pathways that might serve as targets for atheroprotection. Thus, our data suggest that other anti-inflammatory interventions, such as those that directly inhibit NLRP3 function or that alter downstream interleukin-6 signaling, may also be beneficial in reducing [CV] risk.”

Robert Harrington
Robert A. Harrington

“CANTOS has helped move the inflammatory hypothesis of [CAD] forward scientifically,” Robert A. Harrington, MD, interventional cardiologist, Arthur L. Bloomfield Professor of Medicine and chairman of the department of medicine at Stanford University, wrote in a related editorial. “However, the modest absolute clinical benefit of canakinumab cannot justify its routine use in patients with previous [MI] until we understand more about the efficacy and safety trade-offs and unless a price restructuring and formal cost-effectiveness evaluation supports it.”

Canakinumab and lung cancer

Ridker and colleagues published a secondary analysis of the results from the CANTOS trial in The Lancet, which showed that patients free from previously diagnosed cancer who were treated with canakinumab had reduced risk for incident lung cancer and lung cancer mortality.

Increased high-sensitivity CRP levels have been previously linked to an increased risk for inflammatory cancers, especially lung cancer, according to the analysis’ background.  

Patients who developed incident lung cancer had higher concentrations of high-sensitivity CRP and interleukin 6 at baseline compared with those who did not have a cancer diagnosis.

During follow-up, patients in the canakinumab groups had fewer cases of total cancer mortality vs. the placebo group (P = .0158). Those assigned 300 mg of canakinumab had significantly lower rates of total cancer mortality (HR = 0.49; 95% CI, 0.31-0.75) compared with placebo.

Incident lung cancer was diagnosed in 129 patients, and was less frequent in the 150-mg (HR = 0.61; 95% CI, 0.39-0.97) and 300-mg groups (HR = 0.33; 95% CI, 0.18-0.59) compared with the other groups (P for trend across all groups < .0001).

Compared with the placebo group, patients assigned 300 mg of canakinumab had fewer lung cancer deaths (HR = 0.23; 95% CI, 0.1-0.54).

“We think that our data warrant prospective assessment of canakinumab as a potential therapy for early lung cancers or after imaging-based lung-cancer screening, perhaps in combination with debulking procedures, radiation and other immunomodulating treatments,” Ridker and colleagues wrote. “There is precedent for such an interleukin-1-targeted cytokine approach for other cancer types.” – by Darlene Dobkowski

References:

Ridker PM, et al. Hot Line: Late Breaking Clinical Trials 1. Presented at: European Society of Cardiology Congress; August 26-30, 2017; Barcelona, Spain.

Harrington RA. N Engl J Med. 2017;doi:10.1056/NEJMe1709904.

Ridker PM, et al. Lancet. 2017;doi:10.1016/S0140-6736(17)32247-X.

Ridker PM, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1707914.

Disclosures: The study was funded by Novartis. Ridker reports he receives grants from Kowa, Novartis and Pfizer, personal fees from AstraZeneca, CSL-Behring, Eisai, Janssen, Novartis, Sanofi and Teva and has patents with royalties paid to AstraZeneca and Siemens. Harrington reports he receives grants from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Merck, Novartis, Regado, Sanofi Aventis and The Medicines Company, receives personal fees from Amgen, Gilead, The Medicines Company, Merck, MyoKardia and WebMD, receives other support from Element Science and MyoKardia, and serves on the board of directors for Scanadu and SignalPath. Please see the full studies for a list of the other authors’ relevant financial disclosures.

    Perspective
    Mark Creager

    Mark Creager

    This is the first study to report that blocking a specific inflammatory pathway, the interleukin-1b innate immunity pathway, improves CV outcomes in patients who have had a prior MI.

    It has important implications regarding the role of inflammation in the pathobiology of atherosclerosis and subsequent CV events. Though the findings raise the possibility that a new class of anti-inflammatory drugs may be added to the therapeutic armamentarium to treat patients with CAD, it’s premature to recommend changes in clinical practice. It is the first report of canakinumab in patients with CVD, though it is approved for use for some anti-inflammatory diseases in adults and pediatric patients.

    As we understand more about how the effects of inhibiting inflammation improve outcomes, there is a very good possibility that drugs that work in this manner will be used in the future in addition to our currently accepted regimens for treating patients who have CAD. There is an ongoing trial, CIRT, looking at another anti-inflammatory drug, methotrexate, being conducted under the auspices of the NIH.

    As we gather more information and get more evidence, it will lend even greater credibility to the fact that targeting inflammation is an effective way to treat patients who have CVD, particularly CAD, and may provide an additional option for therapy over that of the antiplatelet agents and cholesterol-lowering drugs that we currently employ.

    I view this as an exciting study that opens a potential new paradigm in the treatment of patients with CAD.

    • Mark Creager, MD
    • Anna Gundlach Huber Professor in Medicine Geisel School of Medicine, Dartmouth Director, Heart and Vascular Center Dartmouth-Hitchcock Health System Past President, American Heart Association

    Disclosures: Creager reports he has no relevant financial disclosures.

    Perspective
    C. Michael Valentine

    C. Michael Valentine

    These findings will greatly impact the future of research into inflammation and how treating inflammation will help us treat CAD, vascular disease and lung cancer.

    This is an exciting study for science and for the future research but it may not have major applications for today, because canakinumab is an injectable drug with high cost and small effective returns so far. This will not shake up the marketplace now, but it will spur research into further actions and medications that may help us in several areas.

    We have known for many years that inflammation is a significant contributor to vascular disease, acute MI and stroke. These findings give us more ammunition to study further drugs and activities to reduce inflammation, morbidity and mortality. It is difficult to predict which routes this will go, but future research should be of great interest.

    The editorial by Robert A. Harrington, MD, in NEJM summarized nicely the limited clinical applicability right now, but the excitement it may bring to the future of research in vascular disease and oncology.

    • C. Michael Valentine, MD, FACC
    • Cardiologist, Stroobants Cardiovascular Center Centra Health, Lynchburg, Virginia Vice President, American College of Cardiology

    Disclosures: Valentine reports he has no relevant financial disclosures.

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