CANTOS: Anti-Inflammatory Drug Cuts CV Events, Cancer

Patrice Wendling

August 27, 2017

BARCELONA, SPAIN — The anti-inflammatory drug canakinumab (Ilaris, Novartis) significantly decreased the risk of recurrent major CV events without any effect on cholesterol and, in a surprising twist, also dramatically cut rates of new lung cancer and lung-cancer mortality, according to results of the eagerly anticipated CANTOS trial[1].

The study, in more than 10,000 high-risk patients who had a prior MI and persistently elevated high-sensitivity C-reactive protein (hs-CRP) levels, showed that patients who received subcutaneous canakinumab 150 mg every 3 months had a 15% reduced risk for the composite primary end point of nonfatal MI, nonfatal stroke, and CV death compared with those receiving placebo (P=0.02075).

For the secondary composite end point that also included unstable-angina hospitalization leading to urgent revascularization, the risk was reduced 17% (P=0.00525).

A 300-mg dose of canakinumab produced similar reductions but failed to meet the prespecified threshold after adjustment for multiplicity for statistical significance, while a 50-mg dose had no effect.

The benefit of treatment was consistent across all patient groups. Treatment with the monoclonal antibody also reduced the need for revascularization by about 30% (P<0.0001).

Dr Paul M Ridker

The results affirm the inflammatory hypothesis of atherothrombosis and are in line with those recently reported for the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab (Repatha, Amgen) in the high-profile FOURIER trial, co–senior author Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) reported here at European Society of Cardiology (ESC) 2017 Congress. The results were published simultaneously in the New England Journal of Medicine[1] and Lancet[2].

"To me this is like going back to 1994 and the very first statin trial, the 4S trial, and the first time we in cardiology recognized there is a class of drugs with an important biology behind it that really matters for our patients," Ridker said in an interview.

"This is the first time we have rock-solid evidence that in the absence of lowering cholesterol but by lowering inflammation, we have risk reductions that are substantial and in this case identical to what you get for lowering LDL. That's really exciting and will open up an enormous amount of biology and drug-development programs and is clearly telling us something fundamental about atherosclerosis that we are going to have to learn about."

Enthusiasm for the results may be tempered by a lack of effect on CV death in the trial and a significant increase in deaths due to infection with canakinumab vs placebo (incidence rate 0.31 vs 0.18 events per 100 person-years; P=0.02). These events happened relatively early on and were more likely in older patients with diabetes.

Should canakinumab move forward in CVD, Ridker said patients will require monitoring for early signs and symptoms similar to what is done for patients taking biologic drugs.

That said, all other adverse events were remarkably clean, with canakinumab actually significantly reducing the incidence of arthritis, osteoarthritis, gout, and fatal cancers.

Dr Eugene Braunwald

"This was a historic moment," Dr Eugene Braunwald (Brigham and Women's Hospital, Boston, MA) told the | Medscape Cardiologyafter the standing-room-only presentation.

"I've been coming to these meetings since the ESC started in the 1960s, I haven't missed a meeting, and I think this is probably the most important paper that I've heard at the ESC, because it shows a new direction for a very important cardiac condition, the most important of all, atherosclerosis."

He added, "We've all been chasing LDL cholesterol and the PCSK9s reduce the LDL even further and that's fine. But what he's done is open up the fact there's another course."

Eagerly Awaited Data

Canakinumab, already approved in the US for rare autoimmune diseases, selectively inhibits the proinflammatory cytokine interleukin-1 beta (IL-1ß). As reported by | Medscape Cardiology, CANTOS' positive top-line results were released in June, but without details or a hint at the cancer findings.

"Canakinumab was originally used to treat gout, so the immunology community is certainly familiar with it and the rheumatology community is familiar with it, but I don't think a potential use for this drug in cancer was on anybody's radar. So these results are surprising, to say the least," Dr Laurie Glimcher (Dana Farber-Cancer Institute, Boston, MA) told | Medscape Cardiology.

CANTOS randomized 10,061 patients (74.3% male; mean age 61 years) with a history of MI and an hs-CRP level of >2 mg/L (median 4.20 mg/L) to placebo or one of three doses of subcutaneous canakinumab.

Most participants (66.7%) had undergone PCI, and 93.4% were on high-dose statins. More than a third of patients had diabetes and almost a quarter were current smokers.

Benefits Tied to hs-CRP Reductions

Cholesterol levels remained constant in the study, while hs-CRP median reductions in the 50-mg, 150-mg, and 300-mg groups were 26%, 37%, and 41% greater than in the placebo group (P<0.001).

Ridker remarked that just as lower is better for LDL-C, patients who responded to the drug with hs-CRP reductions greater than or equal to the median at 3 months had a 27% reduction in the risk of major adverse events compared with those with hs-CRP reductions less than the median (P=0.0001).

"This suggests to me from an inflammation biologist's perspective and from a clinician's perspective that we have a very simple way of knowing which patients might well benefit from this drug; in the same way that we can measure on-treatment LDL cholesterol, we can measure on-treatment CRP and find a patient population. We can maximize the benefits and minimize the risks," he said.

Asked to comment, Dr David C Goff (National Heart, Lung, and Blood Institute [NHLBI], Bethesda, MD) agreed the results suggest the possibility for personalized treatment. PCSK9 inhibitors may be more appropriate for patients who, despite a statin, continue to have high LDL levels, whereas IL-1ß antibodies like canakinumab may be more appropriate for those with residual inflammation even though their LDL has responded nicely to statins.

"What we don't know is in people who have evidence that despite a statin their LDL stays higher than desired and there's evidence of inflammation which would be the better route to go," he added.

Goff said more information is needed about the fatal infections but that "on balance, the safety profile looks pretty reasonable."

To put the findings in context, he noted that about 15 million Americans have atherosclerotic CVD, about half have had a heart attack, and a quarter of those will have a second heart attack within 5 years.

"Although they didn't report this, you can calculate a number needed to treat of about 33 or 34 people treated for 5 years to prevent a cardiovascular event and for a number needed to treat, that's a very reasonable number," Goff said.

Still, he and others said the findings represent proof of principle and underscore the need for further research in the field, including completion of the NHLBI-sponsored CIRT trial examining whether low doses of the less costly rheumatology drug methotrexate can reduce CV events in patients with a prior MI who have diabetes or metabolic syndrome.

Why Just Lung Cancer?

In an exploratory analysis of cancer events adjudicated by an oncology committee blinded to drug and dose allocation, there was a clear dose-dependent risk reduction in cancer mortality that reached 51% with the 300-mg dose (P=0.0009).

A great majority of this benefit was due to a 67% reduction in incident lung cancer (P=0.00008), with the 300-mg dose also associated with a 77% reduction in fatal lung cancer (P=0.0002).

Notably, a citizen's watchdog group called on the US Food and Drug Administration in 2011 to suspend CANTOS and a type 1 diabetes trial, citing a risk of life-threatening infections and the possible risk of malignancy with canakinumab.

"This is the importance of actually getting evidence rather than opinion. Had this study caved to this pressure, we would never have learned the benefit for cardiovascular disease, and we would never have learned the benefit for cancer," said Ridker to | Medscape Cardiology.

Glimcher commented that the results are very consistent with a well-known role for inflammation in cancer and that the next step is to create trials to determine whether there is an adjunctive role for canakinumab in lung cancer.

"I think we also need to see if pairing this kind of anti-inflammatory intervention with other immunomodulators like checkpoint blockers could have a broader role in cancer treatment," she said. "But this is a big first step and highly promising since the data are in people."

As for why the monoclonal antibody did not show benefits in other cancers, Glimcher said, "I think that's honestly a mystery. There are only six or seven cancers at this point that respond to immunotherapy and we're talking here about the immune system."

Similarly, Dr Barnett Kramer (National Cancer Institute, Rockville, MD) said in an interview, "The easiest answer to this [question] is the most honest one: we don't know, and actually that is additional justification for studying this more deeply at both the basic level and clinical level."

Cost a "Major" Issue

Commenting to | Medscape Cardiology, Dr Roxana Mehran (Mount Sinai Medical Center, New York, NY) said the significant reductions in cancer-related deaths and lung-cancer–related deaths "will open doors in this arena and allow us to further investigate the highest-risk patients, those with inflammation post-MI."

That said, she noted that cost is "a major issue, since it will prohibit widespread usage."

Dr Udo Sechtem (Robert Bosch Krankenhaus, Stuttgart, Germany) offered similar thoughts. "The most interesting question I think is how expensive will this be, and is the effect of a 15% general reduction impressive enough, or would it be only the responders who will get the funding for continuing their treatment?"

In an editorial[3] accompanying the New England Journal of Medicine publication, Dr Robert Harrington (Stanford University, Stanford, CA) notes that the cost of canakinumab in the US is about $200,000 a year.

"Such pricing may be suitable for rare diseases, but not for a common indication such a coronary artery disease, even if given every 3 months," he said.

Harrington concludes, "CANTOS has helped moved the inflammatory hypothesis of coronary artery disease forward scientifically. However, the modest absolute clinical benefit of canakinumab cannot justify its routine use in patients with previous myocardial infarction until we understand more about the efficacy and safety trade-offs and unless a price restructuring and formal cost-effectiveness evaluation supports it."

The study was funded by Novartis. Ridker reports serving as a consultant to Novartis and is coinventor on patents held by the Brigham & Women's Hospital that relate to the use of inflammatory biomarkers in CVD and diabetes that have been licensed to AstraZeneca and Siemens. Disclosures for the coauthors are listed in the Lancet paper and on the New England Journal of Medicine website. Harrington reports grants from Novartis, Merck, GlaxoSmithKline, Regado, Sanofi, AstraZeneca, Janssen, Bristol-Myers Squibb, and the Medicines Company; personal fees from Merck, the Medicines Company, Amgen, Gilead, and WebMD; personal fees and other from MyoKardia; other from Element Science; and serving on the boards of directors for SignalPath, Scanadu, AHA, and Stanford HealthCare. Braunwald reports grants from GlaxoSmithKline, Merck, Novartis, AstraZeneca, Johnson & Johnson, and Daiichi Sankyo and personal fees from the Medicines Company and Theravance. Glimcher reported recently stepping down from the board of directors at Bristol Myers Squibb; joining the board of directors at GlaxoSmithKline; and founding the immunotherapy company Quentis Therapeutics. Goff and Kramer report no relevant conflicts of interest. Mehran has reported numerous relationships with industry including serving as a consultant for Medscape.

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