Tofacitinib's Cancer, CV Risks Outlined in Older Patients With Rheumatoid Arthritis

By Gene Emery

January 27, 2022

NEW YORK (Reuters Health) - Using Pfizer's tofacitinib to treat rheumatoid arthritis increases the risk of developing cancer by 48% compared with therapy with a TNF inhibitor, and might also carry cardiovascular and other risks, according to a safety analysis published in Thursday's New England Journal of Medicine.

The findings already resulted in a "black box" warning for tofacitinib and other JAK inhibitors after the drug failed the noninferiority test mandated by the U.S. Food and Drug Administration (FDA).

Tofacitinib is now recommended for arthritis patients who have not been helped by either methotrexate or a TNF inhibitor.

But there may be cases where the Pfizer drug, sold under the brand name Xeljanz, could be the preferred choice, coauthor Dr. Steven Ytterberg told Reuters Health by phone.

And patients may have a strong preference for the oral medication.

Dr. Ytterberg and his colleagues estimated that during five years of therapy, for every 113 patients treated with 5 mg of tofacitinib twice daily instead of a TNF inhibitor, there would be one major adverse cardiovascular event. For every 55 patients there would be one additional cancer.

The guidelines are steering patients and doctors away from tofacitinib-type drugs, but "there are patients who have been on a JAK inhibitor and are doing well with it," said Dr. Ytterberg, a retired associate professor of medicine at the Mayo Clinic in Rochester, Minnesota.

"The problem is, it often takes trial and error to get people into remission, to get them on a drug or a combination of drugs that work for them," he said. "I think that for the patients who are at low risk for cardiovascular events and who are on tofacitinib and are doing well, it's probably reasonable to continue. But it should be with a discussion with the patient so they know the risks. On the other hand, if the patient on the drug is 68 and has hypertension or diabetes, they're at much more risk, and the question is should those patients be taken off (tofacitinib). That's where the conversation has to be had."

The Pfizer-funded study of 4,362 patients who received either 5 mg or 10 mg of tofacitinib twice daily was mandated after researchers noted that the drug increased serum lipid levels and users seemed more prone to cancers, including lymphoma.

All of the volunteers in the ORAL trial were at least 50 years old, had active rheumatoid arthritis despite treatment with methotrexate, and had at least one cardiovascular risk factor. Nonmelanoma skin cancer was not counted as cancer in the trial.

Patients were randomly assigned to therapy with a TNF inhibitor (adalimumab or etanercept), tofacitinib 5 mg twice daily or tofacitinib 10 mg twice daily. Five years into the study, everyone in the 10-mg group was switched to 5 mg twice daily because of a higher risk of pulmonary embolism in the higher-dose group. All patients continued to receive methotrexate unless contra-indicated.

After a median follow-up of 4.0 years, the risk of suffering a major cardiovascular event was 43% higher with 10 mg of tofacitinib and 24% higher with 5 mg than with a TNF inhibitor. The risk for the two tofacitinib groups combined was increased 1.33-fold (95% CI, 0.91 to 1.94).

Nonfatal myocardial infarction was the most common cardiovascular side effect among tofacitinib patients, and the cumulative probability of having one over 5.5 years was 2.2% within the experimental group and 0.7% in the control group. Nonfatal stroke was the most common cardiovascular event for TNF inhibitor recipients.

The added risk for cancer was essentially the same regardless of the dose (hazard ratio for the combined doses, 1.48; 95% CI, 1.04 to 2.09).

The incidence of cancer was 4.2% with both doses of tofacitinib versus 2.9% among TNF patients.

"The most common cancers were lung cancer with tofacitinib and breast cancer with a TNF inhibitor," the researchers said.

The 5.5-year cumulative probability of getting cancer was 6.1% with tofacitinib and 3.8% with a TNF inhibitor.

When the team looked at secondary outcomes, they found that the 10-mg dose produced a 48% greater risk of serious infection, a two-fold increase in hepatic events, and eight-fold increase in the risk of pulmonary embolism, and a two-fold increase in both deep-vein thrombosis and death by any cause.

Both doses of tofacitinib showed an elevated risk of herpes zoster and opportunistic infections.

"The bottom line is, life has risk," said Dr. Ytterberg, who reported that he typically treated his rheumatoid arthritis patients with a TNF inhibitor before resorting to a JAK inhibitor. Dr. Ytterberg has been a paid consultant to Pfizer.

"Patients often focus on the risk of the drugs they are using. You really want to balance risk. There's risk of undertreatment as much as there is risk of overtreatment and side effects from medications," he said. "If you undertreat, you're left with ongoing pain, joint swelling and joint damage, as well as risk of increased cardiovascular events and damage just because of chronic inflammation. So undertreatment has risks also. You have to recognize what risks are worth taking."

SOURCE: https://bit.ly/327e9We The New England Journal of Medicine, online January 26, 2022.

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