Tofacitinib linked to higher cardiovascular, cancer risks than TNF inhibitors in RA
Patients with rheumatoid arthritis who received tofacitinib demonstrated a greater risk for major adverse cardiovascular events and cancer than those treated with TNF inhibitors, according to data in The New England Journal of Medicine.
In the study — a safety trial ordered by the FDA following reports of increased lipid levels and cancer incidence associated with tofacitinib (Xeljanz, Pfizer) — the drug failed to show noninferiority with TNF inhibitors. Opportunistic infections, including herpes zoster, and nonmelanoma skin cancer also occurred more often with both tofacitinib doses than with a TNF inhibitor.
“Tofacitinib is a targeted synthetic DMARD that selectively inhibits Janus kinase (JAK)1, JAK3, and, to a lesser extent, JAK2, and is approved for the treatment of rheumatoid arthritis by the Food and Drug Administration (FDA) at doses of 5 mg twice daily or 11 mg once daily (extended-release formulation),” Steven R. Ytterberg, MD, of the Mayo Clinic, in Rochester, Minnesota, and colleagues wrote. “During drug development, increases in serum lipid levels and the incidence of cancers, including lymphoma, were observed, which prompted the FDA to require a prospective, head-to-head safety trial comparing tofacitinib with TNF inhibitors.”
To assess the safety of tofacitinib in patients with RA, Ytterberg conducted the Oral Rheumatoid Arthritis Trial (ORAL) Surveillance trial, a randomized, open-label, post-authorization, noninferiority study. Participants included adults aged 50 years or older with active RA despite receiving methotrexate, and who had at least one additional cardiovascular risk factor. A total of 1,455 participants were randomly assigned to receive 5 mg of tofacitinib twice daily, while 1,456 were treated with 10 mg of the drug twice daily and 1,451 received a TNF inhibitor. Median follow-up was 4 years.
Coprimary endpoints included adjudicated major adverse cardiovascular events and cancers, excluding nonmelanoma skin cancer. To achieve noninferiority, the upper boundary of the two-sided 95% CI for the HR would have to be less than 1.8 for the combined tofacitinib doses, compared with a TNF inhibitor.
According to the researchers, incidences of major adverse cardiovascular events and cancer were higher among the combined tofacitinib dose groups — at 3.4% and 4.2%, respectively — compared with the TNF inhibitor arm — 2.5% and 2.9%, respectively. Hazard ratios were 1.33 (95% CI, 0.91-1.94) for major adverse cardiovascular events and 1.48 (95% CI, 1.04-2.09) for cancers, meaning tofacitinib failed to show noninferiority with TNF inhibitors.
Meanwhile, incidences of adjudicated opportunistic infections — including herpes zoster and tuberculosis — all nonserious and serious herpes zoster, and adjudicated nonmelanoma skin cancer were higher among patients who received tofacitinib, compared with a TNF inhibitor.
Efficacy was similar in all three groups, according to the researchers. Improvements observed from month 2 were sustained through the end of the trial.
“This study underscores the need to consider and address cardiovascular risk in patients with RA,” Ytterberg told Healio. “There is a need to understand the FDA black box warning and label change that was made based on these data. The FDA included other JAK inhibitors in the black box warning as there is no compelling evidence to show that the results are not a group effect of JAK inhibitors and only applicable to tofacitinib.
“It should go without saying that shared decision-making is important, especially when considering use of tofacitinib or other JAK inhibitors,” he added. “For a patient not responding adequately to methotrexate monotherapy, a TNF inhibitor should be used rather than a JAK inhibitor. For a patient not responding to methotrexate and a TNF inhibitor, or already on tofacitinib and doing well, risk for MACE and cancer should be considered when deciding on whether to start or continue tofacitinib, respectively.”