In a phase IIIb/IV safety endpoint trial (ORAL Surveillance) reported in The New England Journal of Medicine, Ytterberg et al found that treatment with the JAK inhibitor tofacitinib for rheumatoid arthritis was associated with higher rates of cancer and major cardiovascular events compared with tumor necrosis factor (TNF) inhibitor treatment, with tofacitinib failing to meet noninferiority criteria for both endpoints.
Study Details
The open-label, noninferiority, postauthorization trial included patients with active rheumatoid arthritis despite methotrexate treatment who were aged ≥ 50 years and had at least one additional cardiovascular risk factor. They were enrolled from sites in 30 countries between March 2014 and July 2020. A total of 4,362 patients were randomly assigned 1:1:1 to receive tofacitinib at 5 mg twice daily (n = 1,455), tofacitinib at 10 mg twice daily (n = 1,456), or a TNF inhibitor (n =1,415); TNF inhibitors consisted of subcutaneous adalimumab at 40 mg every 2 weeks or etanercept at 50 mg once weekly depending on study region.
The co-primary endpoints were adjudicated cancers (excluding nonmelanoma skin cancers) and major cardiovascular events. Noninferiority of tofacitinib would be established if the upper bound of the 95% confidence interval (CI) for the hazard ratio (HR) was < 1.8 for the combined tofacitinib doses vs the TNF inhibitor group.
In this trial comparing combined tofacitinib doses with a TNF inhibitor in a cardiovascular risk–enriched population, risks of major adverse cardiovascular events and cancers were higher with tofacitinib and did not meet noninferiority criteria.— Ytterberg et al
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Key Findings
During a median follow-up of 4.0 years, the incidence of cancer (excluding nonmelanoma skin cancers) was 4.2% in the combined tofacitinib groups vs 2.9% in the TNF inhibitor group (HR = 1.48, 95% CI = 1.04–2.09), with noninferiority not being established. Hazard ratios were 1.47 (95% CI = 1.00–2.18) for the 5-mg group and 1.48 (95% CI = 1.00–2.19) for the 10-mg group vs the TNF inhibitor group. No difference was observed between the 10-mg group vs the 5-mg tofacitinib groups (HR = 1.00, 95% CI = 0.70–1.43). Over 5.5 years, the cumulative probability of developing cancers was 6.1% in the combined tofacitinib doses group vs 3.8% in the TNF inhibitor group. The most common cancers were lung cancer in the tofacitinib groups and breast cancer in the TNF inhibitor group. Nonmelanoma skin cancers occurred in 2.1% of patients in the 5-mg group (HR = 1.90, 95% CI = 1.04–3.47) and 2.3% of those in the 10-mg group (HR = 2.16, 95% CI = 1.19–3.92) vs 1.1% of those in the TNF inhibitor group.
During a median follow-up of 4.0 years, the incidence of major cardiovascular events was 3.4% in the combined tofacitinib groups vs 2.5% in the TNF inhibitor group (HR = 1.33, 95% CI = 0.91–1.94), with noninferiority not being established. Hazard ratios were 1.24 (95% CI = 0.81–1.91) for the 5-mg group and 1.43 (95% CI = 0.94–2.18) for the 10-mg group vs the TNF inhibitor group. No significant difference was observed between the 10-mg group vs the 5-mg group (HR = 1.15, 95% CI = 0.77–1.71) Over a period of 5.5 years, the cumulative probability of major cardiovascular events was 5.8% in the combined tofacitinib doses group vs 4.3% in the TNF inhibitor group. The most common major cardiovascular events were nonfatal myocardial infarction in the tofacitinib groups and nonfatal stroke in the TNF inhibitor group.
The investigators concluded, “In this trial comparing combined tofacitinib doses with a TNF inhibitor in a cardiovascular risk–enriched population, risks of major adverse cardiovascular events and cancers were higher with tofacitinib and did not meet noninferiority criteria.”
Steven R. Ytterberg, MD, of Mayo Clinic, Rochester, is the corresponding author for The New England Journal of Medicine article.
Disclosure: The study was funded by Pfizer. For full disclosures of the study authors, visit nejm.org.
