Study: Malignancies Associated with Tofacitinib Consistent with Those Reported for Other Rheumatoid Arthritis Treatments

A recent study in Annals of the Rheumatic Diseases reviewed data from six phase II, six phase III, and two long-term extension studies to examine the safety profile of tofacitinib, the first oral Janus kinase inhibitor for the treatment of rheumatoid arthritis.

Malignancies such as lymphoma, leukemia, and lung cancer occur more frequently in rheumatoid arthritis (RA) patients than in the general population. This makes sense, certainly, given the pathology of RA, but there is an open question about the role that treatments for RA play in this increased malignancy. In other words, do treatments for conditions that involve modulation of the immune system also increase a patient’s risk of progressing from RA to, say, myeloma?

A recent study in Annals of the Rheumatic Diseases reviewed data from six phase II, six phase III, and two long-term extension (LTE) studies to examine the safety profile of tofacitinib, the first oral Janus kinase inhibitor for the treatment of RA. Because tofacitinib constitutes a new mechanism of action for treatment of RA, assessing the potential for adverse drug reactions—including development of malignancies—is of great importance.

Eligible patients aged ≥18 years with active, moderate-to-severe RA were enrolled globally from North America, Europe, Latin America and Asia, who had an inadequate response to methotrexate or anti-TNF agents. Patients with a previous malignancy were also excluded. The LTE studies (tofacitinib 5 or 10 mg twice daily) enrolled patients from qualifying prior phase I, II and III index studies.

Of 5,671 tofacitinib-treated patients, 107 developed malignancies (excluding non-melanoma skin cancer (NMSC)). The most common malignancy was lung cancer (n=24) followed by breast cancer (n=19), lymphoma (n=10) and gastric cancer (n=6). The rate of malignancies by 6-month intervals of tofacitinib exposure indicates rates remained stable over time. The overall rates and types of malignancies observed with tofacitinib remained stable over time with increasing tofacitinib exposure.

According to the study authors, “In this analysis, the most frequently reported malignancy in tofacitinib-treated patients was lung cancer and, of 24 patients with lung cancer, 20 were current or former smokers. Five patients were diagnosed with lung cancer within 6 months of tofacitinib start. Given the known growth rate of solid tumors, it is highly likely these cancers were pre-existent prior to tofacitinib therapy.” The types of lymphomas reported for those taking tofacitinib were consistent with lymphomas described in the RA and general populations.

The study authors, many of whom have acted as a consultant for Pfizer or are employees and shareholders of Pfizer (tofacitinib was developed by Pfizer under the brand name Xeljanz), indicated that the analysis was “limited by reliance on randomized, placebo-controlled and LTE trials that reflect a selected patient cohort (here, the exclusion of patients with any previous cancer). While patients’ general health was assessed, there were no specific screening procedures that would detect undiagnosed malignancies.”

They also noted that “the most susceptible patients at highest risk of cancer who develop a malignancy early are excluded from further trial participation, leading to a less at-risk cohort over time. However, we found that rates were generally stable over time or were even numerically lower during the first year of exposure …This phenomenon has been observed in RA studies with TNFi and other biological DMARDs, and it has been suggested that the lower rates might be an effect of recruitment bias of healthier patients.”