Rome, Italy—Tofacitinib does not appear to increase the risk for nonmelanoma skin cancer (NMSC), according to a safety review across the entire tofacitinib rheumatoid arthritis (RA) clinical program, which was presented at the 2015 annual meeting of the European League Against Rheumatism.
“This is good news when it comes to cancer risk. It doesn’t appear that NMSC risk is increased with tofacitinib, nor does risk increase over time with continued exposure,” said lead author Jeffrey Curtis, MD, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham.
Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. NMSC is a concern with therapeutic agents such as tofacitinib that modulate the immune system. Previous studies have shown that NMSC is one of the most commonly occurring cancers associated with immune-modulator therapy in RA.
The clinical development program for tofacitinib in RA includes randomized phase 2 and 3 studies, and ongoing open-label, long-term extension studies.
The study was based on pooled data from 2 phase 1 studies, 8 randomized phase 2 studies, 6 randomized phase 3 studies, and 2 open-label long-term studies that included a total of 6092 patients who received at least 1 dose of tofacitinib. Mean age was 52.2 years and 82.7% were female.
Patients were excluded from the safety study if they had a malignancy or history of malignancy with the exception of adequately treated or excised nonmetastatic basal cell carcinoma, squamous cell carcinoma of the skin, or cervical carcinoma in situ. The cut-off date for this analysis was August 30, 2013.
NMSC was identified by review of investigator-reported adverse events, serious adverse events, and output from a central laboratory histology review.
Results were analyzed according to dose of tofacitinib within each study (5 mg vs 10 mg twice a day), tofacitinib monotherapy versus combination therapy, previous treatment with tumor necrosis factor (TNF) inhibitors or glucocorticoids, age at baseline, ethnic background, geographic location, prior NMSC, and occurrence of NMSC events over time.
Incidence ratio (IR) was expressed as patients with events per 100 patient-years.
Overall, 125 cases of NMSC were observed in 83 tofacitinib-treated patients: 51 cases of squamous cell carcinoma in 39 patients, 71 cases of basal cell carcinoma in 52 patients, 2 cases of atypical fibroxanthoma in 2 patients, and 1 case of Merkel cell carcinoma. Eleven (13.3%) patients had both basal cell carcinoma and squamous cell carcinoma events. Fourteen (16.9%) patients had a recurrent NMSC event following initiation of tofacitinib; 2 of 14 had a history of NMSC prior to initiating treatment.
Patients who were receiving background disease-modifying antirheumatic drug (DMARD) treatment in addition to tofacitinib had a numerically higher IR of NMSC than those on tofacitinib monotherapy: 0.64 versus 0.43, respectively. Also, a higher incidence of NMSC was observed in patients previously treated with a TNF inhibitor versus those who were TNF-naive: 1.01 versus 0.47, respectively.
Patients who used glucocorticoids prior to enrollment had an NMSC IR of 0.61 compared with an IR of 0.48 in those with no previous exposure to glucocorticoids.
Among the 83 patients with incidence of NMSC, the most commonly administered concomitant medications were anti-inflammatory and antirheumatic treatments, used by 74 (89.2%) patients. Methotrexate was the most commonly used drug (50 patients, 60.2%).
Further subgroup analyses revealed that 22 of the NMSC events that occurred during the study were in a total of 5 patients with a history of NMSC; 1 of these patients accounted for 17 NMSC events. Among 78 patients with no history of NMSC, the IR was 0.52.
NMSC IR appeared higher in older patients (≥65 years): 1.67 compared with 0.38 in patients <65 years; also the IR for NMSC was higher in men than in women: 1.22 versus 0.42.
Regarding geographic region, patients in the United States (vs the rest of the world) had the highest NMSC IR: 1.41. White patients had the highest NMSC IR of any ethnic group: 0.86 for whites compared with 0.03 for Asians, 0 for blacks, or 0.14 for other ethnicities.
The IRs for NMSC appear stable over time.
The results of this pooled analysis are consistent with reports in the literature.
Curtis JR, Lee EB, Martin G, et al. Analysis of non-melanoma skin cancer across the tofacitinib rheumatoid arthritis clinical programme. Presented at: 16th Annual European Congress of Rheumatology; June 10-13, 2015; Rome, Italy. Abstract THU0174.