Background There have been conflicting reports whether patients with rheumatoid arthritis (RA) receiving conventional or biologic immunosuppressive therapies are at increased risk of specific malignancies. Melanoma is an aggressive malignancy with risk factors including sex, age, fair skin and elevated cumulative UV exposure. Interleukin-6 (IL-6) has a role in pro- and antitumorigenic pathways. Whether tocilizumab (TCZ), a biologic that alters IL-6 signaling, increases the risk of melanoma in patients with RA is unclear.
Objectives This age- and sex-adjusted standardized incidence ratio (SIR) analysis compared the observed reports of melanoma in patients with RA treated with TCZ in clinical trial and postmarketing settings with the expected number of cases across geographic regions.
Methods SIRs for melanoma were calculated from the TCZ clinical trials all-exposure population. Postmarketing rates were estimated from the TCZ Global Safety Database population. Both databases were searched cumulatively from 11 April 2005 to 10 October 2015. For clinical trials, observed reports of melanoma in patients with RA treated with TCZ were compared with expected number of cases in the general population based on the 2012 US Surveillance, Epidemiology, and End Results using an age- and sex-adjusted SIR. Postmarketing regional SIRs were calculated based on the estimated commercial exposure in each region and the incidence of melanoma as reported by Globocan by age and sex (2012). Crude postmarketing rates were age- and sex-adjusted according to the clinical trial demographic profile to estimate the expected number of cases of melanoma in each region.
Results In the clinical trial setting, 4 qualifying cases of melanoma were identified among 7093 patients with RA treated with TCZ (20,828 PY of exposure). The SIR estimate (0.71 [95% CI, 0.19–1.81]) for melanoma incidence in patients with RA treated with TCZ in clinical trials was comparable to that in the general population (Table 1). In the postmarketing setting, the number of observed reports of melanoma was comparable to the expected number of cases in Europe and Japan and fewer than expected in North America (Table 2). The exception is Australia, where SIR estimates indicated more than the expected number of cases in patients with RA receiving TCZ in Australia compared with the general population in that region (SIR 3.71 [95% CI: 2.16, 5.93]).
Conclusions In clinical trials, no evidence was found to suggest there were more cases of melanoma than expected in patients with RA treated with TCZ compared with the general population. Consistent with this, no evidence was found to suggest that patients with RA treated with TCZ in Europe, North America or Japan had more cases of melanoma than expected compared with the general population in each region. In contrast, the estimated SIR of melanoma in patients with RA treated with TCZ in Australia indicated more than the expected number of cases in the general population. This finding is consistent with reports of elevated risk of melanoma in patients with RA in Australia (compared with the general population), where UV exposure is high and methotrexate is a common first-line therapy.1,2
Buchbinder et al. Arthritis Rheum. 2008.
Buchbinder et al. BMC Musculoskelet Disord. 2015.
Acknowledgements Funded by Roche/Genentech.
Disclosure of Interest S. Gale Employee of: Genentech, J. Wang Employee of: Roche, J. Nebesky Employee of: Roche, A. Linke Employee of: Genentech, E. Berber Employee of: Genentech