Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development programme

Abstract

ObjectivesTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To further assess the potential role of Janus kinase inhibition in the development of malignancies, we performed an integrated analysis of data from the tofacitinib RA clinical development programme.MethodsMalignancy data (up to 10 April 2013) were pooled from six phase II, six Phase III and two long-term extension (LTE) studies involving tofacitinib. In the phase II and III studies, patients with moderate-to-severe RA were randomised to various tofacitinib doses as monotherapy or with background non-biological disease-modifying antirheumatic drugs (DMARDs), mainly methotrexate. The LTE studies (tofacitinib 5 or 10 mg twice daily) enrolled patients from qualifying prior phase I, II and III index studies.ResultsOf 5671 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. Standardised incidence ratios (comparison with Surveillance, Epidemiology and End Results) for all malignancies (excluding NMSC) and selected malignancies (lung, breast, lymphoma, NMSC) were within the expected range of patients with moderate-to-severe RA.ConclusionsThe overall rates and types of malignancies observed in the tofacitinib clinical programme remained stable over time with increasing tofacitinib exposure.

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“…The drug has not yet been approved by the European Medicines Agency (EMA)—mainly due to safety concerns 66. Serious infection-related events (3.09 events per 100 patient-years, overall)67 and malignancies (0.85 events per 100 patient-years, overall)68 were higher than with placebo. The most common malignancies were lung cancer, breast cancer, lymphoma and gastric cancer (in Japan only for the latter).…”

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“…20 Malignancy data were adjudicated as previously described. 21 GI perforations were blindly adjudicated by two sponsorindependent reviewers (US board-certified practising gastroenterologists). SAEs in the clinical and safety databases that might reflect a GI perforation (see online supplementary appendix) were reviewed.…”

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“…There are a number of JAK inhibitors in development. Ruxolitinib (INCB1824), an inhibitor of JAK1/2, is FDA approved for myelofibrosis and tofacitinib 89 , an inhibitor of JAK1/3, is approved in rheumatoid arthritis. Ruxolitinib has been evaluated in vitro in NSCLC cell lines and will inhibit STAT 3 activation 90 .…”