BackgroundTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA).ObjectivesThe incidence of non-melanoma skin cancer (NMSC) in the tofacitinib RA programme was evaluated using data from randomised Phase (P) 1, 2, 3 and open-label long-term extension (LTE) RA studies (P1P2P3LTE studies).MethodsNMSC data (cut-off date: 30 Aug 2013) were pooled from two P1, eight P2, six P3 and two LTE studies; LTE data collection and analyses are ongoing; study databases unlocked. Patients (pts) with RA in P1, P3 and LTE studies received tofacitinib 5 or 10 mg twice daily (BID) either as monotherapy or with background disease-modifying antirheumatic drugs (DMARDs). LTE pts were enrolled from qualifying P1, P2 and P3 studies; pts from P2 studies received tofacitinib 1 to 30 mg BID or 20 mg once daily. Incidence rates (IRs) per 100 pt-years (py) of exposure for first NMSC were calculated for combined doses (all doses) of tofacitinib in the P1P2P3LTE pt population. The overall NMSC IR was analysed as well as IRs for subgroup analyses according to the following conditions: tofacitinib dose (5 mg vs 10 mg BID); tofacitinib monotherapy vs tofacitinib + background DMARDs; prior tumour necrosis factor inhibitors (TNFi); pt age (≥65 vs <65); ethnic background; and time period.Results6092 pts (15103 py of exposure) received tofacitinib (all doses) in the P1P2P3LTE studies. ≥1 events of NMSC occurred in 83 pts receiving tofacitinib (all doses), of which squamous cell carcinomas (SCC) and basal cell carcinomas (BCC) occurred in 39 and 52 pts, respectively. Five pts had a history of NMSC prior to tofacitinib exposure; 78 pts did not. In the P1P2P3LTE population, IRs were 0.55 (95% confidence interval [CI] 0.45, 0.69), 0.26 (0.19, 0.35) and 0.35 (0.26, 0.45) for NMSC overall, SCC and BCC, respectively. NMSC IRs for pts from the P1/2/3 and LTE cohorts receiving tofacitinib 5 mg BID were 0.61 (0.34, 1.10) and 0.41 (0.26, 0.66), respectively; for pts receiving tofacitinib 10 mg BID, NMSC IRs were 0.47 (0.24, 0.90) and 0.79 (0.60, 1.05), respectively. P1P2P3LTE pts on background DMARDs had a numerically higher IR (IR 0.64, 95% CI 0.49, 0.84) than tofacitinib monotherapy pts (IR 0.43, 95% CI 0.30, 0.64). There was a higher rate of NMSC in pts with prior TNFi (IR 1.01, 95% CI 0.67, 1.51) vs TNFi-naïve pts (IR 0.47, 95% CI 0.37, 0.61). Pts ≥65 years had a higher rate of NMSC (IR 1.67, 95% CI 1.19, 2.35) vs pts <65 years (IR 0.38, 95% CI 0.29, 0.51). Pts of White ethnicity had the highest IR of NMSC vs pts of Asian, Black or Other ethnicity (0.86 vs 0.03, 0.00 or 0.14). NMSC IRs, analysed in 6-month intervals (through >84 months), were stable over time.ConclusionsNMSC IRs appeared consistent with published estimates in pts with RA treated with TNFi (IR 0.22-0.66).1 The overall NMSC IR in the tofacitinib clinical development programme remained stable over time.ReferencesAskling J et al. Pharmacoepidemiol Drug Saf 2011;20:119-130.AcknowledgementsPreviously presented (Curtis JR et al. Arthritis Rheum 2014; 66(11): S196 ...

Background Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis (RA). Objectives To evaluate the malignancies that occurred in the tofacitinib RA programme from the Phase (P) 2, 3, and long-term extension (LTE) studies up to 29 March 2011. Methods Data were pooled from 6 randomized P2, 5 randomized P3 studies and 2 open-label LTE studies. Patients (pts) in P3 and LTE studies were treated with tofacitinib 5 or 10 mg twice daily. Analyses included malignancy data from 1608 pts in P2, 3315 pts in P3, and 3227 pts in LTE studies (LTE pts rolled over from the P2 and P3 studies). Results A total of 4789 patients (5651 pt-yr) received tofacitinib in the P2, P3 and LTE studies. Fifty pts receiving tofacitinib (all doses) reported malignancies (excluding non-melanoma skin cancer [NMSC]); the most common were lung (12 cases) and breast cancer (9 cases). There were 3 lymphoma cases. The overall incidence rate (IR, events per 100 pt-yr) for all malignancies (excluding NMSC) was 0.89 (95% confidence interval [CI]: 0.67,1.17). The IRs (95% CI) of all malignancies (excluding NMSC) broken down into 0-6, 6-12, 12-18, 18-24 and >24 months based on exposure to study drug were 0.75 (0.46,1.23), 0.73 (0.41,1.28), 0.97 (0.48,1.94), 1.28 (0.53,3.08), and 1.37 (0.71,2.63), respectively. The number of cases in each time interval was small, with resultant wide CIs. The standardised incidence ratio (SIR) (95% CI) (as compared with the Surveillance Epidemiology and End Result database covering the general population) for all malignancies (excluding NMSC), lung, breast cancer and lymphomas in the tofacitinib group were 1.11 (0.82-1.47), 2.16 (1.12,3.77), 0.82 (0.38,1.56) and 1.74 (0.36,5.10), respectively. Twenty-one pts experienced NMSCs, for an IR of 0.37 (95% CI: 0.24,0.57). By comparison, the IR of NMSC in patients treated with anti-TNF was 0.47 (0.37-0.59) in a meta-analysis of randomized controlled trials and ranged from 0.23 to 0.35 in a meta-analysis of registries.1,2 Conclusions The malignancies that occurred in the tofacitinib RA programme are consistent with the type and distribution of malignancies expected for patients with moderate to severe RA. The IRs for all malignancies (excluding NMSC), lung cancer, breast cancer and lymphomas are consistent with published estimates in RA patients treated with biologic and non-biologic DMARDs.3-6 Longer follow-up is necessary to further evaluate the potential risk of malignancies in the CP RA programme. References Askling J, et al. Pharmacoepidemiol Drug Saf 2011;20:119-30. Mariette X, et al. Ann Rheum Dis 2011;70:1895-904. Carmona L, et al. Semin Arthritis Rheum 2011;41:71-80. Pallavicini FB, et al. Autoimmun Rev 2010;9:175-80. Simon TA, et al. Ann Rheum Dis 2009;68:1819-26. Wolfe F, Michaud K. Arthritis Rheum 2007;56:2886-95. Disclosure of Interest X. Mariette Consultant for: Pfizer Inc, J. Curtis Grant/Research support from: Pfizer Inc, Consultant for: Pfize...

BackgroundTofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). Cytokines involved in lymphocyte development, function and homeostasis are known to signal through JAKs.ObjectivesTo characterise the effects of tofacitinib treatment on absolute lymphocyte counts (ALCs) and lymphocyte subset counts (LSCs) and their reversibility after treatment discontinuation.MethodsALCs were collected as part of safety monitoring procedures throughout the tofacitinib RA clinical programme. Short-term (ST) changes were evaluated in five Phase (P) 2 studies (tofacitinib 1–30 mg twice daily [BID]; treatment duration 6 weeks–6 months). Long-term (LT) changes were assessed in an LT substudy (LSS) of NCT00413699 (study ongoing; database not locked) in which patients (pts) had received tofacitinib 5 or 10 mg BID for up to 8 years. Reversibility of changes in ALCs was evaluated in pts who permanently discontinued tofacitinib due to lymphopenia as defined by a confirmed ALC <500 cells/mm3. Reversibility of changes in LSCs was evaluated in a P2 study (NCT00147498) through a 6-week withdrawal phase after 6 weeks' tofacitinib treatment and in the LSS during a 4 week temporary withdrawal phase in pts with an ALC ≤1000 cells/mm3 and ≥40% decrease in ALC vs baseline (NCT00413699).ResultsIn total, there were 1432 and 4867 pts from P2 and LT extension (LTE) studies, respectively. Approximately 1050 pts from LTE study NCT00413699 were enrolled into the LSS for evaluation of ALCs and LSCs (median tofacitinib exposure of 5 years). Pre-treatment baseline for natural killer (NK) cells, B cells, T cells (CD3+, CD4+ and CD8+) were available for 130, 133, 133, 52 and 52 pts, respectively. Effects of tofacitinib on ALCs and LSCs are summarised in Table 1. Tofacitinib treatment resulted in a transient increase in ALC at Month 1, followed by a gradual decline to stabilise below baseline levels by ∼4 years. Magnitude and time course of changes in CD4+ and CD8+ T cells mirrored those of ALC. CD4+ and CD8+ cell counts were well correlated with ALC. LT treatment showed higher NK cell counts vs baseline, in contrast to decreases seen after ST dosing. B cell counts increased with ST treatment but returned toward baseline with LT treatment.ConclusionsTofacitinib treatment was associated with decreases in ALC. Changes in CD4+ and CD8+ T cell counts were reflected in ALC, while B cell and NK cell counts tended to return to or exceed baseline levels. Reversibility is observed following ST and LT dosing.AcknowledgementThis study was sponsored by Pfizer Inc. Editorial support was provided by Claire Cridland of Complete Medical Communications and funded by Pfizer Inc.Disclosure of InterestR. van Vollenhoven Grant/research support from: Pfizer Inc, Consultant for: Pfizer Inc, E. Choy Grant/research support from: Amgen, Boehringer Ingelheim, Chugai Pharma, Ferring Pharmaceuticals, Novimmune, Pfizer Inc, Roche, and UCB, Speakers bureau: Amgen, Boehringer Ingelheim, Chugai Pharma, Eli Lilly, Hospira, MSD, Novartis, Pfizer Inc, Reg...

Background Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor investigated as a targeted immunomodulator for rheumatoid arthritis (RA). Objectives This is an analysis of the populations pooled across Phase 2 and 3 RA studies to assess whether there is consistency in the treatment effect of tofacitinib in subgroups of patients. Methods The demographic and baseline disease characteristics of patients in the Phase 2 and Phase 3 studies were similar, which supports the pooling of these data. Data from patients receiving tofacitinib 5 or 10 mg twice daily (BID) or placebo in all randomised Phase 2 and Phase 3 studies ≥3 months in duration (monotherapy studies NCT00550446, NCT00687193, and NCT00814307; background DMARD Studies NCT00413660, NCT00603512, NCT00960440, NCT00847613, NCT00856544, and NCT00853385) were pooled. ACR20 response rates and rates of improvement from baseline of at least 0.22 in the HAQ-DI at Month 3 were analysed by baseline demographics and disease characteristics and results were expressed as probability ratios (proportion of responders randomised to tofacitinib treatment(s) divided by that of placebo at Month 3) and 95% confidence intervals (CIs). Treatment comparisons included 5 mg BID, 10 mg BID, and 5 and 10 mg BID groups combined, vs placebo. Additionally, ACR20 response rates and change from baseline in the HAQ-DI at Month 3 were analysed by previous treatment experience (traditional DMARDs and TNF inhibitors). Results In an analysis of 3442 patients in total, tofacitinib demonstrated consistent efficacy in reducing signs and symptoms of RA and improving physical function, as measured by ACR20 and HAQ-DI, respectively, compared to placebo. The probability ratios for all treatment comparisons for ACR20 and HAQ-DI responder rates were ≥1, with the lower boundary of the 95% CIs also ≥1 for all but one subgroup. Efficacy was seen in all subgroups evaluated including: age (18-44, 45-64, and ≥65 years); gender; weight (<60, 60-100, and >100 kg); body mass index (BMI, <18.5, 18.5 to <25, 25 to <30, and ≥30); race (white, black, Asian, other); region (USA, Latin America, Europe plus Canada, and rest of the world); RA duration (<2, 2 to <5, 5 to <10, and ≥10 years); serological status (RF or CCP +), and baseline DAS28-4 (ESR) (≤5.1 and >5.1). The black race group appeared to have lower response rates than the other race groups, although the CI for this group was wide and the sample size relatively small. Tofacitinib also demonstrated consistent efficacy in patients previously treated with traditional DMARDs or TNF inhibitors, irrespective of the number of previous treatments. Conclusions Tofacitinib was consistently efficacious, as measured by ACR20 and HAQ-DI, across the range of baseline demographics and disease characteristics such as age, gender, weight, BMI, race, geographic region, disease duration, serological status, disease activity and previous treatment experience. Disclosure of Interest J. Kremer Grant/Research support from: Pfizer Inc, Consultant for: Pfizer Inc, ...