Identification of two tofacitinib subpopulations with different relative risk versus TNF inhibitors: an analysis of the open label, randomised controlled study ORAL Surveillance

Abstract

Objectives: Based on primary results from ORAL Surveillance, an event-driven clinical trial of risk-enriched patients, identify subpopulations with different relative risk (ie, 'high-risk' and 'low-risk') with tofacitinib versus tumour necrosis factor inhibitors (TNFi).

Methods: Patients with rheumatoid arthritis aged ≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 or 10 mg two times a day or TNFi. Prior analyses had identified age and smoking as risk factors of particular interest across safety outcomes. Hazard ratios (HRs) and incidence rates were evaluated by age and smoking individually and in combination. Results were validated across tofacitinib development programmes.

Results: 'Age ≥65 years or ever smoker' defined a group ('high-risk') with increased risk of malignancies (excluding non-melanoma skin cancer), major adverse cardiovascular events, myocardial infarction, venous thromboembolism and all-cause death with tofacitinib (combined doses) versus TNFi (HRs 1.41-5.19). In patients 'aged <65 years and never smokers' ('low-risk'), there was no detectable risk increase with tofacitinib versus TNFi (HRs ≈1.0) up to 6 years of follow-up, and absolute risk remained low and was corroborated across tofacitinib rheumatoid arthritis, psoriatic arthritis and ulcerative colitis programmes with up to 10 years of observation.

Conclusions: This posthoc analysis of ORAL Surveillance identified two tofacitinib subpopulations with different relative risk versus TNFi. High risk was confined to patients defined by distinct risk factors age ≥65 years or smoking, and these differentiating risk factors accounted for the excess risk observed with tofacitinib versus TNFi. These findings can guide individualised benefit/risk assessment and clinical decision-making on treatment with tofacitinib.

Trial registration numbers: NCT02092467, NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661, NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612, NCT01877668, NCT01882439, NCT01976364.

Keywords: Antirheumatic Agents; Arthritis; Therapeutics; Tumor Necrosis Factor Inhibitors.

Figure 1

Risk of malignancies (excluding NMSC), MACE, MI, VTE and all-cause death with tofacitinib versus TNFi in ORAL Surveillance by (A) age (≥ or <65 years) or (B) history of smoking (current, past or never) or (C) composite of age and smoking (‘Age ≥65 years and Ever smoked’ or ‘Age <65 years or Never smoked’). HRs (95% CIs), shown on a logarithmic scale, are based on a simple Cox proportional hazard model comparing combined tofacitinib doses versus TNFi. Arrow heads indicate that CI extends beyond the graph axis. IRs express the number of patients with first events per 100 PY. IRs, n and PY are for combined tofacitinib doses. *Results previously reported in Ytterberg et al. †Results reported in Curtis et al. IR, incidence rate; MACE, major adverse cardiovascular events; n, number of evaluable patients; N, number of patients with events; NMSC, non-melanoma skin cancer; PY, patient-years; TNFi, tumour necrosis factor inhibitor; VTE, venous thromboembolism.

Figure 2

Risk of malignancies (excluding NMSC), MACE, MI, VTE and all-cause death with tofacitinib versus TNFi in ORAL Surveillance by subgroups of high-risk and low-risk patients. HRs (95% CIs), shown on a logarithmic scale, are based on a simple Cox proportional hazard model comparing combined tofacitinib doses versus TNFi. Arrow heads indicate that CI extends beyond the graph axis. IRs express the number of patients with first events per 100 PY. Treatment-by-risk interaction p values were calculated based on IR differences (two-sided, normal approximation of difference in IR). NNH (PY) should be interpreted as the number of patient-years of exposure to tofacitinib required to have one additional event versus TNFi. All data are for combined tofacitinib doses. *Results reported in Curtis et al. IR, incidence rate; MACE, major adverse cardiovascular events; N, number of evaluable patients; n, number of patients with events; NMSC, non-melanoma skin cancer; NNH, numbers needed to harm; PY, patient-years; TNFi, tumour necrosis factor inhibitor; VTE, venous thromboembolism.

Figure 3

Cumulative probability of patients with malignancies (excluding NMSC), MACE, MI, VTE and all-cause death in ORAL Surveillance overall population and by subgroups of high-risk and low-risk patients. Overall population received tofacitinib 5 mg or 10 mg two times a day (N=2911) or TNFi (N=1451). High-risk patients were ≥65 years of age or ever smoker (tofacitinib, N=1895; TNFi, N=926). Low-risk patients were <65 years of age and never smoker (tofacitinib, N=1016; TNFi, N=525). Cumulative probabilities of events were calculated based on Kaplan-Meier estimates. Cumulative probability plots for malignancies (excluding NMSC) and MACE in overall population have been reported in Ytterberg et al and are included for reference. MACE, major adverse cardiovascular events; MI, myocardial infarction; NMSC, non-melanoma skin cancer; TNFi, tumour necrosis factor inhibitor; VTE, venous thromboembolism.

Figure 4

Risk of malignancies (excluding NMSC), MACE, MI, VTE and all-cause death in low-risk populations in ORAL Surveillance and tofacitinib clinical development programmes. Low-risk patients were <65 years of age and never smoker. Horizontal dotted line represents IR in low-risk patients treated with tofacitinib in ORAL Surveillance. IRs express the number of patients with first events per 100 PY. All data are for combined tofacitinib doses. *Excluding ORAL Surveillance. Data from ORAL Surveillance overall populations have previously been published and are included for reference; malignancies (excluding NMSC) and MACE (Ytterberg et al 1), MI (Charles-Schoeman et al 5). Also, previously published are data from the tofacitinib RA and PsA development programmes on MACE (Burmester et al 25) and VTE (Mease et al 26). IR, incidence rate; MACE, major adverse cardiovascular events; MI, myocardial infarction; N, number of evaluable patients; n, number of patients with events; NMSC, non-melanoma skin cancer; PsA, psoriatic arthritis; PY, patient-years; RA, rheumatoid arthritis; TNFi, tumour necrosis factor inhibitor; UC, ulcerative colitis; VTE, venous thromboembolism.