Upadacitinib as monotherapy in patients with rheumatoid arthritis and prior inadequate response to methotrexate: results at 260 weeks from the SELECT-MONOTHERAPY randomised study

Abstract

Introduction: The phase III SELECT-MONOTHERAPY trial (NCT02706951) demonstrated the safety and efficacy of upadacitinib (UPA) monotherapy through 84 weeks in patients with rheumatoid arthritis who responded inadequately to methotrexate. Here we report week 260 results.

Methods: Patients were randomised to continue methotrexate or UPA 15 mg (UPA15) or 30 mg (UPA30) monotherapy for 14 weeks. From week 14, patients continuing methotrexate switched to UPA15 or UPA30 per prespecified assignment; patients randomised to UPA continued treatment. Following a protocol amendment, all cohorts switched to open-label UPA15. Safety was summarised using exposure-adjusted event and incidence rates. Efficacy was reported as observed and using non-responder imputation (NRI).

Results: Of 648 randomised patients, 598 entered the long-term extension. Of these, 249 (41.6%) discontinued study drug by week 260 primarily due to adverse events (14.5%), consent withdrawal (9.9%), lost to follow-up (3.3%), lack of efficacy (2.2%), COVID-19 (0.7%) or other reasons (11.0%). Rates of herpes zoster, non-melanoma skin cancer, hepatic disorder, neutropenia, lymphopenia and creatine kinase elevation were higher with UPA30 versus UPA15. Long-term UPA safety data were consistent with the established UPA safety profile. Based on NRI, >39% of patients treated continuously with UPA achieved low disease activity per Clinical Disease Activity Index ≤10 (UPA15, n=93/217; UPA30, n=91/215) and 28-joint Disease Activity Score using C reactive protein ≤3.2 (UPA15, n=90/217; UPA30, n=94/215) at week 260. Efficacy was similar among patients switching from methotrexate to UPA.

Conclusion: No new safety risks were identified with long-term UPA treatment. UPA monotherapy was efficacious in treating rheumatoid arthritis through week 260.

Trial registration number: NCT02706951.

Keywords: Arthritis, Rheumatoid; Methotrexate; Pain; Patient Reported Outcome Measures; Therapeutics.

Figure 1. Patient disposition. *The primary reason is shown. AE, adverse event; LTE, long-term extension; MTX, methotrexate; UPA, upadacitinib.

Figure 2. AEs of special interest through week 260 (exposure-adjusted event rate). *For patients who switched from UPA 30 mg to UPA 15 mg, AEs and exposure to UPA 30 mg were censored at the time of dose switch. Subsequent AEs and exposure starting from the day of the first UPA 15 mg dose are summarised as a separate group (ie, UPA 15 mg switched from UPA 30 mg). †Malignancy (excluding NMSC) included 9 events of breast cancer; other types of malignancy (excluding NMSC) were reported in ≤2 patients for each UPA group. ‡MACE was defined as CV death, non-fatal MI and non-fatal stroke and included 4 CV deaths (UPA 15 mg, 3 deaths; UPA 30 mg, 1 death), 2 non-fatal MIs (UPA 30 mg) and 5 non-fatal strokes (UPA 15 mg, 2 deaths; UPA 30 mg, 3 deaths). §VTE was defined as DVT and PE. All events were non-fatal: 5 DVT (UPA 15 mg, 4; UPA 15 mg switched from UPA 30 mg, 1), 5 PE (UPA 15 mg, 3; UPA 30 mg, 2) and 1 concurrent DVT and PE (UPA 30 mg). ¶A total of 16 deaths occurred (5 related to COVID-19 infection): 10 treatment-emergent deaths (UPA 15 mg, 0.4 E/100 PY: 1 haemorrhagic stroke, 1 COVID-19 pneumonia, 1 sudden cardiac death, 1 sudden death; UPA 30 mg, 0.5 E/100 PY: 2 myocardial infarctions, 1 cardiorespiratory arrest, 1 general physical health deterioration; UPA 15 mg switched from UPA 30 mg, 0.7 E/100 PY: 1 cardiac arrest, 1 COVID-19 infection) and 6 non-treatment-emergent deaths (UPA 15 mg, 0.3 E/100 PY: 1 congestive cardiomyopathy, 1 COVID-19 pneumonia, 1 squamous cell carcinoma of the lung; UPA 30 mg, 0.1 E/100 PY: 1 cardiorespiratory arrest; UPA 15 mg switched from UPA 30 mg, 0.7 E/100 PY: 1 COVID-19 pneumonia, 1 sepsis related to COVID-19 infection) (adapted from Smolen et al [28]). AE, adverse event; CK, creatine kinase; CV, cardiovascular; DVT, deep vein thrombosis; E/100 PY, events per 100 patient-years; excl, excluding; MACE, major adverse cardiovascular event; MI, myocardial infarction; NMSC, non-melanoma skin cancer; PE, pulmonary embolism; QD, once per day; TB, tuberculosis; UPA, upadacitinib; VTE, venous thromboembolism.

Figure 3. Proportion of patients achieving (A) ACR20, (B) ACR50, and (C) ACR70 responses through week 260 (NRI). Raw data are provided in the online supplemental material. ACR20/50/70, ≥20%/≥50%/≥70% improvement in American College of Rheumatology criteria; MTX, methotrexate; NRI, non-responder imputation; QD, once per day; UPA, upadacitinib.

Figure 4. Proportion of patients achieving CDAI and SDAI disease activity states or remission through week 260 (NRI): (A) CDAI ≤10.0, (B) CDAI ≤2.8, (C) SDAI ≤11.0, (D) SDAI ≤3.3, (E) ACR/EULAR Boolean remission 1.0, and (F) ACR/EULAR Boolean Remission 2.0. Raw data are provided in the online supplemental material. ACR/EULAR, American College of Rheumatology/European Alliance of Associations for Rheumatology; CDAI, Clinical Disease Activity Index; MTX, methotrexate; NRI, non-responder imputation; QD, once per day; SDAI, Simple Disease Activity Index; UPA, upadacitinib.

Figure 5. Proportion of patients achieving DAS28(CRP) disease activity states through week 260 (NRI): (A) DAS28(CRP) ≤3.2 and (B) DAS28(CRP) ≤2.6. Raw data are provided in the online supplemental material. DAS28(CRP), 28-joint Disease Activity Score using C reactive protein; MTX, methotrexate; NRI, non-responder imputation; QD, once per day; UPA, upadacitinib.

Figure 6. Change from baseline in pain and physical function, and proportion of patients achieving MCID in HAQ-DI through week 260: (A) Pain (100 mm VAS; MMRM), (B) HAQ-DI (MMRM), and (C) MCID in HAQ-DI (NRI).*n=107 for MMRM analyses. †n=216 for MMRM analyses. ‡n=214 for MMRM analyses. Raw data are provided in the online supplemental material. HAQ-DI, Health Assessment Questionnaire-Disability Index; MCID, minimal clinically important difference; MMRM, mixed-effects model for repeated measures; MTX, methotrexate; NRI, non-responder imputation; QD, once per day; UPA, upadacitinib; VAS, visual analogue scale.