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Switching Between Janus Kinase Inhibitor Upadacitinib and Adalimumab Following Insufficient Response: Efficacy and Safety In Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218412 on 4 November 2020. Downloaded from Rheumatoid arthritis CLINICAL SCIENCE Switching between Janus kinase inhibitor upadacitinib and adalimumab following insufficient response: efficacy and safety in patients with rheumatoid arthritis Roy M Fleischmann ,1 Ricardo Blanco ,2 Stephen Hall,3 Glen T D Thomson,4 Filip E Van den Bosch,5,6 Cristiano Zerbini,7 Louis Bessette,8,9 Jeffrey Enejosa,10 Yihan Li,10 Yanna Song,10 Ryan DeMasi,10 In- Ho Song10 Handling editor Josef S ABSTRACT Key messages Smolen Objectives To evaluate efficacy and safety of immediate switch from upadacitinib to adalimumab, or ► Additional material is What is already known about this subject? published online only. To view, vice versa, in patients with rheumatoid arthritis with non- ► In patients with rheumatoid arthritis, a treat- please visit the journal online response or incomplete- response to the initial therapy. to- target strategy is recommended, in which (http:// dx. doi. org/ 10. 1136/ Methods SELECT-COMP ARE randomised patients to therapy is optimised every 3–6 months until annrheumdis- 2020- 218412). upadacitinib 15 mg once daily (n=651), placebo (n=651) remission, or low disease activity, is achieved. or adalimumab 40 mg every other week (n=327). A For numbered affiliations see Recent treatment recommendations suggest the treat-to- target study design was implemented, with end of article. addition of a biological or targeted- synthetic blinded rescue occurring prior to week 26 for patients disease- modifying antirheumatic drug in Correspondence to who did not achieve at least 20% improvement in both patients who do not achieve treatment goals, Dr Roy M Fleischmann, The tender and swollen joint counts (’non-responders’) and and switches between mechanisms of action University of Texas at week 26 based on Clinical Disease Activity Index Southwestern Medical Center, occur commonly in clinical practice. (CDAI) >10 (’incomplete- responders’) without washout. Dallas, TX 75231, USA; The SELECT- COMPARE study followed treat- to- Results A total of 39% (252/651) and 49% (159/327) ► rfleischmann@ arthdocs. com target principles. Patients were blindly switched of patients originally randomised to upadacitinib and from upadacitinib, a Janus kinase (JAK) Received 23 June 2020 adalimumab were rescued to the alternate therapy. In Revised 15 October 2020 inhibitor, to adalimumab, a tumour necrosis both switch groups (adalimumab to upadacitinib and Accepted 17 October 2020 factor (TNF) inhibitor, and vice versa following vice versa) and in non- responders and incomplete- insufficient response to the initial therapy. responders, improvements in disease activity were Previously reported high- level efficacy data observed at 3 and 6 months following rescue. CDAI low from this study showed that patients switched disease activity was achieved by 36% and 47% of non- to either agent experienced improved response responders and 45% and 58% of incomplete-responders http://ard.bmj.com/ following switch. switched to adalimumab and upadacitinib, respectively, 6 months following switch. Overall, approximately 5% What does this study add? of rescued patients experienced worsening in disease This observation from SELECT- COMPARE activity at 6 months postswitch. The frequency of adverse ► provides clinically relevant and detailed switch events was similar between switch groups. efficacy data in the subgroups of patients Conclusions These observations support a treat-to- who switched due to initial non-response or on September 24, 2021 by guest. Protected copyright. target strategy, in which patients who fail to respond incomplete-response . Following a blinded initially (or do not achieve sufficient response) are switch in mechanism of action, more patients switched to a therapy with an alternate mechanism were able to achieve treatment goals of of action and experience improved outcomes. No new remission and low disease activity, in both safety findings were observed despite immediate switch the non-responder and incomplete-responder without washout. groups. This study also reports minimal risk of flare following a switch in treatment. ► Additionally, not previously reported, unique © Author(s) (or their and important details on the safety of an employer(s)) 2020. Re- use INTRODUCTION immediate switch from a JAK inhibitor to a TNF permitted under CC BY- NC. No It is recommended that the rheumatoid arthritis commercial re- use. See rights inhibitor are also provided. This study revealed and permissions. Published (RA) treatment paradigm use a treat- to- target no new safety signals despite an immediate by BMJ. strategy in which therapy is optimised every 3–6 switch in mechanism of action without months until clinical remission, or at minimum, washout. To cite: Fleischmann RM, low disease activity (LDA) is achieved.1–5 For Blanco R, Hall S, et al. Ann Rheum Dis Epub ahead patients who do not achieve these goals with Against Rheumatism (EULAR) guidelines suggest of print: [please include Day conventional synthetic disease- modifying antirheu- the addition of a biological DMARD (bDMARD) Month Year]. doi:10.1136/ matic drugs (csDMARDs), both American College or a targeted synthetic DMARD (tsDMARD).2 3 If annrheumdis-2020-218412 of Rheumatology (ACR) and European League patients continue to exhibit unacceptable disease Fleischmann RM, et al. Ann Rheum Dis 2020;0:1–8. doi:10.1136/annrheumdis-2020-218412 1 Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218412 on 4 November 2020. Downloaded from Rheumatoid arthritis adalimumab was administered 2 weeks prior to starting upad- Key messages acitinib; (2) switching to adalimumab: adalimumab was injected 1 day after the last dose of upadacitinib. Each patient could How might this impact on clinical practice or future only be switched once. Further details on the blinded rescue are developments? provided in the online supplemental text. The observations of Findings here indicate that an immediate switch in ► efficacy and safety of patients switching between upadacitinib mechanism of action (from a JAK inhibitor to a TNF inhibitor and adalimumab (and vice versa) are presented here. and vice versa) following treat- to- target principles is feasible The study was conducted in accordance with the International with minimal risk of flare regardless of whether patients Conference on Harmonization guidelines, applicable regulations are switched due to non- response or incomplete- response and the Declaration of Helsinki. All patients provided written without an increase in clinically meaningful adverse events. informed consent. Assessments activity, a switch to a different bDMARD, or to a tsDMARD, Efficacy was evaluated up to 6 months (±2 weeks) postswitch is recommended. Although therapeutic options continue to using validated outcome measures including ACR response increase, many patients with RA do not achieve stringent treat- criteria (ACR20/50/70 (improvement of ≥20%, 50% and 70% ment goals. Therefore, data on the effectiveness and safety of in ACR criteria)); CDAI LDA (≤10) and remission (≤2.8); switching between different mechanisms of action (MoAs) have 28- joint Disease Activity Score based on C- reactive protein become increasingly important. Results from controlled trials (DAS28(CRP))≤3.2 and<2.6 and change from baseline in suggest that patients with insufficient response to a bDMARD Health Assessment Questionnaire- Disability Index (HAQ- DI), may respond to a Janus kinase inhibitor (JAKi).6–9 In contrast, patient assessment of pain (0–100 mm visual analogue scale), there is limited evidence regarding the efficacy and safety of TJC68, SJC66, Patient’s Global Assessment of Disease Activity switching patients to a tumour necrosis factor inhibitor (TNFi) (PtGA), Physician’s Global Disease Activity (PhGA) and hsCRP. following insufficient response to a JAKi.10 Response criteria and change from baseline were evaluated as Upadacitinib, an oral JAKi, has been studied across various change from original baseline value at randomisation. patient populations in RA, including methotrexate (MTX)- Disease worsening after switch was determined based on inadequate responders in SELECT- COMPARE.11–13 The most DAS28(CRP) increase >0.6 or >1.2 from rescue, evaluated at 3 recent EULAR recommendations for RA treatment address the and 6 months following rescue.14 shifting therapeutic paradigm.3 This study employed a unique Treatment- emergent adverse events (TEAEs) were evaluated rescue strategy, permitting blinded rescue from upadacitinib to 0–3 months postswitch to assess the safety of an immediate adalimumab, and vice versa, in the subgroup of patients who did switch and, separately, 4–6 months following switch.10 11 To not achieve treatment targets with their initial therapy. Although better understand the safety preswitch and postswitch, TEAEs preliminary data on an immediate switch from either a TNFi to a were evaluated for the same patients both before and after JAKi or vice versa have been reported,10 11 the safety of an imme- switch. In this analysis, a matching follow- up period was used to diate switch and the efficacy of a switch from a JAKi to a TNFi ensure a consistent evaluation across patients who were rescued in patients who either do not have an initial response or experi- at different time points. Finally, TEAEs were also evaluated in ence an insufficient response have not been fully described. The patients who switched and those who remained on continuous present
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