Baseline Corticosteroid Research Articles

Etrasimod Corticosteroid-Free Efficacy, Impact of Concomitant Corticosteroids on Efficacy and Safety, and Corticosteroid-Sparing Effect in UC: Analyses of the ELEVATE UC Clinical Programme

Abstract Background Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). This post hoc analysis reports efficacy and safety by baseline corticosteroid use in the ELEVATE UC clinical programme. Methods Patients with UC received etrasimod 2 mg or placebo for up to 52 weeks. Corticosteroid use was permitted; tapering was recommended from Week 12. Efficacy was assessed at Weeks 12 and 52 in ELEVATE UC 52, and Week 12 in ELEVATE UC 12, in patients in the corticosteroid (CS) and no-CS subgroups. CS-free efficacy at Week 52 was assessed in patients with baseline CS use. Results In ELEVATE UC 52 and ELEVATE UC 12, 93/289 (32.2%) and 65/238 (27.3%) patients receiving etrasimod and 42/144 (29.2%) and 34/116 (29.3%) patients receiving placebo, respectively, had concomitant CS use at baseline. In the CS and no-CS subgroups, higher proportions of patients who received etrasimod vs placebo achieved clinical remission (p < 0.05) in ELEVATE UC 52 at Weeks 12 (CS: 32.3% vs 16.7%; no-CS: 26.0% vs 4.9%) and 52 (CS: 31.2% vs 9.5%; no-CS: 33.2% vs 6.9%). In the CS subgroup, significantly more patients receiving etrasimod than placebo achieved CS-free clinical remission at Week 52 (31.2% vs 7.1%). No increases in infection rates were observed with baseline CS use. Safety was comparable between subgroups. Conclusions Etrasimod demonstrated efficacy in inducing and maintaining remission in both subgroups. CSfree remission was achieved in the CS subgroup. Safety was consistent, with no increase in infections.

Impact of baseline steroids on the efficacy of neoadjuvant immunochemotherapy in locally advanced esophageal squamous cell carcinoma.

Immunochemotherapy involving the combination of programmed cell death 1/programmed cell death ligand 1 inhibitors with chemotherapy has advanced the treatment of locally advanced esophageal squamous cell carcinoma (ESCC). The use of corticosteroids as pretreatment might reduce immunotherapy efficacy. To investigate the impact of baseline corticosteroid use on neoadjuvant immunochemotherapy (nIC) outcomes in locally advanced ESCC patients. Patients with locally advanced ESCC who received nIC at Sun Yat-sen University Cancer Center and the Third Affiliated Hospital of Sun Yat-sen University were included. Patients were divided into dexamethasone and antihistamine groups on the basis of the administered pretreatment. Antiallergic efficacy and safety were evaluated, as well as its impact on short-term efficacy [complete pathological response (pCR), major pathological response (MPR)] and long-term efficacy [overall survival (OS), progression-free survival (PFS)] of nIC. From September 2019 to September 2023, 142 patients were analyzed. No severe treatment-related adverse events or deaths were observed. Allergy occurrence was greater in the antihistamine group (P = 0.014). Short-term efficacy was not significantly different: The pCR rates were 29.9% and 40.0%, and the MPR rates were 57.9% and 65.7% in the dexamethasone and antihistamine groups, respectively. The long-term efficacy was not significantly different: The 2 years OS rates were 95.2% and 93.5%, and the 2 years PFS rates were 90.3% and 87.8%. Subgroup analysis revealed no difference in OS between the 20 mg dexamethasone group and the < 20 mg dexamethasone group, but PFS was significantly greater in the 20 mg dexamethasone group (93.9% vs 56.4%, P = 0.001). Dexamethasone or antihistamines can be used before nIC in locally advanced ESCC without affecting short- or long-term efficacy. Administering 20 mg dexamethasone before nIC may improve PFS in ESCC.

Corticosteroid Prescribing Patterns in the Emergency Department for Acute COPD Exacerbations: A Retrospective Analysis Following an Educational Intervention.

COPD is a progressive lung disease with marked airflow limitation. It has a large global prevalence and is managed with antibiotics, bronchodilators, and corticosteroids. Despite the prevalence, corticosteroid prescribing regimens differ widely amongst providers. This study aims to evaluate baseline corticosteroid prescribing patterns, the ability to change corticosteroid prescribing patterns with the utilization of an educational initiative, and to evaluate the effect of corticosteroid dose on length of stay, 30-day hospital readmission, mortality, and total hospital insulin dosing. This study was conducted via a retrospective observational study. Providers at a single institution answered a baseline questionnaire on COPD corticosteroid prescribing patterns and subsequently received an educational presentation regarding evidence-based corticosteroid recommendations. Data were then retrospectively obtained and analyzed evaluating corticosteroid prescribing patterns both pre- and post-educational intervention. Data were analyzed using IBM SPSS Version 25. The provider survey revealed that most (95.3%) administered 125 mg of methylprednisolone to patients treated for AECOPD. The most common reason a particular dose of corticosteroid was administered was due to previous teaching or practice patterns. The mean initial steroid dose of methylprednisolone decreased following the educational initiative from 114.24 mg to 72.8 mg (p < 0.01). This corresponded to a 69% (n=41) decrease of providers using 125 mg methylprednisolone (p < 0.01), and increased prescribing of 62.5 mg methylprednisolone by 42.6% (n=66). The mean LOS following hospital admission for AECOPD in the pre-intervention group was 5.80 days, while the mean LOS following the targeted educational intervention decreased to 4.82 days (p = 0.01). The implementation of an educational intervention may change provider corticosteroid prescribing patterns. Additionally, lower corticosteroid dose in the Emergency Department may decrease patient length of stay. Keywords: Corticosteroid, COPD, LOS, recommendations, steroid.

Machine learning prediction and explanatory models of serious infections in patients with rheumatoid arthritis treated with tofacitinib

BackgroundPatients with rheumatoid arthritis (RA) have an increased risk of developing serious infections (SIs) vs. individuals without RA; efforts to predict SIs in this patient group are ongoing. We assessed the ability of different machine learning modeling approaches to predict SIs using baseline data from the tofacitinib RA clinical trials program.MethodsThis analysis included data from 19 clinical trials (phase 2, n = 10; phase 3, n = 6; phase 3b/4, n = 3). Patients with RA receiving tofacitinib 5 or 10 mg twice daily (BID) were included in the analysis; patients receiving tofacitinib 11 mg once daily were considered as tofacitinib 5 mg BID. All available patient-level baseline variables were extracted. Statistical and machine learning methods (logistic regression, support vector machines with linear kernel, random forest, extreme gradient boosting trees, and boosted trees) were implemented to assess the association of baseline variables with SI (logistic regression only), and to predict SI using selected baseline variables using 5-fold cross-validation. Missing values were handled individually per prediction model.ResultsA total of 8404 patients with RA treated with tofacitinib were eligible for inclusion (15,310 patient-years of total follow-up) of which 473 patients reported SIs. Amongst other baseline factors, age, previous infection, and corticosteroid use were significantly associated with SI. When applying prediction modeling for SI across data from all studies, the area under the receiver operating characteristic (AUROC) curve ranged from 0.656 to 0.739. AUROC values ranged from 0.599 to 0.730 in data from phase 3 and 3b/4 studies, and from 0.563 to 0.643 in data from ORAL Surveillance only.ConclusionsBaseline factors associated with SIs in the tofacitinib RA clinical trial program were similar to established SI risk factors associated with advanced treatments for RA. Furthermore, while model performance in predicting SI was similar to other published models, this did not meet the threshold for accurate prediction (AUROC > 0.85). Thus, predicting the occurrence of SIs at baseline remains challenging and may be complicated by the changing disease course of RA over time. Inclusion of other patient-associated and healthcare delivery-related factors and harmonization of the duration of studies included in the models may be required to improve prediction.Trial registrationClinicalTrials.gov: NCT00147498; NCT00413660; NCT00550446; NCT00603512; NCT00687193; NCT01164579; NCT00976599; NCT01059864; NCT01359150; NCT02147587; NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055; NCT02831855; NCT02092467.

Efficacy and safety of risankizumab by baseline corticosteroid use and achievement of corticosteroid-free clinical and endoscopic outcomes in patients with moderately to severely active Crohn's disease.

Risankizumab is efficacious and well tolerated in adults with moderately to severely active Crohn's disease (CD). To evaluate the corticosteroid-sparing effect of risankizumab in CD. During the 12-week induction period, patients maintained stable baseline corticosteroid doses, up to 20 mg/day prednisone or equivalent. At week 0 of maintenance, a mandatory corticosteroid taper was started. This post hoc analysis evaluated corticosteroid-free clinical and endoscopic outcomes at week 52 of maintenance; safety was also assessed. Of 889 patients randomised to induction with risankizumab 600 mg or placebo, 285 (32.1%) were taking baseline concomitant corticosteroids. Week 12 clinical remission and endoscopic response rates were greater for risankizumab 600 mg versus placebo, regardless of concomitant corticosteroid use. At week 52, 66.7%, 50.0% and 41.2% of patients taking risankizumab 180 mg, risankizumab 360 mg and (withdrawal) placebo, respectively, discontinued corticosteroids. Week 52 corticosteroid-free clinical remission per stool frequency/abdominal pain score (risankizumab 180 mg [42.7%] or 360 mg [49.8%]; [withdrawal] placebo [39.0%]), corticosteroid-free clinical remission per Crohn's Disease Activity Index (risankizumab 180 mg [51.0%] or 360 mg [49.5%]; [withdrawal] placebo [40.2%]), and corticosteroid-free endoscopic response (risankizumab 180 mg [44.6%] or 360 mg [44.7%]; [withdrawal] placebo [20.7%]) rates were greater for risankizumab than placebo. Adverse event rates were generally similar,regardless of baseline corticosteroid use. Efficacy of risankizumab 600 mg induction therapy was independent of concomitant corticosteroid use. Risankizumab 180 and 360 mg maintenance therapy yielded high rates of corticosteroid-free clinical and endoscopic outcomes at week 52.

What role do socioeconomic and clinical factors play in disease activity states in rheumatoid arthritis? Data from a large UK early inflammatory arthritis audit

BackgroundPersistently active rheumatoid arthritis (pactiveRA) may be due to the interplay between biological and non-biological factors. The role of socioeconomic factors remains unclear.ObjectivesTo explore which biological and non-biological factors associate...

Adaptive steroid tapering impedes corticosteroid-free remissions compared to forced tapering in clinical trials of ulcerative colitis.

It is unclear if steroid tapering protocols can impact clinical trial outcomes in ulcerative colitis (UC), particularly fixed versus adaptive steroid tapering. Fixed steroid tapering involves incremental dose decreases at prespecified intervals and adaptive steroid tapering utilizes investigator discretion as determined by the patient's response. In this post-hoc analysis from six clinical trials of UC (VARSITY, ACT 1, PURSUIT, GEMINI1, OCTAVE and ULTRA2), responders to induction therapy with baseline corticosteroid use were considered as the primary population of interest. Adjustments were made to account for treat-through versus re-randomization designs and multivariate regression was performed to account for other potential confounding variables. The primary outcome was corticosteroid-free clinical remission (CR) at one-year and secondary outcomes were CR and endoscopic improvement. There was a total of 861 patients who had achieved clinical response after induction and were using corticosteroids. Within multivariate analysis, patients using adaptive steroid tapering regimens were less likely to achieve corticosteroid-free CR at one year (odds ratio [OR] 0.66 [95% CI 0.48-0.92], p=0.015) but had increased odds for achieving CR at one year (OR 1.9 [95% CI 1.43-2.52], p<0.001). The steroid tapering regimen was not associated with achievement of endoscopic improvement at one year. Among patients with UC on corticosteroids in clinical trials, patients using adaptive steroid weaning regimens were less likely to achieve corticosteroid-free CR at one year but more likely to achieve CR at one year. Consideration should be given to implementing mandatory fixed steroid weaning protocols in future clinical trials of UC.

Relationships between Spatial Biology and Physiological Ecology in the Gopher Tortoise, Gopherus polyphemus.

AbstractThe overlap between spatial and physiological ecology is generally understudied, yet both fields are fundamentally related in assessing how individuals balance limited resources. Herein, we quantified the relationships between spatial ecology using two parameters of home range (annual home range area and number of burrows used in 1 yr) and four measures of physiology that integrate stress and immunity (baseline plasma corticosterone [CORT] concentration, plasma lactate concentration, heterophil-to-lymphocyte [H∶L] ratio, and bactericidal ability [BA]) in a wild free-ranging population of the gopher tortoise (Gopherus polyphemus) to test the hypothesis that space usage is correlated with physiological state. We also used structural equation models (SEMs) to test for causative relationships between the spatial and physiological parameters. We predicted that larger home ranges would be negatively correlated with traditional biomarkers of stress and positively correlated with immunity, consistent with our hypothesis that home ranges are determined based on individual condition. Males had larger home ranges, used more burrows, and had higher baseline CORT than females. We found significant negative correlations between lactate and home range (, , ). CORT was negatively correlated with the number of burrows used in both sexes (, , , adjusted ). No correlations were observed between space use and BA or, notably, H∶L ratio. SEMs suggested that variation in the number of burrows used was a result of variation in baseline CORT. The lack of a relationship between H∶L ratio and home range suggests that home range differences are not associated with differences in chronic stress, despite the pattern between baseline CORT and number of burrows used. Instead, this study indicates that animals balance trade-offs in energetics, likely by way of baseline corticosteroid, in such a way as to maintain function across continuously variable home range strategies.

P689 Adaptive steroid tapering impedes corticosteroid-free remissions compared to forced tapering in UC clinical trials

Abstract Background Protocols for managing steroids in clinical trials of ulcerative colitis (UC) vary. Most trials mandate steroid tapering at the beginning of maintenance phase. Adaptive steroid tapering allows for some discretion on whether to taper steroids for a patient. It remains unclear what impact steroid tapering protocols have on trial outcomes. Methods This post-hoc analysis from many clinical trials of advanced therapies in UC (VARSITY, ACT 1/2, PURSUIT, GEMINI1, OCTAVE and ULTRA2) was carried out under protocols with Vivli (00007656) and YODA (20224882). Responders to induction therapy with baseline corticosteroid use were considered as the primary population of interest. Adjustments were made to account for re-randomization designs and treatment exposure. Univariate analyses were conducted to identify baseline variables that had an association with the primary outcome of interest, one-year corticosteroid-free clinical remission (CR). All covariates with a significant univariate association (p &amp;lt; 0.05) were considered for inclusion in the multivariate model. Logistic regression was used to assess the impact of steroid-weaning regimen on the outcome of interest. Secondary outcome of interest was one-year CR. Results There was a total of 861 patients from the seven included trials who had achieved clinical response after induction and were using corticosteroids. Within multivariate analysis, patients using adaptive steroid weaning regimens were less likely to achieve one year corticosteroid-free CR (odds ratio (OR) 0.66 (95% CI 0.48-0.92), p=0.015). Patients with higher partial Mayo scores were also less likely to achieve one year corticosteroid-free CR (OR 0.88 (95% 0.8-0.97), p=0.012). Other variables found significant on univariate analysis were no longer significant once considered within the multivariate model (smoking, race, albumin, endoscopic Mayo score). For the secondary outcome of one year CR, patients using adaptive steroid weaning regimens had increased odds for achieving one year CR as compared to those using fixed regimens (OR 1.9 (95% 1.43-2.52), p&amp;lt;0.001). Several other variables were also found to have an association with one year CR within the multivariate model (Table 1). Conclusion Among patients with UC on corticosteroids at the time of study enrolment, adaptive steroid weaning regimens were less likely to achieve one-year corticosteroid-free CR but more likely to achieve one-year CR. This may help explain the findings within the VARSITY study, where patients treated with vedolizumab had increased odds for one-year CR but were less likely to achieve one-year corticosteroid-free CR. Consideration should be given to implementing mandatory steroid weaning protocols in future clinical trials of UC.

P1063 Comparison of all paediatric patients and young adults with Crohn’s Disease treated with ustekinumab in the REALITI Real-World Evidence Effectiveness Study

Abstract Background Treatment of paediatric patients (pts) with Crohn’s disease (CD) can offer some challenges to providers. There is an urgent need to inform prescribers about paediatric efficacy, safety, and dosing. REALITI evaluated the effectiveness and safety of ustekinumab (UST) routine clinical care in paediatric pts (age 2 to &amp;lt;18) regardless of disease severity or baseline corticosteroid use. Reference data are shown for young adults (age 18 to 25) with CD, for whom UST is approved. Data were obtained from the ImproveCareNow (ICN) Registry. Methods Data from pts from ICN with CD initiating treatment with UST between 10 January 2010 and 29 February 2020 were evaluated. A supplemental, retrospective chart review collected data not in ICN. The primary endpoint was clinical remission (Short Paediatric CD Activity Index [sPCDAI] score ≤10) at Week (Wk) 52. Data were summarized descriptively, and the proportion of pts achieving clinical remission and associated 2-sided 95% confidence intervals (CI) were calculated along with rates of inflammatory bowel disease (IBD)-related hospitalization and surgeries and serious/opportunistic infections. Results Overall, 479 pts in ICN with CD were treated with UST. We report an analysis of paediatric pts (n=348) compared to young adults (n=131). Most paediatric pts (98.9%) and young adults (95.4%) had received prior biologic therapy, with approximately half (47.1% and 50.4%, respectively) receiving corticosteroids at baseline. Slightly higher proportions of pts had moderate to severe disease (sPCDAI ≥30) among paediatric pts (49.7%) vs young adults (44.8%). Clinical remission at Wk52 was achieved in 30.2% of paediatric pts (105/348; 95% CI: [25.6%, 35.2%]) vs 28.2% of young adults (37/131; 95% CI: [21.2%, 36.5%]) (Figure 1A). Clinical remission rates decreased slightly over time from Wk 20-52 (Figure 1B); discontinuation rates through WK 52 remained low and were similar between groups (21.0%, 22.9%, respectively). Overall, 31.9% of paediatric pts and 19.8% of young adults had IBD-related hospitalizations; IBD-related surgery was reported in 16.1% and 9.2% of pts, respectively. Serious infections occurred in 7.5% of paediatric pts and 3.8% of young adults. Rates of opportunistic infections were low (1.4%, 0%, respectively). No events of tuberculosis, malignancy, or anaphylaxis requiring UST discontinuation occurred. One death, deemed by investigators as unrelated to IBD or UST treatment, was reported among paediatric pts; no deaths were reported among young adults. Conclusion Using real-world data from the ICN Registry, the remission rates for using UST to treat CD were found to be generally comparable between paediatric pts and young adults. No new safety signals were identified.

Contact allergy in atopic dermatitis: A prospective study on prevalence, incriminated allergens and clinical insights.

The relationship between atopic dermatitis (AD) and allergic contact dermatitis (ACD) is a matter of debate. The purpose of our study is to assess the frequency of ACD in patients with AD, the incriminated allergens and the potential risk factors. This is a prospective study, including cases of AD diagnosed based on Hanifin and Rajka's criteria. All patients were patch tested to the European baseline series and corticosteroid series. Ninety-three patients were included. Fifty-six patients (60.2%) had positive patch test results of which 71.4% were relevant. The most frequent allergens were: textile dye mix (24.7%), nickel (20.4%), cobalt (12.9%), isothiazolinone (8.6%), quanterium 15 (4.3%) and balsam of Peru (4.3%). Chromium, fragrance mix I, fragrance mix II and PTBP were positive in three cases (3.2%). Two cases of allergy to corticoids were identified. Facial involvement and duration of AD were significantly associated with contact sensitization (p = 0.04 and p = 0.005, respectively). Avoidance of relevant allergens resulted in a statistically significant decrease in SCORAD (p < 0.001). ACD remains an important co-morbidity of AD. We observed a high frequency of ACD to textile dyes, isothiazolinones and fragrances. Avoidance of relevant allergens has resulted in an improvement of patients' skin symptoms.

Impact of Baseline Corticosteroid Use on the Efficacy and Safety of Upadacitinib in Patients with Ulcerative Colitis: A Post Hoc Analysis of the Phase 3 Clinical Trial Programme.

This post hoc analysis assessed the efficacy and safety of upadacitinib in patients with moderately to severely active ulcerative colitis stratified by corticosteroid use from the ulcerative colitis Phase 3 clinical trial programme. Patients were randomised [1:2] to 8 weeks' placebo or upadacitinib 45 mg once daily; Week 8 responders were re-randomised [1:1:1] to 52 weeks' placebo or upadacitinib 15 or 30 mg daily. Corticosteroid dose was kept stable during induction but tapered according to a protocol-defined schedule [or investigator discretion] during maintenance Weeks 0-8. Efficacy outcomes and exposure-adjusted, treatment-emergent adverse event [TEAE] rates were assessed for induction and maintenance stratified by corticosteroid use at induction baseline. Overall, 377/988 [38%] patients were receiving corticosteroids at induction baseline [placebo, n = 133; upadacitinib 45 mg, n = 244] and 252 [37%] of the 681 clinical responders who entered maintenance were on corticosteroids at induction baseline [n = 84 for each treatment]. Similar proportions of patients receiving upadacitinib achieved clinical remission per Adapted Mayo Score with and without baseline corticosteroids at Weeks 8 and 52. The total proportion of patients re-initiating corticosteroids was higher with placebo [24/84;29%] vs upadacitinib 15 mg [16/81; 20%)] and 30 mg [11/81; 14%]. During induction, patients receiving corticosteroids at baseline had higher rates of TEAEs, serious TEAEs, and serious infections vs those not receiving corticosteroids; however, TEAE rates were similar during maintenance after corticosteroid withdrawal. Upadacitinib is an effective steroid-sparing treatment in patients with moderately to severely active ulcerative colitis. Clinicaltrials.gov identifiers: NCT02819635; NCT03653026.

Propensity Score Matching Analysis Comparing the Efficacy and Steroid Tapering Benefit of Extracorporeal Photopheresis to Best Available Therapy in Third-Line or Beyond Treatment for Chronic GvHD

Graft-versus host disease (GVHD) is one of the major limitations to allogeneic hematopoietic stem cell transplantation (HCT). Although corticosteroids with calcineurin inhibitors are established first line-therapy for chronic graft-versus-host disease (cGVHD), approximately one-half of cGVHD patients are refractory to corticosteroid therapy. The goal of the present study was to compare treatment outcomes of patients treated with extracorporeal photopheresis (ECP) and best available therapy (BAT) as third-line or beyond treatment for cGVHD. Using propensity score matching (PSM), treatment outcomes were compared between ECP-treated patients (n=74) and a historical cohort of cGVHD patients treated with BAT (n=132). By adjusting for unbalanced risk factors between the groups, including GVHD severity at the start of therapy, acute GVHD history, and baseline corticosteroid dose, 62 patients were balanced and selected for PSM. In the PSM cohort, the ECP group showed a 12-month failure-free survival (FFS) rate of 70.1% versus 32.5% in the BAT group (P < .0001; hazard rate [HR], .214), and 93.1% 12 months' overall survival (OS) rate of 93.1% versus 68.1% in the BAT group (P=.0249; HR, .3811); multivariate analysis confirmed ECP's superior FFS and OS compared with BAT. Generalized linear model analysis showed faster tapering of corticosteroids and higher rates of prednisone discontinuation in the ECP versus BAT PSM groups in the first 6 months. The ECP group also had a higher percentage of prednisone discontinuation, by 6% at month 0, by 14.9% at month 3, and by 22.5% at month 6. The current study demonstrates superior FFS, OS, and steroid tapering efficacy for ECP compared with BAT as third-line therapy or beyond in cGVHD patients.

A31 MIRIKIZUMAB IMPROVES QUALITY OF LIFE IN MODERATELY-TO-SEVERELY ACTIVE UC: IMPROVEMENT IN IBDQ SCORES IN PARTICIPANTS OF LUCENT-1 AND LUCENT-2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 3 TRIALS

A31 MIRIKIZUMAB IMPROVES QUALITY OF LIFE IN MODERATELY-TO-SEVERELY ACTIVE UC: IMPROVEMENT IN IBDQ SCORES IN PARTICIPANTS OF LUCENT-1 AND LUCENT-2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 3 TRIALS

Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies

Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis. In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4-6 vs 7-9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively. Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients; p<0·0001) and at week 52 (88 [32%] of 274 patients vs nine [7%] of 135 patients; p<0·0001). In ELEVATE UC 12, 55 (25%) of 222 patients in the etrasimod group had clinical remission compared with 17 (15%) of 112 patients in the placebo group at the end of the 12-week induction period (p=0·026). Adverse events were reported in 206 (71%) of 289 patients in the etrasimod group and 81 (56%) of 144 patients in the placebo group in ELEVATE UC 52 and 112 (47%) of 238 patients in the etrasimod group and 54 (47%) of 116 patients in the placebo group in ELEVATE UC 12. No deaths or malignancies were reported. Etrasimod was effective and well tolerated as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Etrasimod is a treatment option with a unique combination of attributes that might address the persistent unmet needs of patients with ulcerative colitis. Arena Pharmaceuticals.

Impact of Concomitant Corticosteroids on Tofacitinib Induction Efficacy and Infection Rates in Ulcerative Colitis

BackgroundTofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis.AimTo report efficacy and infection rates in patients receiving tofacitinib induction treatment, by baseline corticosteroid status.MethodsWe evaluated efficacy and safety data from OCTAVE Induction 1&2 in patients with moderately-to-severely active ulcerative colitis who received tofacitinib 10 mg twice daily or placebo for 8 weeks, based on induction baseline oral corticosteroid use (Corticosteroid-Yes/No) and dose (< 20/ ≥ 20 mg/day). Infections of interest included serious infections, herpes zoster (HZ), and adjudicated opportunistic infections (OIs).ResultsAt OCTAVE Induction 1&2 baseline, 478/1092 (43.8%) patients were receiving corticosteroids. Tofacitinib demonstrated significant induction efficacy versus placebo for both Corticosteroid-Yes and Corticosteroid-No. With adjustment for prior tumor necrosis factor inhibitor and immunosuppressant failure, there were no statistically significant differences in remission and clinical response rates for Corticosteroid-Yes versus Corticosteroid-No. Among tofacitinib-treated patients, HZ and OIs occurred more frequently in Corticosteroid-Yes versus Corticosteroid-No, regardless of dose (< 20 mg vs. ≥ 20 mg). Infection incidence rates (regardless of severity/seriousness) during tofacitinib induction were generally similar regardless of baseline corticosteroid use. The proportion of tofacitinib-treated patients with HZ was 0.2% for Corticosteroid-No versus 1.1% for Corticosteroid-Yes < 20 mg and 1.0% for Corticosteroid-Yes ≥ 20 mg. Two out of three patients had HZ OIs.ConclusionsTofacitinib induction efficacy (clinical response and remission) was similar in baseline corticosteroid subgroups. Infections of interest were rare; HZ and OIs occurred more frequently among those receiving tofacitinib and corticosteroids versus those receiving tofacitinib without corticosteroids.Trial Registrationhttp://www.clinicaltrials.gov (NCT01465763[21/10/2011]; NCT01458951[21/10/2011]).

Selected Articles from This Issue

Highlights| February 01 2023 Selected Articles from This Issue Author & Article Information Online ISSN: 1557-3265 Print ISSN: 1078-0432 ©2023 American Association for Cancer Research2023American Association for Cancer Research Clin Cancer Res (2023) 29 (3): 503. https://doi.org/10.1158/1078-0432.CCR-29-3-HI Related Content A commentary has been published: Clinical Features Associated with Outcomes and Biomarker Analysis of Dabrafenib plus Trametinib Treatment in Patients with BRAF-Mutant Melanoma Brain Metastases A commentary has been published: Safety and Efficacy of MEDI0457 plus Durvalumab in Patients with Human Papillomavirus–Associated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma A commentary has been published: A Phase II Window of Opportunity Study of Neoadjuvant PD-L1 versus PD-L1 plus CTLA-4 Blockade for Patients with Malignant Pleural Mesothelioma View more A commentary has been published: HER2 Copy Number and Resistance Mechanisms in Patients with HER2-positive Advanced Gastric Cancer Receiving Initial Trastuzumab-based Therapy in JACOB Trial View less Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record February 1 2023 Citation Selected Articles from This Issue. Clin Cancer Res 1 February 2023; 29 (3): 503. https://doi.org/10.1158/1078-0432.CCR-29-3-HI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search The study from Wilmott and colleagues aimed to identify baseline clinical features associated with the outcomes of patients enrolled in the COMBI-MB phase II study of dabrafenib and trametinib treatment in patients with V600 BRAF-mutant metastatic melanoma with melanoma brain metastases (MBM). Exploratory biomarker analysis also was conducted as part of the synergistic COMBI-BRV trial (BRV116521) to identify molecular and immunological changes associated with dabrafenib in MBM and extracranial (ECM) metastases. Corticosteroid treatment was associated with reduced ICRR and PFS in COMBI-MB, similar to results with immunotherapy for MBM. Baseline corticosteroid treatment is a key factor to consider in MBM patient management and clinical trial design/interpretation. Immune checkpoint blockade (ICB) with nivolumab and ipilimumab has become standard treatment for patients with unresectable malignant pleural mesothelioma (MPM). However, the impact of neoadjuvant ICB in MPM has not yet been evaluated. Lee and colleagues report the results of a randomized, phase II,... You do not currently have access to this content.

P649 Does serum triiodothyronine-to-thyroxine (T3/T4) ratio predict therapeutic outcome to anti-TNF therapies in biologic-naïve patients with active luminal Crohn’s disease?

Abstract Background Lower serum free triiodothyronine-to-thyroxine (fT3/fT4) ratio has been linked to non-response to treatment in a range of diseases, including in biologic-treated patients with IBD. We sought to assess whether baseline serum fT3/fT4 ratio predicted primary non-response (PNR) and non-remission to infliximab and adalimumab in patients with Crohn’s disease. Methods We included 997 adult participants from the Personalised Anti-TNF Therapy in Crohn’s Disease study (PANTS). Thyroid function tests, using the Roche Elecsys TSH immunoassay and T3 and T4 electrochemiluminescence assays, were measured on stored baseline samples (prior to biologic treatment). PNR, assessed at week 14, was defined as treatment failure (including IBD-related surgery), ongoing corticosteroid use, or both CRP failing to fall to ≤3 mg/L, or by 50% from baseline, and HBI failing to fall to ≤4, or by 3 points. Non-remission, assessed at week 54, was defined as either CRP of &amp;gt; 3mg/L or HBI of &amp;gt;4 points, ongoing corticosteroid therapy, or exit for treatment failure. Results Serum fT3, fT4 and TSH concentrations were similar in infliximab (n=549) and adalimumab treated (n=448) patients. Baseline median [IQR] fT3/fT4 ratios were lower in women than men (0.30 [0.27 - 0.34] vs 0.32 [0.28 - 0.36], p&amp;lt;0.001), in patients with more severe inflammatory disease, and in patients receiving corticosteroids (0.28 [0.25 - 0.33] vs 0.32 [0.29 - 0.36], p&amp;lt;0.001). Multivariable logistic regression analysis demonstrated that fT3/fT4 ratio was independently associated with PNR at week 14 (OR 0.51, 95% CI 0.31 – 0.85, p = 0.009), however when stratified by drug and adjusted for variables known to be associated with PNR, low fT3/fT4 ratio remained associated with PNR for adalimumab, but not infliximab. After excluding patients treated with corticosteroids at baseline, there was no difference in fT3/fT4 ratio in those who experienced PNR compared to those who did not (PNR: [128/630] 0.31 [0.28 – 0.35] vs no PNR: [502/630] 0.32 [0.29 – 0.36], p = 0.095). The optimal threshold to determine PNR was 0.31 (AUC 0.57 [95% CI 0.54 - 0.61] sensitivity 0.62 [95% CI 0.41 - 0.74], specificity 0.53 [95% CI 0.42 - 0.73]). No association was seen for baseline fT3/fT4 ratio and non-remission or changes in faecal calprotectin concentrations at week 54. Conclusion Lower baseline serum fT3/fT4 ratio was independently associated with female sex, higher inflammatory burden at baseline, and baseline corticosteroid use, and predicted PNR to anti-TNF therapy at week 14, but not non-remission or change in faecal calprotectin concentrations at week 54. Overall, however, the diagnostic accuracy of baseline fT3/fT4 ratio to predict PNR to anti-TNF treatment was modest, limiting its clinical utility.

DOP42 Efficacy of etrasimod on symptomatic relief in patients with ulcerative colitis: an analysis of the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials

Abstract Background Patient-reported outcomes such as stool frequency (SF) and rectal bleeding (RB) are important measures of ulcerative colitis (UC) activity and treatment effect. Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active UC. We evaluated RB and SF subscores to assess symptomatic relief in the ELEVATE UC phase 3 programme. Methods In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). ELEVATE UC 52 utilized a treat-through design comprising a 12-week induction period followed by a 40-week maintenance period. ELEVATE UC 12 comprised a 12-week induction period. A key secondary endpoint was the proportion of patients with symptomatic remission (SF =0 [or =1 with a ≥1-point decrease from baseline] and RB =0) at week 12 and at week 52. RB and SF subscores, achievement of symptomatic remission, complete symptomatic remission (SF =0 and RB =0), and symptomatic response (≥30% decrease from baseline in composite RB/SF subscores) were assessed at each visit. Achievement of symptomatic remission was also summarized by subgroups in patients with prior biologic/Janus kinase inhibitor (bio/JAKi) use (yes [1, &amp;gt;1], no) and baseline corticosteroid use (yes, no). Results More etrasimod- vs PBO-treated patients achieved symptomatic remission by week 2 in ELEVATE UC 52 (15.3% vs 8.9%; P=0.049) and week 4 in ELEVATE UC 12 (27.5% vs 16.1%; P=0.007). Symptomatic remission increased in etrasimod- vs PBO-treated patients at each time point through week 12 in both ELEVATE UC 52 (46.0% vs 21.5%; P&amp;lt;0.001) and ELEVATE UC 12 (46.8% vs 29.5%; P=0.001) and was maintained through week 52 in ELEVATE UC 52 (43.4% vs 18.5%; P&amp;lt;0.001) (Figure 1A). Achievement of symptomatic response (Figure 1B), and significant improvements in RB and SF subscores, began as early as week 2 or week 4 for etrasimod vs PBO in ELEVATE UC 12 and ELEVATE UC 52, respectively. A significant difference in complete symptomatic remission was achieved at week 4 in both studies (Figure 1C). Subgroup analyses of symptomatic remission suggested a trend towards greater benefit in patients who were bio/JAKi naïve and patients with 1 prior bio/JAKi (vs &amp;gt;1) (Figures 2A-C). Conclusion In this analysis, symptomatic relief was achieved by a greater proportion of patients treated with etrasimod vs PBO as early as week 2 and was sustained through week 52. At week 2, symptomatic response and improvements in RB and SF subscores were observed. The greatest benefits were seen in patients who had no prior exposure to bio/JAKi or 1 prior bio/JAKi therapy.

Real-World Comparison of Time to Next Treatment for Patients with CLL Initiated on First-Line Treatment with Ibrutinib Versus Acalabrutinib

Introduction: Treatment guidelines recommend Bruton's tyrosine kinase inhibitors (BTKi) ibrutinib (once-daily) and acalabrutinib (twice-daily) as preferred regimens for chronic lymphocytic leukemia (CLL); however, there are no studies comparing the effectiveness of ibrutinib and acalabrutinib as first-line (1L) therapy in CLL. This study investigated time to next treatment (TTNT) for patients with CLL initiated on 1L ibrutinib or acalabrutinib in real-world (RW) clinical practice in the US. Methods: Specialty pharmacy electronic medical records from academic integrated care networks (11/21/2018-4/30/2022) were used to identify adults with CLL who initiated ibrutinib or acalabrutinib in 1L (index date) on or after the date of acalabrutinib approval for CLL (11/21/2019). A washout period of ≥12 months without antineoplastic agent use pre-index was required to confirm use as 1L therapy. Patients were excluded if there was concomitant use of another antineoplastic agent during the first 28 days post-index. Characteristics evaluated in the 12-month baseline period were compared between ibrutinib and acalabrutinib cohorts using t-tests for continuous variables and chi-square tests for categorical variables. TTNT was defined as the time from the index date to the initiation a next or additional treatment. Patients without a next/additional treatment were censored at death or end of data (4/30/2022). Patients with a within-class BTKi switch at any time post-index were censored at time of switch, as this may have indicated a switch due to tolerability rather than progression. Patients who added an anti-CD20 antibody or venetoclax to the BTKi within 180 days post-index were censored at time of add-on, as these may not have indicated overt disease progression but rather late initiation of a second anti-cancer agent as a 1L combination treatment strategy. Beyond 180 days, anti-CD20 or venetoclax add-ons were considered as a next/additional treatment. TTNT was described using Kaplan Meier curves and compared between ibrutinib and acalabrutinib using a Cox proportional hazards model adjusted for the following baseline variables: age, gender, region, race, year of index date, Quan-Charlson Comorbidity Index (Quan-CCI), chronic pulmonary disease (CPD), peripheral vascular disease, hypertension, atrial fibrillation (AF), metastatic cancer, use of corticosteroids, and use of antiplatelets. Results: Among 710 and 373 patients in the ibrutinib and acalabrutinib cohorts, respectively, mean age was 71.5 and 72.4 years (P=0.159) and 38.5% and 38.3% were female (P=0.971; Table). Mean baseline Quan-CCI score was similar for ibrutinib and acalabrutinib (3.1 vs 3.0; P=0.597); a higher proportion of patients in the ibrutinib cohort had CPD (13.6% vs 8.8%; P=0.024), peripheral vascular disease (7.8% vs 4.1%; P=0.022), and hypertension (41.4% vs 32.2%; P=0.003) at baseline, while AF was similar (7.0% vs 9.9%, P=0.098). Baseline corticosteroid use was lower in the ibrutinib cohort (14.5% vs 20.1%; P=0.018), but antiplatelet use was higher (7.0% vs 3.5%; P=0.017). Mean (median [range]) follow-up was 17.1 (18.1 [1.0-29.3]) months for the ibrutinib cohort and 12.5 (11.9 [1.0-29.1]) months for the acalabrutinib cohort. Four/710 (0.6%) patients in the ibrutinib cohort and 16/373 (4.3%) in the acalabrutinib cohort added an anti-CD20 antibody to the BTKi within 180 days and were censored at that point. Ten/710 (1.4%) and 8/373 (2.1%) patients added venetoclax to ibrutinib or acalabrutinib within 180 days and were censored at that point. The proportion of patients in the ibrutinib cohort who initiated a next or additional treatment was 5.9% relative to 7.5% for acalabrutinib. After adjusting for baseline characteristics, patients treated with acalabrutinib were 89% more likely to start a next or additional treatment than those treated with ibrutinib (hazard ratio = 1.89 [95% confidence interval] = [1.12, 3.13]; P=0.016; Figure). Results were similar when censoring anti-CD20 add-ons at any time (hazard ratio = 1.82 [95% confidence interval] = [1.08, 3.03]; P=0.025). Conclusions: In this large US RW study, patients with CLL treated with 1L acalabrutinib were significantly more likely to start a next treatment or add/intensify therapy than those treated with 1L ibrutinib. RW treatment patterns also suggest a higher propensity to add an anti-CD20 antibody to acalabrutinib versus ibrutinib in 1L CLL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal