Exposure-adjusted Incidence Rates Research Articles

P405 Long-term safety of 3 years of ozanimod in moderately to severely active ulcerative colitis: an interim analysis of the True North open-label extension

Abstract Background The phase 3, randomised True North (TN) study demonstrated the efficacy and safety of ozanimod for up to 52 weeks in patients (pts) with moderately to severely active ulcerative colitis (UC). The ongoing TN open-label extension (OLE) aims to assess the long-term efficacy and safety of ozanimod in UC. This analysis evaluated the cumulative long-term safety of ozanimod in these studies, which included pts with up to ~3 years of treatment exposure. Methods In TN, pts were randomised to once-daily ozanimod 0.92 mg or placebo, or to open-label ozanimod for a 10-week induction period. Ozanimod clinical responders were rerandomised at Week 10 to ozanimod or placebo in the maintenance period through Week 52. TN pts were eligible to enrol in the OLE and receive ozanimod if they did not achieve clinical response at the end of induction (Week 10), lost response during maintenance, or completed maintenance at Week 52. This interim analysis of the TN OLE (data cutoff: 10 January 2022) included all pts who entered the OLE from TN (n=823). Safety was monitored from the first dose of ozanimod in TN and throughout the subsequent OLE. Exposure-adjusted incidence rates per 100 patient-years (PY) were calculated. Results The average age of TN OLE study participants was 41.7 years (±13.6), 41% were female, 62% had left-sided UC disease, and 35% had prior exposure to tumor necrosis factor inhibitors. Total PY exposure to ozanimod was 2219 years (mean [SD] exposure = 2.7 [1.6]). The most frequent treatment-emergent adverse events (TEAEs) reported through OLE Week 94 (up to 146 weeks of continuous treatment) are listed in the Table. Most TEAEs were nonserious; TEAEs leading to discontinuation were uncommon. Bradycardia was reported in 3 pts (0.4%; EAIR 0.1/100 PY; 2 in TN and 1 in OLE; no pts were discontinued from treatment). Macular edema was reported in 2 (0.2%; EAIR 0.1/100 PY) pts. Reductions in ALC were common (470 [57.1%] had ALC < 500 cells/mm3), as previously described, but ALC reductions were not associated with the occurrence of TEAEs. Malignancies were uncommon (n=13 [1.6%]; EAIR 0.6/100 PY), and included 6 basal cell carcinomas and 3 colorectal neoplasms. Two deaths were reported: 1 due to COVID-19 and 1 sudden death. Investigators deemed both to be unrelated to treatment. Ozanimod was not associated with an increased risk of ischemic heart disease or thromboembolic events. Conclusion Long-term exposure to ozanimod for up to 3 years was well tolerated in pts with moderately to severely active UC. No new safety signals were observed with long-term ozanimod use in UC (2219 PY exposure). Safety findings are consistent with previous reports from the UC and multiple sclerosis development programs (>16,512 PY exposure).

P518 Safety of upadacitinib in ulcerative colitis: Long-term data from the phase 3 open-label extension study (U-ACTIVATE)

Abstract Background Upadacitinib (UPA), an oral reversible and selective JAK inhibitor, has demonstrated efficacy, with a well-characterised safety profile, in two replicate induction studies of UPA 45 mg once daily (QD; U-ACHIEVE induction and U-ACCOMPLISH), and a maintenance study of UPA 15 mg or UPA 30 mg QD (U-ACHIEVE maintenance).1 Here, we report safety data from the ongoing, Phase 3, open-label, 288-week long-term extension (LTE) study in patients with ulcerative colitis (UC) who previously participated in the induction studies. Methods Rates of treatment-emergent adverse events (TEAEs) and TEAEs of special interest were calculated by treatment sequence in patients who received ≥1 dose of UPA in the induction studies, maintenance study, or by the data cut-off of 13 December 2021 in the LTE study. Rates are presented as exposure-adjusted event rates (EAERs; events/100 patient-years [PYs]), except for events that typically occur as a single instance, which are presented as exposure-adjusted incidence rates (EAIRs; n/100 PYs). PYs were calculated from the first dose of UPA 45 mg received during induction through to the last UPA dose received or the data cut-off date for ongoing patients. Results Overall, 1,308 patients representing 2,350.2 PYs of UPA exposure were evaluated (mean age: 43 years; female: 38%). Across treatment groups, EAERs of serious TEAEs, severe TEAEs, TEAEs leading to UPA discontinuation, TEAEs with reasonable possibility of being related to UPA, or TEAEs leading to death were numerically similar across all UPA treatment sequences (Table 1). EAERs of serious infections, herpes zoster, neutropenia, hepatic disorder, and creatine phosphokinase elevation were numerically higher with UPA 15 mg and 30 mg vs placebo; and creatine phosphokinase elevation with UPA 30 mg vs UPA 15 mg (Table 2). The EAER of anaemia was numerically lower with UPA 30 mg vs UPA 15 mg and placebo. Of note, no remarkable differences were observed in EAIRs of adjudicated major adverse cardiovascular events, adjudicated venous thromboembolic events, or malignancy (excluding non-melanoma skin cancer). Conclusion: Long-term use of UPA 15 or 30 mg among patients with UC continuing to benefit from prolonged therapy representing 2,350.2 PYs of exposure was well tolerated. The ongoing safety profile of UPA is consistent with previous analyses, with no new safety signals identified compared with previous UC analyses following 52 weeks’ maintenance therapy,1,2 or other immune-mediated indications for which UPA is approved.3,4

OP35 Efficacy and safety outcomes up to ~4 years of treatment with filgotinib 200 mg among patients with Ulcerative Colitis: Results from the SELECTIONLTE study

Abstract Background Filgotinib (FIL) is a once-daily, oral, Janus kinase 1 preferential inhibitor approved for the treatment of ulcerative colitis (UC). FIL 200 mg (FIL200) was effective in inducing and maintaining clinical remission vs placebo (PBO) and well tolerated in patients with UC in the randomized, phase 2b/3 SELECTION trial (NCT02914522).1 The efficacy and safety of continued FIL200 therapy are being assessed in the continuing SELECTION long-term extension (LTE) study. Methods The SELECTION programme comprises SELECTION and the associated LTE study (SELECTIONLTE; NCT02914535). In SELECTION, adults with moderately to severely active UC received induction (IND) FIL200, FIL 100 mg (FIL100) or PBO once daily for 11 weeks. Patients in clinical remission or with a Mayo Clinic Score (MCS) response at week 10 (responders) could enter the 47-week Maintenance (MNT) Study. SELECTIONLTE enrolled patients who completed IND and MNT (completers), patients who were not responders at IND week 10 (non-responders), and patients with disease worsening during MNT. This interim analysis assessed the efficacy and safety of open-label FIL200 through LTE week 144 in completers and LTE week 192 in non-responders, respectively, representing a total of 3.9 years of treatment each (completers: 58 + 144 weeks; non-responders 10 + 192 weeks). The cut-off date was 24 February 2022. Continuous measures of partial MCS (pMCS) and proportions of patients achieving the minimal clinically important difference (MCID) in total IBDQ score (≥16-point increase vs baseline) were assessed without imputation (as observed). Safety was assessed by the exposure-adjusted incidence rate per 100 patient-years of exposure (PYE) for treatment-emergent adverse events (TEAEs) and TEAEs of interest. Results This analysis included 148 completers and 372 non-responders (IND FIL100, n=212; IND FIL200, n=160). Among completers, the reductions in mean pMCS in SELECTION over weeks 0–10 were maintained up to LTE week 144 (Figure 1). In non-responders, mean pMCS decreased from LTE baseline to week 192 (Figure 2). High proportions of completers (>90%) and non-responders (>60%) achieved the MCID in IBDQ score; proportions were maintained over time (Table 1). Safety events among all patients treated with open-label FIL200 in the LTE study (total PYE=2055.5) are reported in Table 2. Conclusion: FIL200 was effective in maintaining symptomatic remission and health-related quality of life for up to ~4 years. No new safety signals were observed over ~4 years of treatment, and safety events were comparable with those seen in previous analyses.2 1. Feagan BG et al. Lancet 2021;397:2372–84. 2. Feagan BG et al. J Crohns Colitis 2022;16(Suppl1):i456–7.

314 Injection site reactions from an integrated analysis of phase 2 and phase 3 clinical trials of lebrikizumab treatment in moderate-to-severe atopic dermatitis

Abstract Lebrikizumab is an injectable, IgG4 monoclonal antibody that selectively binds to interleukin-13 with high affinity. Injection-site reactions (ISRs) are localized adverse events in the immediate site of administration of a drug and are common with injectable therapies. This analysis reports ISRs in patients from eight lebrikizumab (LEB) clinical trials in atopic dermatitis. To report ISRs in patients with moderate-to-severe atopic dermatitis treated with LEB, from an integrated safety analysis of phase 2 and 3 LEB clinical trials. These data sets include adolescents and adult patients who received at least one dose of LEB from a total of eight atopic dermatitis clinical trials, including four 16-week placebo-controlled clinical trials. Eight trials consist of: ADvocate1, ADvocate2, ADhere, ADore, ADjoin (ongoing), ARBAN, TREBLE and Phase 2b study. Treatment duration ranged from a single dose to 100 weeks. ISRs were defined using the preferred terms from the Medical Dictionary for Regulatory Activities high-level term, injection site reactions, excluding terms related to joints. This analysis includes ISRs frequencies in patients treated with LEB compared to placebo (ALL PC week 0–16), and all patients who received any dose of LEB (ALL LEB), and reports ISRs type, exposure adjusted incidence rates (EAIR) per 100 patient-years, the timing of ISRs occurrence, and ISRs leading to discontinuation. In the ALL PC week 0–16 analysis, 2.6% (n = 20/783, EAIR 9.0) of patients in the LEB group reported ISRs vs. 1.5% (n = 6/404 EAIR 5.4) in the placebo group. Injection site pain (n = 7, 0.9%) and injection site erythema (n = 7, 0.9%) were the most frequent reactions reported in the LEB group. Most ISRs were mild or moderate, with only 1 (0.1%) severe event. In the ALL LEB analysis, 3.1% of patients reported ISRs (n = 53/1720, EAIR 3.3). Injection site pain (n = 16, 0.9%) and injection site erythema (n = 12, 0.7%) were the most frequent reactions. Almost all reports were mild or moderate, with 3 (0.2%) severe. The incidence of ISRs did not increase with a longer duration of LEB exposure. The majority of ISRs were reported between weeks 0 and 16 (n = 38, 2.2%). The frequency of ISRs from week 16 to 32 was 1.0% (n = 15), from week 32 to 48 was 0.4% (n = 4) and from week 48 to 64 was 0.2% (n = 2). Treatment discontinuation due to ISRs occurred in a few patients (n = 5, 0.3%). Overall, a low proportion of patients reported ISRs (<3%) with a numerically higher frequency of LEB-treated patients who reported ISRs compared to placebo (1.5%). Most events were mild or moderate in severity, did not lead to treatment discontinuation, occurred within the first 16 weeks of treatment, and ISRs incidence did not increase with a longer duration of exposure.

309 Tralokinumab demonstrated a consistent safety profile with up to 42 months of treatment in moderate-to-severe atopic dermatitis: including adverse events of special interest

Abstract As atopic dermatitis (AD) is a chronic and potentially life-long disease, it is important to determine the long-term safety of new treatments. Tralokinumab, which specifically targets interleukin-13, is approved in Europe, Canada and the United States for the treatment of adults with moderate-to-severe AD. During the initial 12–16 week placebo-controlled treatment period of Phase 2 and 3 trials, tralokinumab was well-tolerated with an overall frequency of adverse events (AEs) similar to the placebo. An ongoing open-label extension trial, ECZTEND (NCT03587805), is assessing the safety and efficacy of tralokinumab up to 5 years after parent trials (PT). To report an interim safety analysis of patients treated with tralokinumab for up to 42 months (≤ 1 year in PT and ≤ 2.5 years in the open-label extension ECZTEND), including AEs of special interest (AESI). In ECZTEND, moderate-to-severe AD patients who completed the previous tralokinumab PT received subcutaneous tralokinumab 300 mg every 2 weeks after a 600 mg loading dose; topical corticosteroid use was optional. All AEs were recorded, coded, and classified by severity, causality and outcome. AESIs were predefined in PT based on areas of safety interest for monoclonal antibodies in AD, including eye disorders (e.g. conjunctivitis), skin infections requiring systemic treatment, eczema herpeticum and malignancies diagnosed after dosing. Event rates are presented as the number of events (nE) per 100 patient-years of exposure (PYE). All AEs described were treatment-emergent AEs, defined as AEs reported after the first dosing of the study drug. As of 30 April 2021, the interim safety analysis included 1442 patients from the PT ECZTRA 1, 2, 3, 4, 5 and 7 who had received ≥1 dose of tralokinumab in ECZTEND, with 121.0 weeks mean exposure time on tralokinumab [median 131.5 weeks (IQR 83.4–161.8); min 0.0, max 186.4 weeks]. Total exposure time in ECZTEND was 2446.2 PYE. Overall, 1127 patients experienced an AE (198.7 nE/100 PYE), the majority of which were mild (132.6 nE/100 PYE). The most frequently reported AEs (≥5.0% of patients) were the same as in the PT, including viral upper respiratory tract infection (18.2 nE/100 PYE, mainly reported as the common cold), atopic dermatitis (17.9 nE/100 PYE), upper respiratory tract infection (5.8 nE/100 PYE), headache (4.4 nE/100 PYE) and conjunctivitis (3.8 nE/100 PYE). The rates of AEs were generally lower as compared to short-term rates in the PT. Most of the serious AEs (SAEs; 4.9 nE/100 PYE) were reported as single events without clustering on the type. No events of conjunctivitis AEs were SAEs, and only five patients discontinued due to conjunctivitis AEs. AESI eye disorders, skin infections requiring systemic treatment, eczema herpeticum and malignancies were observed at rates similar to or lower than reported in PT. Consistent safety was demonstrated during up to 42 months of tralokinumab treatment in patients with moderate-to-severe AD. Exposure-adjusted incidence rates of AESIs, including eczema herpeticum and skin infections requiring systemic treatment, were generally lower than rates reported during the short-term, placebo-controlled period up to week 16. Exposure-adjusted incidence rates of conjunctivitis were lower with long-term exposure, and only five patients discontinued due to conjunctivitis. This analysis supports the long-term benefit-risk profile of targeted IL-13 inhibition with tralokinumab for patients with moderate-to-severe AD.

Uveitis in psoriatic arthritis: study of 406 patients in a single university center and literature review

Background/purposeThe manifestations of uveitis are well established in axial spondyloarthritis (ax-SpA), but not in psoriatic arthritis (PsA). We aimed to assess, in a large unselected series of PsA: (A) the...

Bimekizumab efficacy and safety in patients with moderate-to-severe plaque psoriasis who switched from adalimumab, ustekinumab or secukinumab: results from phase III/IIIb trials.

Discontinuation of biologics is common among patients with psoriasis due to treatment failure or adverse events. To achieve improvements in disease management, patients and clinicians may choose to switch biologics. To evaluate the efficacy and safety of switching to bimekizumab from adalimumab, ustekinumab and secukinumab. Data are reported for up to 80 weeks after patients switched to bimekizumab from adalimumab at week 24 in BE SURE, ustekinumab at week 52 in BE VIVID [upon entry into the BE BRIGHT open-label extension (OLE)] and secukinumab at week 48 in BE RADIANT (upon entry into the BE RADIANT OLE). Efficacy outcomes are reported by number of weeks after switching to bimekizumab and were split based on whether patients had achieved a ≥90% improvement from baseline in Psoriasis Area and Severity Index (PASI 90) at the time of switch. Treatment-emergent adverse events (TEAEs) are reported using exposure-adjusted incidence rates (EAIRs) per 100 patient-years. Trial registration: BE SURE (NCT03412747), BE VIVID (NCT03370133), BE BRIGHT (NCT03598790), BE RADIANT (NCT03536884). Rapid and durable improvements in clinical responses and benefits in health-related quality of life were observed among PASI 90 nonresponders who switched to bimekizumab. Most PASI 90 nonresponders achieved PASI 90 4 weeks after switching to bimekizumab from adalimumab (67%), ustekinumab (79%) and secukinumab (53%). After 48 weeks of bimekizumab, 91%, 90% and 79% of PASI 90 nonresponders had achieved PASI 90 after switching from adalimumab, ustekinumab or secukinumab, respectively. Durable improvements were also observed for PASI 100, Investigator's Global Assessment score 0/1, body surface area affected by psoriasis ≤ 1%, absolute PASI ≤ 2, and Dermatology Life Quality Index 0/1. Among PASI 90 responders, existing treatment responses were maintained or improved after switching to bimekizumab. The majority of TEAEs were mild or moderate. EAIRs were generally similar between active-comparator treatment periods and after switching to bimekizumab. EAIRs typically decreased with a longer duration of bimekizumab exposure. High proportions of patients who did not adequately respond to adalimumab, ustekinumab or secukinumab achieved high levels of skin clearance after switching to bimekizumab. Bimekizumab was well tolerated and there were no new safety findings.

Characterisation of the safety profile of evobrutinib in over 1000 patients from phase II clinical trials in multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus: an integrated safety analysis

ObjectiveAnalyse the integrated safety profile of evobrutinib, a Bruton’s tyrosine kinase inhibitor (BTKi), using pooled data from multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) trials.MethodsPhase II,...

Real-World Outcomes with First-Line Ibrutinib (Ibr) Versus Chemoimmunotherapy (CIT) in Patients with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): Final Analysis Results from the InformCLL Registry

Background: The therapeutic landscape for CLL/SLL has rapidly evolved with the introduction of novel agents such as Ibr. The informCLL registry (PCYC-1134; NCT02582879) is the largest US-based prospective, observational registry of patients (pts) initiating FDA-approved treatment for CLL/SLL in the era after approval of Ibr. Here, we report real-world (RW) outcomes in pts with CLL/SLL receiving first-line (1L) therapy, including comparison of 1L Ibr versus CIT, from the final analysis of informCLL. Methods: Pts with CLL/SLL who initiated FDA-approved treatment (within ±45 days of enrollment) were enrolled between 10/2015 and 6/2019. Pts were primarily enrolled from community-based practices (comprising 93% of sites). Data were collected for baseline characteristics, treatment patterns, and safety. Time to next treatment (TTNT) was estimated by Kaplan-Meier method and for comparison of outcomes with 1L Ibr versus CIT, by Cox proportional hazards regression analysis in weighted cohorts. Inverse probability of treatment weighting (IPTW) was performed to balance the baseline characteristics between cohorts. Adverse events (AEs) were evaluated using overall incidence and exposure-adjusted incidence rates (EAIRs). Results: Of the 1459 eligible pts enrolled, 854 were treated in the 1L setting (59%). In the overall 1L cohort, median age was 70 years (≥75 years in 33%); 90% had ECOG performance status of 0 or 1; 47% had Rai stage III/IV (among n=547 with Rai staging); median Charlson Comorbidity Index (CCI) score was 1 (range 0-12) with CCI ≥3 in 16%; median time from initial diagnosis to 1L treatment was 19 mo. FISH testing data were available in 57% of pts in the 1L cohort; among these pts, 12% had del(17p). The most common 1L therapies were Ibr (45%; single-agent Ibr in 43% of all 1L therapies) and CIT (43%: most commonly BR, 24%); immunotherapy was given in 11% while chemotherapy (0.9%) and other novel agents (0.7%) were rare. With a median follow-up of 31.8 mo in the 1L cohort, median TTNT was not reached (NR); estimated proportions of pts without next-line therapy (NLT) were 79% at 24 mo, 71% at 36 mo, and 64% at 48 mo. The 1L cohort included 383 pts treated with Ibr and 363 pts treated with CIT; median follow-up was 31.4 mo for the Ibr cohort and 34.3 mo for CIT. Compared with the CIT cohort, pts in the Ibr cohort were older, had longer time from diagnosis to treatment, were more likely to have a history of other malignancy, and were more likely to have del(17p) or TP53 mutation (Table). Baseline characteristics in the weighted cohorts were balanced. In the IPTW-adjusted cohorts, median TTNT was NR for Ibr and 56.5 mo for CIT; TTNT was improved with Ibr relative to CIT (hazard ratio 0.744; 95% CI, 0.563-0.981) (Figure). Estimated proportions free of NLT in the weighted Ibr cohort were 75% at 36 mo and 69% at 48 mo; rates in the weighted CIT cohort were 66% and 57%, respectively. Median duration of index treatment was 24.0 mo for 1L Ibr and 4.7 mo for CIT. In the Ibr cohort (n=383), serious AEs occurred in 144 pts (38%), most commonly (≥3% of pts) pneumonia (n=23; 6%) and atrial fibrillation (Afib; n=21; 5%); AEs led to discontinuation of Ibr in 135 pts (35%), most commonly Afib (n=19; 5%) and fatigue (n=12; 3%). In the CIT cohort (n=363), serious AEs occurred in 85 pts (23%), most commonly febrile neutropenia (n=13; 4%) and pneumonia (n=11; 3%). AEs led to discontinuation of CIT in 61 pts (17%), and no single AE term led to discontinuation in ≥3% of pts (most common was anemia, 2%). EAIRs per 100 pt-mo for serious AEs were 1.93 with Ibr and 4.55 with CIT. EAIRs per 100 pt-mo for AEs leading to discontinuation were 1.53 with Ibr and 3.09 with CIT. Conclusion: In this large RW registry of pts with CLL/SLL, results from IPTW-adjusted analysis showed that 1L Ibr was associated with longer TTNT than CIT, with sustained benefit up to 4 years of follow-up. Pts receiving 1L Ibr therapy tended to be older, more often had a history of other malignancy, and more often had high-risk genomic features (del(17p) or TP53 mutation among those tested) than pts treated with CIT. The spectrum and frequency of AEs observed with these 1L regimens appear consistent with data from clinical studies and other RW studies. When adjusted for exposure, rates of AEs leading to discontinuation and serious AEs were lower with Ibr than CIT. Future analyses examining the impact of factors such as age/comorbidity and race are warranted to further our understanding of RW outcomes in pts with CLL/SLL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes by Cardiac Stage in Patients With Newly Diagnosed AL Amyloidosis: Phase 3 ANDROMEDA Trial

BackgroundPatients with amyloid light chain amyloidosis and severe cardiac dysfunction have a poor prognosis. Treatment options that induce rapid and deep hematologic and organ responses, irrespective of cardiac involvement, are needed. ObjectivesThe aim of this study was to evaluate the impact of baseline cardiac stage on efficacy and safety outcomes in the phase 3 ANDROMEDA trial. MethodsRates of overall complete hematologic response and cardiac and renal response at 6 months and median major organ deterioration–progression-free survival and major organ deterioration–event-free survival were compared across cardiac stages (I, II, or IIIA) and treatments (daratumumab, bortezomib, cyclophosphamide, and dexamethasone [D-VCd] or bortezomib, cyclophosphamide, and dexamethasone [VCd]). Rates of adverse events (AEs) were summarized for patients with and without baseline cardiac involvement and by cardiac stage. ResultsMedian follow-up duration was 15.7 months. The proportions of stage I, II, and IIIA patients were 23.2%, 40.2%, and 36.6%. Across cardiac stages, hematologic and organ response rates were higher and major organ deterioration–progression-free survival and major organ deterioration–event-free survival were longer with D-VCd than VCd. AE rates were similar between treatments and by cardiac stage; serious AE rates were higher in patients with cardiac involvement and increased with increasing cardiac stage. The incidence of cardiac events was numerically greater with D-VCd vs VCd, but the rate of grade 3 or 4 events was similar. The exposure-adjusted incidence rate for cardiac events was lower with D-VCd than VCd (median exposure 13.4 and 5.3 months, respectively). ConclusionsThese findings demonstrate the efficacy of D-VCd over VCd in patients with newly diagnosed amyloid light chain amyloidosis across cardiac stages, thus supporting its use in patients with cardiac involvement. (NCT03201965)

Secukinumab long-term efficacy and safety in psoriasis through to year 5 of treatment: results of a randomized extension of the phase III ERASURE and FIXTURE trials.

In the long-term extension study of the ERASURE and FIXTURE trials, the efficacy of secukinumab (a fully human anti-interleukin-17A monoclonal antibody) was demonstrated to have been maintained through to year 3 of treatment in moderate-to-severe plaque psoriasis. To assess the efficacy and safety of secukinumab through to year 5 of treatment in moderate-to-severe plaque psoriasis. Responders with ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) from two core trials - ERASURE and FIXTURE - were randomized 2 : 1 at year 1 (end of core trials) to either the same dose (300 or 150 mg, continuous treatment) or placebo (treatment withdrawal) every 4 weeks, until year 3 or relapse (> 50% reduction in maximal PASI from core study baseline). Partial responders (achieving PASI 50 but not PASI 75) at year 1 continued at the same dose as in the core trials. At year 3, all patients received open-label secukinumab treatment, with those on secukinumab 300 mg continuing on their dose, while those on secukinumab 150 mg or placebo received secukinumab 150 or 300 mg based on the physician's discretion. The study is registered on ClinicalTrials.gov with the identifier NCT01544595. Most patients randomized to placebo at year 1 relapsed, but the response was rapidly recaptured upon reinitiation of treatment. PASI responses were sustained with secukinumab through to year 5. The PASI responses for the 300 mg responders + partial responders group at year 1 (PASI 75/90/100: 86.8%/72.8%/45.9%) trended downwards until year 3 (PASI 75/90/100: 82.3%/58.4%/32.7%) and then remained stable through year 4 (PASI 75/90/100: 83.3%/60.1%/32.2%) until year 5 (PASI 75/90/100: 81.1%/62.8%/35.1%). Dermatology Life Quality Index showed sustained benefit up to year 5. Absolute PASI responses were maintained throughout the study. The most common adverse events (AEs) were infections and infestations, nasopharyngitis, and upper respiratory tract infections (URTIs). The overall exposure-adjusted incidence rate (EAIR; with 95% confidence interval) for all AEs was 139.9 (130.3-149.9). EAIRs for Crohn's disease and neutropenia were 0.1 (0.0-0.3) and 0.5 (0.3-0.8), respectively. The 4-year extension of two pivotal phase III trials demonstrated that secukinumab treatment was effective through to year 5 and improved quality of life in patients with moderate-to-severe plaque psoriasis. The most common AEs were infections and infestations, nasopharyngitis, and URTIs. The safety profile was consistent with that in the secukinumab phase II/III clinical development programme.

Geographic Analysis of the Safety and Efficacy of Filgotinib in Rheumatoid Arthritis.

Global clinical trials in rheumatoid arthritis (RA) often do not recruit enough patients from diverse racial and ethnic backgrounds to identify any potential differences in treatment outcome across such groups. To overcome this limitation, using data from five previous clinical trials and two ongoing trial extensions, this study aimed to assess the efficacy and safety of filgotinib in patients with RA across geographic regions. This was a post hoc, exploratory analysis of data from male and female patients with RA meeting the 2010 RA criteria as defined by the American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology. Data were analyzed from phase 2 (DARWIN 1-2) and phase 3 (FINCH 1-3) clinical trials, as well as two long-term extension studies (DARWIN 3, FINCH 4), of filgotinib. Efficacy endpoints included ACR 20%/50%/70% improvement (ACR20/50/70) responses, disease activity score in 28 joints using C-reactive protein [DAS28(CRP)], Clinical Disease Activity Index scores, Boolean remission, and change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI).Safety data were presented as exposure-adjusted incidence rates per 100 patient-years of exposure of treatment-emergent adverse events. Compared with placebo, at week 12 a greater proportion of patients receiving filgotinib 200mg (FIL200) or 100mg (FIL100) achieved ACR20 (p < 0.01), with similar outcomes in most regions. Overall, the reduction in HAQ-DIwith FIL200 or FIL100was greater thanwith placebo (p < 0.05) at week 12. Compared with placebo, at week 24 the proportions of patients achieving DAS28(CRP) ≤ 3.2 were greater for both doses of FIL, as seen in most regions (p < 0.01). Safety outcomes did not indicate regional or ethnic differences in the safety profile of filgotinib. Filgotinib efficacy and safety in patients with RA were generally consistent across geographic regions. NCT02889796; NCT02873936; NCT02886728; NCT03025308; NCT01888874; NCT01894516; NCT02065700.

Treatment effect measures under nonproportional hazards.

In a clinical trial with a time-to-event endpoint the treatment effect can be measured in various ways. Under proportional hazards all reasonable measures (such as the hazard ratio and the difference in restricted mean survival time) are consistent in the following sense: Take any control group survival distribution such that the hazard rate remains above zero; if there is no benefit by any measure there is no benefit by all measures, and as the magnitude of treatment benefit increases by any measure it increases by all measures. Under nonproportional hazards, however, survival curves can cross, and the direction of the effect for any pair of measures can be inconsistent. In this paper we critically evaluate a variety of treatment effect measures in common use and identify flaws with them. In particular, we demonstrate that a treatment's benefit has two distinct and independent dimensions which can be measured by the difference in the survival rate at the end of follow-up and the difference in restricted mean survival time, and that commonly used measures do not adequately capture both dimensions. We demonstrate that a generalized hazard difference, which can be estimated by the difference in exposure-adjusted subject incidence rates, captures both dimensions, and that its inverse, the number of patient-years of follow-up that results in one fewer event (the NYNT), is an easily interpretable measure of the magnitude of clinical benefit.

IBCL-117 ASPEN: Long-Term Follow-Up Results of a Phase 3 Randomized Trial of Zanubrutinib vs Ibrutinib in Patients With Waldenström Macroglobulinemia

ASPEN is a randomized, open-label, phase 3 study comparing zanubrutinib, a potent and selective Bruton tyrosine kinase inhibitor (BTKi), with the first-generation BTKi, ibrutinib, in Waldenström macroglobulinemia (WM). Data with a median follow-up of 43 months are presented. In cohort 1, patients with MYD88 mutations were randomized 1:1 to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily; stratifications were CXCR4 mutations and prior lines of therapy. In cohort 2, patients without MYD88 mutations received zanubrutinib 160 mg twice daily. The primary endpoint was the proportion of patients with complete response/very good partial response (CR+VGPR). In cohorts 1 and 2, 201 (zanubrutinib=102; ibrutinib=99) and 28 patients were enrolled, respectively. More cohort 1 patients in the zanubrutinib versus ibrutinib arm had CXCR4 mutations (32% [33/98] vs 20% [20/92] with next-generation sequencing data) and were aged >75 years (33% vs 22%). With median treatment durations of 42 (zanubrutinib) and 41 (ibrutinib) months, 67% and 58% remain on treatment, respectively. Investigator-assessed CR+VGPR rate was 36% versus 22% (zanubrutinib vs ibrutinib; P=0.02) and 31% in cohort 2 (1 CR). CR+VGPR rates for wild-type CXCR4 were 45% versus 28% (zanubrutinib vs ibrutinib; P=0.04) and were 21% versus 5% (P=0.15) for mutated CXCR4. Median progression-free survival and overall survival were not yet reached. Rates of atrial fibrillation, diarrhea, hypertension, localized infection, hemorrhage, muscle spasms, pneumonia, grade ≥3 infection, and adverse events leading to discontinuation/death were lower for zanubrutinib versus ibrutinib, as were exposure-adjusted incidence rates of atrial fibrillation/flutter and hypertension (0.2 vs 0.8 and 0.5 vs 1.0 persons/100 person-months; P<0.05); neutropenia rate was higher. Zanubrutinib safety outcomes were similar between cohorts. ASPEN is the largest phase 3 WM trial with head-to-head BTKi comparison. At a median follow-up of 43 months, zanubrutinib had higher CR+VGPR rates and clinically meaningful advantages in long-term safety/tolerability versus ibrutinib.

34346 Pooled safety analysis of respiratory tract infections, including COVID-19, in psoriasis patients treated with secukinumab

Objective: To assess risk of respiratory tract infections (RTIs) in secukinumab treated psoriasis patients, evaluate potential association of COVID-19 risk factors [age >65, diabetes, obesity (BMI >40), heart and respiratory disease] with RTI incidences and report COVID-19 cases from Periodic Safety Update Report (PSUR: 26-Dec-2019–25-Dec-2020). Methods: Pooled data from clinical trials and postmarketing safety surveillance, including patients who received ≥1 secukinumab dose, were analyzed. RTIs were reported as exposure-adjusted incidence rates (EAIRs) per 100 patient-years. Results: EAIR (95% CI; n) for ‘any RTI’ with secukinumab 150 mg/300 mg/150 mg+300 mg, was 42.1 (39.6–44.8; n = 2117)/47.5 (46.1–48.9; n = 9704)/46.6 (45.3–48.0; n = 11232). EAIR for ‘viral RTI’ at same doses was 7.1 (6.2–8.0)/7.4 (6.9–7.9)/7.3 (6.9–7.7), and for ‘other RTI’ was 34.3 (32.1–36.6)/38.8 (37.5–40.1)/ 37.7 (36.6–38.9). EAIR ratios in obese versus nonobese patients for viral pharyngitis/streptococcal pharyngitis/bacterial sinusitis with secukinumab 150 mg+300 mg were 4.2 (1.2–15.1)/3.4 (1.7–7.0)/6.9 (2.1–22.3), respectively. Strong associations with other COVID-19 risk factors were not observed. Of 952 COVID-19 cases retrieved, outcome was reported in 416 cases: completely recovered (n = 101), recovered with sequelae (n = 7), condition improving (n = 68), unchanged (n = 165), deteriorated (n = 54) and fatal (n = 21). Overall, 221 cases were confounded by risk factors (age >65, comorbidities, or concomitant use of immunosuppressant). Of 21 COVID-19 fatal cases, 14 had risk factors (age >65, comorbidities and smoking) whereas 7 had limited information. Conclusion: RTIs in secukinumab treated psoriasis patients from pooled clinical trials and postmarketing surveillance data were consistent with previous publications. In this analysis, obesity increased the risk for RTIs. COVID-19 cases in the PSUR revealed no new safety signals regarding known risk of ‘infections and infestations.’

34367 Safety of long-term dupilumab treatment in adults with moderate-to-severe atopic dermatitis: Results from an open-label extension (OLE) trial up to 4 years

Background: Atopic dermatitis (AD) is a chronic systemic inflammatory disease requiring long-term management. We extend the dupilumab safety profile in patients with moderate-to-severe AD to 204 weeks. Methods: The OLE (NCT01949311), with an initial duration of 3 years, enrolled adults with moderate-to-severe AD who participated in any dupilumab parent study. Protocol amendments allowed for patient re-entry and treatment extension for up to 5 years. Patients were treated with 300 mg dupilumab weekly. In 2019, patients transitioned to 300 mg every 2 weeks to align with approved dosage. Concomitant topical treatments were permitted. Data shown are for the overall study population (N = 2,677). Results: 2207/1065/557/362/352 patients completed up to 52/100/148/172/204 weeks of treatment. 240 patients had treatment duration of >204 weeks. Most withdrawals (59.5%) were due to dupilumab approval/commercialization; 8.4%/4.3% withdrew due to adverse events (AEs)/lack of efficacy. Exposure-adjusted incidence rates of treatment-emergent AEs (TEAEs) were lower in this OLE vs the 300c mg weekly+topical corticosteroid arm of the 1-year CHRONOS trial (167.5 vs 322.4 number of patients/100 patient-years). 10.4% of patients had serious TEAEs; 9.8%, severe TEAEs; 1.2%, ≥1 serious TEAE related to study drug; and 3.7%, TEAEs resulting in permanent drug discontinuation. The most common TEAEs were nasopharyngitis (28.9%) and conjunctivitis (20.0%, including allergic/bacterial/viral/atopic keratoconjunctivitis). The most common severe TEAEs by MedDRA Preferred Term were dermatitis atopic (0.9%) and conjunctivitis (0.7%). 95% patients with conjunctivitis TEAEs were reported as mild/moderate; 87% of conjunctivitis events were recovered/resolved. Conclusions: This analysis extends to 4 years the previous findings demonstrating dupilumab’s acceptable long-term safety profile.

Secukinumab in enthesitis-related arthritis and juvenile psoriatic arthritis: a randomised, double-blind, placebo-controlled, treatment withdrawal, phase 3 trial

BackgroundTreatment options in patients with enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) are currently limited. This trial aimed to demonstrate the efficacy and safety of secukinumab in patients with...

Long-term 2-year safety and efficacy of tralokinumab in adults with moderate-to-severe atopic dermatitis: Interim analysis of the ECZTEND open-label extension trial

Additional long-term treatments are needed for moderate-to-severe atopic dermatitis (AD). An ongoing, open-label, 5-year extension trial, ECZTEND (NCT03587805), assesses tralokinumab plus optional topical corticosteroids in participants from previous tralokinumab parent trials (PTs) with moderate-to-severe AD. To evaluate the safety and efficacy of up to 2years tralokinumab treatment in a post hoc interim analysis. Safety analyses included adults from completed PTs enrolled in ECZTEND, regardless of tralokinumab exposure duration. Efficacy analyses included adult participants treated with tralokinumab in ECZTEND for ≥1year and subgroup analyses of those on tralokinumab for 2years (1year from PT, 1year in ECZTEND). Primary end point was the number of adverse events with additional efficacy end points. Participants on tralokinumab had an exposure-adjusted rate of 237.8 adverse events/100 patient-years' exposure (N=1174) in the safety analysis set. Exposure-adjusted incidence rates of common adverse events were comparable to PTs, although at lower rates. With 2years of tralokinumab, improvements in extent and severity of AD were sustained, with Eczema Area and Severity Index (EASI-75) in 82.5% of participants (N=345). Possible selection bias; no placebo arm; some participants experienced treatment gaps between PTs and ECZTEND. Over 2years, tralokinumab was well tolerated and maintained long-term control of AD signs and symptoms.

Tildrakizumab efficacy and safety in patients with psoriasis and concomitant metabolic syndrome: post hoc analysis of 5‐year data from reSURFACE 1 and reSURFACE 2

BackgroundLimited data are available on long‐term efficacy and safety of biologics in patients with psoriasis and metabolic syndrome (MetS), a common comorbidity.ObjectivesThis analysis updates tildrakizumab efficacy and safety for up to 5 years in patients with and without MetS.MethodsThis was a post hoc analysis of the double‐blind, randomized, placebo‐controlled, phase 3 reSURFACE 1 (NCT01722331) and reSURFACE 2 (NCT01729754) trials in adult patients with moderate to severe chronic plaque psoriasis. Analyses included data through Week 244 from patients who continuously received tildrakizumab 100 (TIL100) or 200 mg (TIL200) and entered the extension studies, stratified by baseline MetS status. Efficacy was assessed via Psoriasis Area and Severity Index (PASI) scores. Safety was evaluated from exposure‐adjusted incidence rates (EAIRs) of treatment‐emergent adverse events (TEAEs).ResultsreSURFACE 1 and reSURFACE 2 analyses included 26 and 44 TIL100‐treated patients with MetS, 98 and 167 TIL100‐treated patients without MetS, 34 and 30 TIL200‐treated patients with MetS, and 111 and 130 TIL200‐treated patients without MetS, respectively. There were no clinically relevant differences in PASI 75/90/100 response rates at Week 244 between patients with vs without MetS. The proportion of patients with vs without MetS achieving absolute PASI score <3 at Week 244 was 53.8% vs 69.4% and 77.3% vs 80.8% in reSURFACE 1 and 2, respectively, for TIL100‐treated patients and 58.8% vs 72.1% and 63.3% vs 72.3%, respectively, for TIL200‐treated patients. In both studies, median reduction from baseline PASI score at all time points in patients with vs without MetS was >83% vs >89% for TIL100 and >85% vs >90% for TIL200. Pooled EAIRs of TEAEs, serious TEAEs, and TEAEs of special interest were similar in patients with and without MetS.ConclusionsTildrakizumab maintains efficacy and a favorable safety profile over 5 years in patients with psoriasis regardless of MetS status.

PB1878: CROSS-TRIAL ANALYSIS OF FIXED-DURATION IBRUTINIB (I) PLUS VENETOCLAX (V) VS FLUDARABINE (F), CYCLOPHOSPHAMIDE (C), AND RITUXIMAB (R) AS FIRST-LINE TREATMENT FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

Background: While continuous single-agent I or I-based therapies are superior to FCR, FCR remains an efficacious fixed-duration regimen for fit patients (pts) with previously untreated CLL. CAPTIVATE (PCYC-1142; NCT02910583) is a multicenter phase 2 study of first-line treatment with the all-oral, once-daily, chemotherapy-free regimen of I+V in fit pts with CLL. Primary analysis of the CAPTIVATE Fixed Duration (FD) cohort demonstrated deep, durable responses with fixed-duration I+V (Ghia et al, ASCO 2021). Aims: We performed a cross-trial analysis to evaluate outcomes with fixed-duration I+V relative to FCR using data from the FD cohort of the CAPTIVATE study and the FCR arm of the recent E1912 study (NCT02048813; Shanafelt et al. NEJM 2019;381:432-43). Methods: This cross-trial analysis included pts with previously untreated CLL or SLL aged ≤70 y who were treated with I+V in the FD cohort of CAPTIVATE or with FCR in E1912. As pts with del(17p) were not enrolled in E1912, pts with del(17p) from CAPTIVATE were excluded from the analysis. In CAPTIVATE, pts received three 28-d cycles of I, followed by 12 cycles of I+V (I 420 mg/d orally; V ramp-up to 400 mg/d orally). In E1912, pts received six 28-d cycles of FCR (F 25 mg/m2 on days 1-3; C 250 mg/m2 on days 1-3; R 50 mg/m2 on day 1 and 325 mg/m2 on day 2 in cycle 1, then 500 mg/m2 on day 1 in cycles 2-6). PFS and OS were estimated by Kaplan-Meier method. Adjusted treatment effects for PFS, OS, and ORR were estimated by inverse probability of treatment weighting (IPTW) using propensity score (PS) which balanced treatment groups for the following baseline prognostic factors: age, sex, ECOG performance status ≥1, CLL/SLL diagnosis, time from diagnosis, advanced Rai stage, absolute lymphocyte count, beta-2 microglobulin >3.5 mg/L, and high-risk genomic features (TP53 mutated, del[11q], unmutated IGHV). AEs were evaluated using overall incidence and exposure-adjusted incidence rates (EAIRs). Results: Analysis included 136 pts without del(17p) treated with fixed-duration I+V in the CAPTIVATE FD cohort and 175 pts treated with FCR in E1912; baseline characteristics were generally well-balanced across groups, with notable differences in the proportions of pts aged ≥65 y and with baseline thrombocytopenia (Table). Median follow-up was 38.7 mo with I+V and 33.7 mo with FCR. After IPTW, PFS was improved with I+V relative to FCR (hazard ratio [HR] 0.42; 95% CI 0.25-0.71; log-rank P=0.0018; 36-mo PFS rate: 89% vs 70%), as was OS (HR 0.19; 95% CI 0.05-0.77; log-rank P=0.0084; 36-mo OS rate: 98% vs 90%). Results were generally similar in unadjusted analyses (Table). Adjusted ORRs were 96% for I+V and 85% for FCR (difference 11.2%; 95% CI 5.1–17.3; Chi-square P=0.0011). Median duration of treatment was 13.8 mo for I+V and 4.7 mo for FCR. Treatment was discontinued due to AEs in 5% and 21% of pts, respectively. Overall, grade ≥3 AEs occurred in 62% of pts with I+V and 90% with FCR. Grade ≥3 AEs in ≥5% of pts with I+V were neutropenia (36%), and with FCR were lymphopenia (67%), neutropenia (45%), leukopenia (41%), lymphocytosis (31%), anemia (18%), thrombocytopenia (18%), febrile neutropenia (16%), hypertension (6%), hyperglycemia (6%), and maculopapular rash (5%). EAIRs for grade ≥3 AEs and AEs of clinical interest of any grade were lower with I+V than with FCR (Table). Image:Summary/Conclusion: Results of this cross-trial analysis suggest superior PFS with fixed-duration I+V relative to FCR in first-line CLL. The safety profile with I+V appeared favorable relative to the safety profile of FCR, with lower AE rates and fewer discontinuations due to AEs.