Pfizer (Switzerland)

BACKGROUND AND AIMS: Pivotal trials in ulcerative colitis have historically excluded patients with isolated proctitis. Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis. This post hoc analysis assessed efficacy and safety of etrasimod 2 mg once daily in patients with isolated proctitis (centrally read) from the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials. METHODS: Patients, including those with isolated proctitis (<10 cm rectal involvement) who met all other inclusion criteria in ELEVATE UC 52 and ELEVATE UC 12, were randomised 2:1 to receive etrasimod or placebo. Primary, secondary and other identified efficacy endpoints and safety were assessed. RESULTS: We analysed data from 64 and 723 patients at Week 12 (both trials pooled), and 36 and 397 patients at Week 52 (ELEVATE UC 52 only) with isolated proctitis and more extensive colitis (≥10 cm rectal involvement), respectively. Patients with isolated proctitis receiving etrasimod demonstrated significant improvements versus placebo, including clinical remission rates at Weeks 12 (42.9% vs 13.6%) and 52 (44.4% vs 11.1%), endoscopic improvement (52.4% vs 22.7%) at Week 12 and bowel urgency numerical rating scale score at Week 12 (all p < 0.01). Generally similar trends were observed in patients with more extensive colitis. Safety was consistent across subgroups, with no new findings. CONCLUSIONS: Etrasimod demonstrated significant improvements versus placebo in patients with isolated proctitis, and those with more extensive disease, in most efficacy endpoints at Week 12 and 52. Clinicaltrials.gov: NCT03945188; NCT03996369.

Introduction: Extraintestinal manifestations (EIMs) in patients with ulcerative colitis (UC) are common. Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC. We evaluated the efficacy of tofacitinib in patients with EIMs, and the impact of tofacitinib on EIMs in patients with UC in the OCTAVE clinical program. Methods: Data from two 8-week induction studies (OCTAVE Induction 1 and 2) and a 52-week maintenance study (OCTAVE Sustain) were analyzed. The effect of tofacitinib on efficacy outcomes stratified by EIM status, proportion of predefined prior and active EIMs at baseline, and change from baseline in EIMs were determined at the end of the treatment period (weeks 8 or 52), or at early termination. Results: At baseline of OCTAVE Induction 1 and 2, and OCTAVE Sustain, 27.0% and 9.0% of patients had a history of EIMs (prior or active), respectively. Patients treated with tofacitinib 10 mg twice daily (BID) achieved remission and had endoscopic improvement in all studies, irrespective of any history of EIMs. A greater proportion of patients had active peripheral arthritis at baseline of OCTAVE Induction 1 and 2 versus OCTAVE Sustain. In OCTAVE Induction 1 and 2, similar proportions of tofacitinib and placebo-treated patients with active peripheral arthritis experienced either no change (81.3% and 85.7%, respectively) or an improvement (15.6% and 14.3%, respectively). By week 52 of OCTAVE Sustain, improvements in active peripheral arthritis were only observed in tofacitinib-treated patients (16.7% and 33.3% with tofacitinib 5 and 10 mg BID, respectively). Conclusion: Any history of EIMs did not influence the efficacy of tofacitinib 10 mg BID for induction or maintenance of UC. The most common active EIM was peripheral arthritis, for which many patients in OCTAVE Induction 1 and 2, and OCTAVE Sustain, reported improvement or no change from baseline with tofacitinib treatment. Clinicaltrials.gov:NCT01465763 ; NCT01458951; NCT01458574

The 4th Davos Declaration was developed during the Global Allergy Forum in Davos which aimed to elevate the care of patients with atopic dermatitis (AD) by uniting experts and stakeholders. The forum addressed the high prevalence of AD, with a strategic focus on advancing research, treatment, and management to meet the evolving challenges in the field. This multidisciplinary forum brought together top leaders from research, clinical practice, policy, and patient advocacy to discuss the critical aspects of AD, including neuroimmunology, environmental factors, comorbidities, and breakthroughs in prevention, diagnosis, and treatment. The discussions were geared towards fostering a collaborative approach to integrate these advancements into practical, patient-centric care. The forum underlined the mounting burden of AD, attributing it to significant environmental and lifestyle changes. It acknowledged the progress in understanding AD and in developing targeted therapies but recognized a gap in translating these innovations into clinical practice. Emphasis was placed on the need for enhanced awareness, education, and stakeholder engagement to address this gap effectively and to consider environmental and lifestyle factors in a comprehensive disease management strategy. The 4th Davos Declaration marks a significant milestone in the journey to improve care for people with AD. By promoting a holistic approach that combines research, education, and clinical application, the Forum sets a roadmap for stakeholders to collaborate to improve patient outcomes in AD, reflecting a commitment to adapt and respond to the dynamic challenges of AD in a changing world.

BACKGROUND: modulator in development for immune-mediated inflammatory disorders. Efficacy and safety of orally administered S1P receptor modulation in atopic dermatitis (AD) have not yet been examined. OBJECTIVE: To assess the efficacy and safety of etrasimod monotherapy in adults with moderate-to-severe AD. METHODS: In this phase 2, randomized, double-blind, placebo-controlled trial, participants (≥18 years) with moderate-to-severe AD defined as baseline validated Investigator's Global Assessment (vIGA-AD) score ≥ 3, Eczema Area and Severity Index (EASI) score ≥ 16, and body surface area involvement ≥10% were randomized 1:1:1 to once-daily oral etrasimod 1 mg, 2 mg or placebo for 12 weeks. The primary outcome was percent change in EASI score from baseline at week 12, assessed in the Full Analysis Set (all randomized participants). Key secondary outcomes were achievement of a vIGA-AD score of 0 or 1 with a ≥2-point improvement from baseline and EASI-75 response at Week 12. Safety was assessed during the double-blind period. RESULTS: One hundred and forty participants were randomized to etrasimod 2 mg (n = 47), 1 mg (n = 47) or placebo (n = 46). At Week 12, percent change in EASI score was -57.2% in the etrasimod 2-mg group versus -48.4% in the placebo group (p = 0.18). A significantly greater proportion of participants receiving etrasimod 2 mg achieved vIGA-AD scores of 0 or 1 with a ≥2-point improvement at Week 12 versus placebo (29.8% vs. 13.0%; p = 0.045); however, EASI-75 response was not statistically significant versus placebo. Treatment-emergent adverse events (AEs) occurred in 59.6%, 40.4% and 47.8% of participants receiving etrasimod 2 mg, 1 mg and placebo, respectively. There were no serious AEs or deaths. CONCLUSIONS: The primary outcome was not met, although efficacy was observed for etrasimod 2 mg on several clinician- and patient-assessed measures, and both 1- and 2-mg doses were well tolerated, warranting further clinical investigation in AD.

BACKGROUND AND AIMS: Infections are a safety concern in patients with ulcerative colitis [UC]. Etrasimod is an oral, once daily [QD], selective sphingosine 1-phosphate [S1P]1,4,5 receptor modulator for the treatment of moderately to severely active UC. It leads to selective and reversible lymphocyte sequestration and partial peripheral lymphocyte count decrease. We report infection events from the phase 3 ELEVATE programme. METHODS: Proportions, incidence rates [IRs; per 100 patient-years], and descriptive analyses of all serious, severe, herpes zoster and opportunistic infections are reported in the Pivotal UC cohort [ELEVATE UC 52 and ELEVATE UC 12]. Cox regression models evaluated potential baseline risk factors. RESULTS: In this analysis [n = 787], proportions [IRs] of all infection events were similar for patients receiving etrasimod 2 mg QD (18.8% [41.1]) or placebo (17.7% [49.0]). Serious infections occurred in three [0.6%] and five [1.9%] patients receiving etrasimod and placebo, respectively. Two herpes zoster events were reported in each group [etrasimod: 0.4%; placebo: 0.8%], all localised and non-serious. One opportunistic infection event was reported in each group. No patient with an absolute lymphocyte count [ALC] < 0.2 × 109/L reported serious/severe or opportunistic infections; no baseline risk factors were identified for such events. No deaths occurred. CONCLUSIONS: Patients receiving etrasimod demonstrated no increased risk of infection. The incidence of serious infections and herpes zoster was similar in each group. Among patients receiving etrasimod, no association between ALC < 0.5 × 109/L and infection events was observed. Longer-term follow-up will further characterise the etrasimod safety profile. Clinicaltrials.gov: NCT03945188; NCT03996369.

INTRODUCTION: Transthyretin amyloidosis (ATTR) is a progressive disease in which amyloid fibril deposition disrupts tissue structure and organ function. Many patients with ATTR present with cardiac involvement; recent studies indicate that ATTR prevalence is higher than expected in patients with certain heart conditions. Although long delays to diagnosis are common, recent treatment advances have made timely diagnosis critical to ensure appropriate patient management. Despite clinical guideline updates, it remains unclear how these are being implemented in routine patient care. METHODS: We performed a survey of practicing cardiologists in Switzerland to assess their knowledge of ATTR and current clinical practice. RESULTS: Overall, 72 cardiologists completed the questionnaire in a face-to-face interview (n = 16) or online (n = 56). Key findings highlighted wide variation in cardiologists' knowledge about the diagnostic tests required for a differential diagnosis of ATTR. In particular, many cardiologists lacked familiarity with radiolabeled bone scintigraphy, an important non-invasive test that is part of the diagnostic algorithm for ATTR. Another challenge in diagnosing amyloidosis appears to be general awareness of ATTR among cardiologists. CONCLUSIONS: Survey results highlight that cardiologists in Switzerland would benefit from information on the latest advances in ATTR to support them in screening heart failure patients and ensure that patients benefit from treatment advances.

BACKGROUND AND AIMS: Ontamalimab is a fully human immunoglobulin G2 monoclonal antibody against mucosal addressin cell adhesion molecule-1, developed as treatment for inflammatory bowel disease. METHODS: Six phase 3, multicentre, randomised, double-blind, placebo-controlled clinical trials compared efficacy and safety of ontamalimab [25 mg and 75 mg once every 4 weeks] with placebo in patients with moderate-to-severe ulcerative colitis or Crohn's disease [two induction studies and one re-randomised maintenance study per condition]. This clinical trial programme was discontinued in 2020 for reasons unrelated to drug safety/efficacy; Crohn's disease studies are described in the Supplementary data. RESULTS: The induction [12-week] and maintenance [52-week] studies included 659 and 366 randomised patients, respectively. More patients who received ontamalimab induction than placebo achieved the primary endpoint of clinical remission at Week 12 [25 mg, 18.5% vs 15.8%, p = 0.617, 27.0% vs 12.5%, p = 0.027; 75 mg, 29.8% vs 15.8%, p = 0.018, 29.5% vs 12.5% p = 0.014]; significantly more patients who received ontamalimab maintenance therapy than placebo achieved Week 52 clinical remission [25 mg, 53.5% vs 8.2%, p <0.001; 75 mg, 40.2% vs 12.8%, p <0.001]. Endoscopic improvement was generally significantly different vs placebo [induction: 25 mg, 27.8% vs 21.1%, p = 0.253, 35.1% vs 12.5%, p = 0.001; 75 mg, 41.1% vs 21.1%, p = 0.002, 33.9% vs 12.5%, p = 0.003; maintenance: 25 mg, 56.3% vs 9.6%, p <0.001; 75 mg, 48.8% vs 15.1%, p <0.001]. Adverse event rates were similar between ontamalimab and placebo groups. CONCLUSIONS: Ontamalimab 75 mg was effective, with no safety concerns, as induction and maintenance therapy for patients with moderate-to-severe ulcerative colitis. [NCT03259334; NCT03259308; NCT03290781; NCT03559517; NCT03566823; NCT03627091].

Several antibiotics show significant pharmacokinetic interactions when they are given orally concomitantly with antacids. The objective of this study was to evaluate the effects of antacid (containing magnesium) on the pharmacokinetics of linezolid. A single dose of 600 mg linezolid was given orally alone and 10 min after administration of the antacid Maalox 70mVal, which contains 600 mg magnesium hydroxide and 900 mg aluminum hydroxide, to nine healthy males and nine healthy females in a crossover and randomized study. Linezolid plasma concentrations were determined by high-performance liquid chromatography, and pharmacokinetic parameters were calculated for both treatments. Coadministration with antacids did not change the pharmacokinetics of linezolid. The ratios (90% confidence intervals) of the individual values of the area under the concentration-time curve and the maximum concentration in plasma (C(max)) (linezolid plus antacid versus linezolid alone) were 1.01 (0.99 to 1.02) and 0.99 (0.96 to 1.02), respectively. Likewise, no significant difference in any of the other pharmacokinetic parameters was observed between the treatment groups (the time to C(max), lag time, volume of distribution [V/F], and clearance [CL/F]). However, a significant sex difference was observed for AUC, C(max), V/F, and CL/F; and these differences could be almost completely explained by the differences in body weight between males and females. No clinically relevant adverse effects were detected under either condition. The coadministration of antacids had no effect on the pharmacokinetics of linezolid. This demonstrates that the oral absorption of linezolid was not affected by the presence of antacids containing magnesium hydroxide and aluminum hydroxide. Antacids can be safely administered together with linezolid.

Abstract Management should focus on interacting and partnering with all stakeholders to enhance corporate performance and firm's value.

TPS8123 Background: D is an orally available, potent and selective irreversible small molecule inhibitor of all catalytically active members of the HER (human epidermal growth factor receptor) family tyrosine kinases that has shown activity in preclinical studies on EGFR mutant cell lines, including those resistant to G. In a phase II trial of NSCLC pts who received 1 st -line D, 75.6% of 45 pts with confirmed EGFR exon 19 or 21 sensitizing mutations (m) experienced a partial response (PR). The median progression-free survival (PFS) was 18.2 mo, and the PFS rate at 1 yr was 76.5% (preliminary data; Mok et al APLCC 2012). Methods: Based on the phase II data, a phase III randomized, open label trial (ARCHER 1050; NCT01774721) was designed to compare the efficacy of 1 st line D with G in pts with adv EGFR m-positive NSCLC. Eligible pts (N=440) have pathologically confirmed stage IIIB/IV NSCLC with at least one activating EGFR m, either exon 19 deletion or exon 21 L858R m. Concurrent m in exon 20 T790M is permitted. Pts must have radiologically measurable disease, ECOG PS 0–1 and no prior systemic therapy. Pts will be randomized (1:1) to receive D 45 mg or G 250 mg orally once daily. The primary endpoint is PFS by Independent Radiologic Review. Secondary endpoints include PFS by investigator assessment, overall survival (OS), OS at 30 mo, best overall response, duration of response, and safety and tolerability. Pt-reported outcomes (HRQoL and disease/treatment-related symptoms) were also assessed. Randomization will be stratified by race (Japanese vs mainland Chinese vs other East Asian vs nonEEast Asian), and EGFR m status (exon 19 deletion vs exon 21 L858R m). A minimum of 268 PFS events is required for 90% power to detect a PFS improvement of ≥50% in D vs G recipients using the intent-to-treat (ITT) analysis population (HR ≤0.667). A significant (0.025 significance level) 1-sided stratified log-rank test for PFS at the final PFS analysis will be indicative of a positive study outcome. An interim analysis is planned to assess safety and whether early discontinuation of the trial is required for futility. Clinical trial information: NCT01774721.

TPS7615 Background: D is a highly selective irreversible small molecule inhibitor of all catalytically active members of the HER (human epidermal growth factor receptor) family of tyrosine kinases. In a randomized phase II trial in patients (pts) who had received 1–2 prior systemic therapy regimens for adv NSCLC, D demonstrated significantly longer progression-free survival (PFS) vs. E in the overall population (12.4 vs. 8.3 weeks; HR=0.66, P=0.012), with benefit consistent across several clinical and molecular subgroups. Median PFS in the KRAS wild-type (WT) subgroup was 16.1 vs. 8.3 weeks for D and E, respectively (HR=0.55, P=0.006). Methods: Based on phase II data, a randomized, double-blinded phase III clinical trial (ARCHER; NCT01360554) was designed to compare the efficacy of D with E in two co-primary populations of pts with adv NSCLC: (a) all enrolled pts with adv NSCLC, and (b) pts with KRAS WT NSCLC. Pts with locally adv/metastatic pathologically confirmed NSCLC, radiologically measurable disease, 1 or 2 prior chemotherapy regimens, ECOG PS 0–2, and tissue available for molecular analysis will be randomized to receive D 45 mg or E 150 mg orally once daily. As of Jan 31, 2012, 117 of a planned 800 pts have been enrolled. The primary endpoint is PFS. Secondary endpoints include overall survival, objective response rate, duration of response, safety and tolerability, and pt-reported outcomes of health-related quality of life and disease-/treatment-related symptoms. Study design provides 90% and 80% power to detect ≥33% and ≥45% improvement in PFS in all pts receiving D vs. E, and in pts with KRAS W T NSCLC, respectively, and HR ≤0.75 and ≤0.69 using a 1-sided stratified log-rank test at a significance level of 0.015 and 0.01, respectively. The final primary analysis stratified log-rank test will include ECOG PS, KRAS mutation status and EGFR mutation status as stratification factors. The sample sizes above will also allow the assessment of OS in the co‑primary populations with adequate power. Post-hoc analyses will be performed to explore EGFR, HER family, and KRAS mutation status, as well as other tumor-derived biomarkers collected from all pts in this trial.

INTRODUCTION: Long-term follow-up (≥4 years) demonstrated a low incidence of cardiac and vascular treatment-emergent adverse events (TEAEs) with bosutinib treatment. We evaluated cardiac, vascular, hypertension, and effusion TEAEs after ≥ 7 years of follow-up in patients with Philadelphia chromosome-positive (Ph+) leukemia. METHODS: This retrospective analysis of a phase I/II study and its ongoing extension study included data from patients with chronic phase chronic myeloid leukemia (CML) treated with bosutinib after resistance/intolerance to imatinib (CP2L) or to imatinib plus dasatinib and/or nilotinib (CP3L), and those with accelerated/blast phase CML or acute lymphoblastic leukemia after treatment with, at a minimum, imatinib (ADV). RESULTS: In all, 570 patients were treated with bosutinib; median treatment duration was 11.1 months (range: 0.03-133.1). The incidence of cardiac, vascular, hypertension, and effusion-related TEAEs was 10.9%, 8.8%, 9.1%, and 13.3%, respectively. Few patients had maximum grade 3-4 TEAEs (cardiac, 3.9%; vascular, 4.0%; hypertension, 3.0%; effusion, 4.6%). Grade 5 TEAEs occurred in the cardiac (0.7%) and vascular (1.8%) clusters only. In years 5-7, fewer than 5% of patients each year had newly occurring cardiac, vascular, hypertension, or effusion TEAEs. The exposure-adjusted TEAE rates (patients with TEAEs/total patient-year) pooled across CP2L, CP3L, and ADV cohorts were as follows: cardiac, 0.044; vascular, 0.035; hypertension, 0.038; and effusion, 0.056, of which, correspondingly, 0.9%, 1.2%, 0%, and 2.1% required treatment discontinuation. CONCLUSIONS: The incidence of cardiac, hypertension, vascular, and effusion events was low in patients with Ph+ CML resistant or intolerant to prior therapy who were treated with bosutinib.

BACKGROUND AND AIMS: 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 subgroup analysis evaluated the efficacy and safety of etrasimod 2 mg once daily vs placebo by prior biologic/Janus kinase inhibitor [bio/JAKi] exposure in ELEVATE UC 52 and ELEVATE UC 12. METHODS: Pre-defined efficacy endpoints were assessed at Weeks 12 and 52 in ELEVATE UC 52 and Week 12 in ELEVATE UC 12 in bio/JAKi-naïve and -experienced patients, and at Week 12 [pooled] based on prior advanced therapy exposure mechanism. RESULTS: In the ELEVATE UC 52 and ELEVATE UC 12 analysis populations, 80/274 [29.2%] and 74/222 [33.3%] patients receiving etrasimod and 42/135 [31.1%] and 38/112 [33.9%] patients receiving placebo, respectively, were bio/JAKi-experienced. In both bio/JAKi-naïve and -experienced patients, a significantly greater proportion receiving etrasimod vs placebo achieved clinical remission [p < 0.05] in ELEVATE UC 52 at Weeks 12 [naïve: 30.9% vs 9.7%; experienced: 17.5% vs 2.4%] and 52 [naïve: 36.6% vs 7.5%; experienced: 21.3% vs 4.8%]; in ELEVATE UC 12, this was observed only for bio/JAKi-naïve patients [naïve: 27.7% vs 16.2%, p = 0.033; experienced: 18.9% vs 13.2%, p = 0.349]. Similar patterns were observed for most efficacy endpoints. Among patients with prior anti-integrin exposure [N = 90], a significantly greater proportion achieved clinical response [54.1% vs 27.6%, p = 0.030], but not clinical remission [9.8% vs 3.4%, p = 0.248], with etrasimod vs placebo. CONCLUSIONS: Bio/JAKi-naïve and -experienced patients had clinically meaningful induction and maintenance treatment benefits with etrasimod vs placebo. CLINICALTRIALS.GOV: NCT03945188; NCT03996369.

BACKGROUND: Abrocitinib efficacy by comorbidity status in patients with moderate-to-severe atopic dermatitis (AD) has not been previously assessed. This post hoc analysis evaluated the efficacy and safety of abrocitinib in patients with AD and allergic comorbidities. METHODS: Data were pooled from patients who received abrocitinib 200 mg, 100 mg, or placebo in phase 2b (NCT02780167) and phase 3 (NCT03349060, NCT03575871) monotherapy trials. Patients with and without allergic comorbidities (allergic asthma, rhinitis, conjunctivitis, or food allergy) were evaluated for Investigator's Global Assessment (IGA) response (clear [0] or almost clear [1]), ≥75% improvement in the Eczema Area and Severity Index (EASI-75), ≥4-point improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4), and Dermatology Life Quality Index (DLQI) response (<2 with baseline score ≥2). Other outcomes were Patient-Oriented Eczema Measure (POEM), SCORing Atopic Dermatitis (SCORAD), Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD), and treatment-emergent adverse events (TEAEs). RESULTS: Of 942 patients, 498 (53%) reported at least one allergic comorbidity (asthma only, 33%; conjunctivitis only or rhinitis only or both, 17%; food allergies only, 15%; >1 allergic comorbidity, 34%). Regardless of comorbidity status, from Week 2 to Week 12, higher percentages of patients treated with either abrocitinib dose achieved IGA 0/1, EASI-75, PP-NRS4, or DLQI 0/1 versus placebo-treated patients. Changes from baseline in POEM, SCORAD, and PSAAD were greater with abrocitinib than with placebo in patients with and without allergic comorbidities. Most TEAEs were mild or moderate. CONCLUSIONS: Efficacy and safety data support abrocitinib use to manage AD in patients with or without allergic comorbidities.

<h2>Abstract</h2><h3>Introduction</h3> The JAVELIN Lung 101 phase 1b/2 trial evaluated avelumab (immune checkpoint inhibitor) combined with lorlatinib or crizotinib (tyrosine kinase inhibitors) in <i>ALK</i>-positive or <i>ALK</i>-negative advanced NSCLC, respectively. <h3>Methods</h3> Starting doses of lorlatinib 100 mg once daily or crizotinib 250 mg twice daily were administered with avelumab 10 mg/kg every 2 weeks. Primary objectives were assessment of maximum tolerated dose (MTD) and recommended phase 2 dose in phase 1 and objective response rate in phase 2. Primary end points were dose-limiting toxicity (DLT) and confirmed objective response per Response Evaluation Criteria in Solid Tumors, version 1.1. <h3>Results</h3> In the avelumab plus lorlatinib group (<i>ALK</i>-positive; n = 31; 28 in phase 1b; three in phase 2), two of 28 assessable patients (7%) had DLT, and the MTD and recommended phase 2 dose was avelumab 10 mg/kg every 2 weeks plus lorlatinib 100 mg once daily. In the avelumab plus crizotinib group (<i>ALK</i>-negative; n = 12; all phase 1b), five of 12 assessable patients (42%) had DLT, and the MTD was exceeded with avelumab 10 mg/kg every 2 weeks plus crizotinib 250 mg twice daily; alternative crizotinib doses were not assessed. Objective response rate was 52% (95% confidence interval, 33%–70%) with avelumab plus lorlatinib (complete response, 3%; partial response, 48%) and 25% (95% confidence interval, 6%–57%) with avelumab plus crizotinib (all partial responses). <h3>Conclusions</h3> Avelumab plus lorlatinib treatment in <i>ALK</i>-positive NSCLC was feasible, but avelumab plus crizotinib treatment in <i>ALK</i>-negative NSCLC could not be administered at the doses tested. No evidence of increased antitumor activity was observed in either group. <h3>ClinicalTrials.gov identifier</h3> NCT02584634

Abstract Background 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 ulcerative colitis (UC). The safety and efficacy of etrasimod for the treatment of moderate to severe UC has been evaluated in the OASIS phase 2 and ELEVATE phase 3 placebo (PBO)-controlled trials. Long-term safety and efficacy of etrasimod for UC are being evaluated in an ongoing, open-label extension (OLE) study. We report an integrated analysis of the cumulative safety profile observed during the clinical development programme. Methods Safety outcomes included adverse event (AE) frequency and exposure-adjusted incidence rates (EAIRs) of AEs of interest determined based on safety data from PBO-controlled trials and OLE trials. Patients who received PBO or etrasimod (1 or 2 mg) were analysed as two cohorts: patients who received either PBO or etrasimod as part of one phase 2 study (etrasimod 1 or 2 mg for 12 weeks; NCT02447302) or two phase 3 studies (etrasimod 2 mg for 12 or 52 weeks; NCT03945188 and NCT03996369) were reported as the PBO-controlled cohort, and all patients who received ≥1 dose of etrasimod in the all UC cohort (studies above, NCT02536404, NCT03950232, and open-label period of NCT04176588; data cut-off January 31, 2022). Patients may have participated in &amp;gt;1 study. Results Overall, 956 patients received ≥1 dose of etrasimod with 769.3 patient years (PY) of exposure with demographics for both cohorts reported in Table 1. In the PBO-controlled cohort, a total of 629 and 314 patients received etrasimod and PBO, respectively, with 288.1 and 115.1 PY of exposure. Mean (SD) exposure per patient was 23.9 (18.5) and 19.1 (15.1) weeks for etrasimod and PBO, respectively. Of the 956 patients who received etrasimod in the all UC cohort, mean (SD) exposure was 42.0 (27.5) weeks. Rates for AEs, serious AEs, and infections (including serious infections, opportunistic infections, and herpes zoster) were similar between treatment arms and between the PBO-controlled and all UC cohorts (Table 2). Eleven (1.8%) etrasimod-treated patients reported events of bradycardia (EAIR=0.04) in the PBO-controlled cohort (9 of 11 events were asymptomatic); no events were reported in PBO-treated patients. Other AEs of special interest including hypertension and macular oedema were similar between treatment arms and with the all UC cohort. Conclusion Etrasimod in patients with moderately to severely active UC was overall well tolerated and had an acceptable safety profile that did not appear to change with longer-term treatment of up to 2.5 years. In the PBO-controlled cohort, serious infections and herpes zoster were more commonly reported among PBO patients.

BACKGROUND: Rheumatoid arthritis (RA) has a variable impact on different synovial joints, with inflammation being more commonly observed in some joints than others. Emerging evidence suggests that the anatomical variation in pathophysiology could result in differential responses to treatments across the joints, both within and between modes of action. This analysis aimed to characterize joint-specific responses to tofacitinib and methotrexate monotherapy in patients with RA. METHODS: This was a post hoc analysis of data from the phase III trial ORAL Start (NCT01039688), in methotrexate-naïve patients with RA. A paired joint pathology score (PJPS), derived from bilateral tender/swollen joint counts, was calculated. The percentage change from baseline in PJPS (%∆PJPS) and treatment-specific responses (tofacitinib 5 and 10 mg twice daily [BID] vs methotrexate; tofacitinib 5 vs 10 mg BID) for each patient joint pair, except for those with baseline/post-baseline PJPS = 0, were calculated at month 3, month 6, and month 12. Radiographic progression was similarly assessed using the Modified Total Sharp Score at month 6 and month 12. RESULTS: In methotrexate-naïve patients, differences in %∆PJPS demonstrated greater responses with tofacitinib vs methotrexate in most joint locations. Lesser responses with tofacitinib vs methotrexate were observed in most joints of the feet, particularly at month 12. Despite this, radiographic progression at month 12 was significantly worse in the foot (and metacarpophalangeal) joints of patients receiving methotrexate vs tofacitinib. CONCLUSION: We observed variation in joint-specific responses with tofacitinib and methotrexate monotherapy. Despite a proximal-distal efficacy gradient, with better clinical responses in the feet, patients receiving methotrexate monotherapy demonstrated more radiographic progression in the foot joints compared with those receiving tofacitinib. These findings suggest that body site- and therapy-specific characteristics may interact to produce differential treatment responses. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01039688.

OBJECTIVE: receptor expression on cardiac cells is involved in cardiac conduction. We report cardiovascular treatment-emergent adverse events (TEAEs) associated with S1P receptor modulators and other cardiovascular events in the etrasimod UC clinical programme. METHODS: Patients were analysed in the Placebo-controlled UC cohort and All UC cohort. Incidence rates (IRs, per 100 patient-years) of cardiovascular-related TEAEs associated with S1P receptor modulators, including bradycardia/atrioventricular (AV) block and hypertension, and other cardiovascular events, including coronary artery disease (CAD) and cerebrovascular disease (CVD), were analysed. RESULTS: In patients receiving etrasimod, cardiovascular-related TEAEs were infrequent (≤2.6% per AE). In the Placebo-controlled UC cohort, IRs (95% CIs) for cardiovascular-related TEAEs were higher for patients receiving etrasimod (n=577) vs placebo (n=314), respectively, for bradycardia/sinus bradycardia, 3.85 (1.58 to 6.13) vs 0 and AV block, 1.40 (0.03 to 2.76) vs 0; and numerically higher for hypertension, 5.31 (2.62 to 7.99) vs 3.40 (0.07 to 6.72). Most bradycardia/AV block events were reported on day 1. All bradycardia and hypertension TEAEs were non-serious. One serious second-degree AV block type 1 TEAE occurred in the etrasimod group; no events of second-degree AV block type 2 or higher were reported. One event each of CAD and CVD occurred in two patients receiving etrasimod. CONCLUSIONS: In the etrasimod UC clinical programme, IRs of cardiovascular-related TEAEs and other cardiovascular events were low. Most cardiovascular-related TEAEs were non-serious. TRIAL REGISTRATION NUMBERS: NCT02447302; NCT03945188; NCT03996369; NCT02536404; NCT03950232; NCT04176588.

Abstract Kaposi sarcoma associated herpesvirus (KSHV) is associated with around 1% of all human tumors, including the B cell malignancy primary effusion lymphoma (PEL), in which co-infection with the Epstein Barr virus (EBV) can almost always be found in malignant cells. Here, we demonstrate that KSHV/EBV co-infection of mice with reconstituted human immune systems (humanized mice) leads to IgM responses against both latent and lytic KSHV antigens, and expansion of central and effector memory CD4 + and CD8 + T cells. Among these, KSHV/EBV dual-infection allows for the priming of CD8 + T cells that are specific for the lytic KSHV antigen K6 and able to kill KSHV/EBV infected B cells. This suggests that K6 may represent a vaccine antigen for the control of KSHV and its associated pathologies in high seroprevalence regions, such as Sub-Saharan Africa.

Introduction: Etrasimod is an investigational, oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator in development to treat immune-mediated inflammatory disorders. Etrasimod regulates lymphocyte egress from secondary lymphatic organs, and therefore may have promise in EoE (T-cell-mediated disease). Methods: VOYAGE (NCT04682639) is a phase 2 study with a 24-week (wk) randomized, double-blind, placebo-controlled treatment period, followed by a 28-wk extension period (ongoing), investigating the efficacy and safety of oral etrasimod 1 and 2 mg QD vs placebo (PBO) in adults with active EoE (Figure 1). The primary efficacy endpoint was the percentage change from baseline (BL) (%CFB) in esophageal peak eosinophil count (PEC) at Wk 16. Other efficacy endpoints assessed the effects of etrasimod on histological and endoscopic features and symptoms of EoE, and included the proportion of patients who achieved PEC < 15 and ≤ 6 eosinophils/high power field, the absolute CFB in EoE-Histology Scoring System (EoE-HSS) grade and stage scores, EoE-Endoscopic Reference Score (EREFS), Patient Global Impression of Severity (PGIS), and Dysphagia Symptom Questionnaire (DSQ) (overall and by BL dilation history) at Wk 24. We present the findings from the double-blind treatment period. Results: We randomized 108 patients with active EoE to etrasimod 2 mg (N=41), etrasimod 1 mg (N=39) or PBO (N=28) (Figure 1). In total, 47.2% of patients were female, and at BL, patients had had EoE for an average of 4.6 years with 55.6% having a history of esophageal dilation and 40.0% having prior corticosteroid treatment. Treatment with etrasimod 2 mg QD resulted in a 46.1% decrease from BL in PEC (PBO-adjusted) at Wk 16 (P=0.0103). There were also statistically significant reductions in %CFB in PEC at Wk 24, and reductions in absolute CFB in EoE-HSS grade and stage scores, EREFS, PGIS, and, in patients without BL dilation history, DSQ score (Table 1). In etrasimod 1 mg- vs PBO-treated patients, there were also statistically significant reductions in %CFB in PEC and absolute CFB in EoE-HSS grade and stage scores at Wk 24. There were no serious treatment-emergent adverse events (TEAEs) reported up to Wk 24; 2 patients discontinued due to TEAEs (Table 1). Conclusion: Etrasimod 2 mg QD met the primary histologic endpoint and significantly improved endoscopic features of EoE, overall symptom severity, and dysphagia (in patients without dilation history only) at Wk 24, and was well tolerated. This supports further evaluation of etrasimod in EoE.Figure 1.: Study Design for VOYAGE. [a] Randomization was stratified by BL history of esophageal dilation and continued use of a stable proton pump inhibitor therapy at study entry; [b] EoE symptom severity and daily dysphagia scores were captured by PGIS and DSQ e-diaries, respectively; esophageal PEC and EoE-HSS (from EGD with biopsy) were centrally read by expert pathologists blinded to treatment assignment. The EREFS was scored by the local endoscopist. %CFB, percentage change from baseline; BL, baseline; DSQ, Dysphagia Symptom Questionnaire; EGD, esophagogastroduodenoscopy; EoE, eosinophilic esophagitis; EREFS, EoE-Endoscopic Reference Score; EoE-HSS, eosinophilic esophagitis Histology Scoring System; N, number of patients in treatment group; PEC, peak eosinophil count; PGIS, Patient Global Impression of Severity; QD, once-daily; R, randomization. Table 1. - Change from Baseline [a] in PEC at Week 16 (Primary Endpoint), Additional Efficacy Endpoints at Week 24 and a Summary of TEAEs up to Week 24 in the VOYAGE Study Etrasimod 2 mg QD (N=41) Etrasimod 1 mg QD (N=39) PBO QD (N=28) Visit/endpoint Baseline value mean (SD) Change from baseline Mean difference from PBO P value Baseline value mean (SD) Change from baseline Mean difference from PBO P value Baseline value mean (SD) Change from baseline Week 16 PEC [b],[c] 116.5 (82.6) -38.3 (77.91) -46.10.0103 106.3 (83.3) 40.3 (269.93) 32.50.2861 116.3 (71.9) 7.8 (87.77) Proportion with PEC < 15 eos/HPF 22.0% 12.8% 0.0% Proportion with PEC ≤ 6 eos/HPF 12.2% 7.7% 0.0% Week 24 PEC 116.5 (82.6) -52.4 (59.66) -113.7<0.0001 106.3 (83.3) -27.4 (78.00) -88.70.0022 116.3 (71.9) 61.3 (143.45) EoE-HSS grade [d],[e] 0.4 (0.18) -0.2 (0.03) -0.21<0.0001 0.4 (0.19) -0.1 (0.03) -0.19<0.0001 0.4 (0.16) 0.05 (0.03) EoE-HSS stage [d],[e] 0.4 (0.20) -0.2 (0.03) -0.23<0.0001 0.4 (0.24) -0.2 (0.03) -0.2000.0001 0.4 (0.22) 0.03 (0.04) EREFS [d],[f] 3.7 (1.74) -1.3 (0.26) -0.910.0303 3.2 (1.59) -1.0 (0.26) -0.610.1473 4.3 (1.39) -0.4 (0.32) PGIS [d],[g] 2.4 (0.6) -0.7 (0.12) -0.480.0121 2.3 (0.5) -0.5 (0.11) -0.280.1312 2.5 (0.6) -0.2 (0.14) DSQ Overall [d],[h] 33.6 (12.9) -18.6 (2.64) -4.160.3061 32.0 (10.0) -15.7 (2.52) -1.290.7451 32.7 (10.3) -14.5 (3.08) History of dilation = Yes 34.9 (11.5) -10.8 (4.40) 0.620.8992 31.6 (9.4) -9.3 (4.22) 2.120.6572 37.8 (8.5) -11.4 (5.10) History of dilation = No 32.2 (14.5) -21.6 (3.83) -11.950.0311 32.5 (11.2) -16.5 (3.82) -6.840.2014 26.9 (9.2) -9.6 (4.70) Proportion with PEC < 15 eos/HPF 31.7% 30.8% 0.0% Proportion with PEC ≤ 6 eos/HPF 24.4% 15.4% 0.0% Summary of TEAEs up to Week 24 in the VOAYGE study, n (%) [i] Etrasimod 2 mg QD (N=41) Etrasimod 1 mg QD (N=39) PBO QD (N=28) All causality TEAEs [j],[k] 29 (70.7) 27 (69.2) 21 (75.0) Serious TEAEs [l] 0 (0.0) 0 (0.0) 0 (0.0) TEAEs leading to study treatment discontinuation 1 (2.4) [m] 0 (0.0) 1 (3.6) [n] TEAEs occurring in ≥ 10% of patients [o] 6 (14.6) 3 (7.7) 3 (10.7) Nausea 4 (9.8) 4 (10.3) 1 (3.6) Dizziness 3 (7.3) 4 (10.3) 5 (17.9) COVID-19 1 (2.4) 1 (2.6) 5 (17.9) Esophageal food impaction EoE 0 (0.0) 1 (2.6) 3 (10.7) TEAEs leading to death 0 (0.0) 0 (0.0) 0 (0.0) [a] %CFB (mean [SD]) calculated for PEC, and absolute change from baseline (LS mean [SE]) calculated for DSQ, PGIS, EOE-HSS grade and stage, and EREFS. All PBO-adjusted differences from PBO are expressed as LS mean, except %CFB in PEC, which is expressed as the mean difference; [b] P-values are from an ANCOVA model for rank score of %CFB including factors for treatment group, baseline history of esophageal dilation (Yes/No), concurrent PPI therapy (Yes/No), and baseline eosinophil PEC (eos/HPF) as a covariate; [c] Full analysis set; includes all randomized patients who receive at least one dose of study treatment; [d] P-values are from a linear mixed effects model for change from baseline including factors for treatment group, visit, interaction of treatment-by-visit, baseline history of esophageal dilation (Yes/No), concurrent PPI therapy (Yes/No), and baseline score as a covariate; [e] Grade and stage score ranges from 0–1; [f] Score ranges from 0–9; [g] Score ranges from 0–4; [h] Score ranges from 0–84; [i] Safety analysis set; includes all patients who were randomized and received at least one dose of study treatment; [j] Severity was classified using CTCAE, version 5.0, i.e., Grade 1 for mild, Grade 2 for moderate, Grade 3 for severe, Grade 4 for life-threatening, Grade 5 for death related to AE; the majority of AEs were Grade 1 or 2; [k] First-dose, transient HR reductions and cardiac conduction aberrations are known on-target effects of sphingosine 1-phosphate receptor modulators. Bradycardia events were reported by 3 patients. One event occurred on Day 1 in a patient taking etrasimod 2 mg QD and was classed as Grade 2; one event occurred on Day 3 in a patient taking etrasimod 2 mg QD and was classed as Grade 1; one event occurred at the Week 24 visit when the patient transitioned from placebo treatment to blinded etrasimod 1 mg or 2 mg QD (ie. Day 1 of etrasimod) and was classed as Grade 1. Two cases associated with the first etrasimod dose (asymptomatic with unremarkable EKG findings) resolved without any interventions at Hour 5 of the cardiac monitor procedure. The third case (without documented HR measurement) was associated with dizziness and nausea and was reported on Study Day 3. The patient continued study treatment and all AEs resolved without interventions on Study Day 23; [l] Where seriousness was not entered/missing, the event was classified as serious; [m] Balance disorder, Grade 2; [n] Dysphagia, Grade 2; [o] TEAEs occurred in ≥ 10% of patients in at least one treatment group. %CFB, percentage change from baseline; AE, adverse event; ANCOVA, analysis of covariance; COVID-19, Coronavirus Disease 2019; CTCAE, common terminology criteria for adverse events; DSQ, Dysphagia Symptom Questionnaire; EKG, electrocardiogram; EoE, eosinophilic esophagitis; EoE-HSS, eosinophilic esophagitis Histology Scoring System; eos, eosinophils; EREFS, Eosinophilic Esophagitis Endoscopic Reference Score; HPF, high power field; HR, heart rate; LS, least squares; n, number of patients with event; N, number of patients in the treatment group; PBO, placebo; PEC, peak eosinophil count; PGIS, Patient Global Impression of Severity; PPI, proton pump inhibitor; QD, once-daily; SD, standard deviation; TEAE, treatment-emergent adverse event.