Clinical Non-responders Research Articles

Right ventricular to pulmonary artery coupling credicts poor outcomes after interatrial shunting in heart failure

Abstract Background Left atrial decompression is under investigation for heart failure (HF) with the potential to improve symptoms and potentially clinical outcomes. However, heterogeneous outcomes have been observed in randomized controlled studies. Purpose This study aimed to explore whether right ventricular (RV) -pulmonary artery (PA) coupling, as assessed from the tricuspid annular plane systolic excursion (TAPSE) /systolic PA pressure ratio, can be useful in predicting outcomes after implantation of the interatrial shunting device. Methods A total of 106 HF patients, n=62 with reduced ejection fraction (HFrEF), n=44 with preserved ejection fraction (HFpEF), were prospectively enrolled in the PRELIEVE registry with the Atrial Flow Regulator (AFR) implantation. Serious adverse events included cardiovascular mortality and HF worsening (W). Results Serious adverse events (SAEs) occurred in a total of 19 (18%) patients. There were no differences in baseline comorbidities, KCCQ scores, the 6-minute walking distance between patients with and without SAEs (Table). Patients with SAEs showed higher systolic pulmonary arterial pressure, NT-proBNP, serum creatinine and lower TAPSE/PASP ratio. Incidence of SAEs was higher in patients within the first TAPSE/PASP vs the third tertile (59% vs 12%, p=0.026), respectively. A TAPSE/PASP of <0.55 was identified to bear the most optimal sensitivity to predict the event (AUC=0.683, CI95% (0.533-0.833). Conclusion The reduced TAPSE/PASP ratio was associated with higher rates of serious adverse events in patients with heart failure undergoing controlled inter-atrial shunting. The hypothesis generating finding that reduced RV-PA coupling may identify potential clinical non-responders to left atrial decompression should be further prospectively validated.

A long-term follow-up study of gastric peroral endoscopic myotomy (G-POEM) in a large cohort of patients with postsurgical gastroparesis.

Postoperative gastroparesis occurs after surgeries which affect the upper digestive tract. Gastric peroral endoscopic myotomy (G-POEM) is a treatment for postoperative gastroparesis. The present study boasts the long-term efficacy and safety of G-POEM in a large cohort of patients. Gastroparesis Cardinal Symptom Index (GCSI) and Gastroesophageal Reflux Disease Questionnaire (GERDQ) were utilized for the assessment of postsurgical gastroparesis symptoms. Gastroscope was used to observe the anastomotic site. Three-dimensional ultrasound was used to measure the morphological structure of the gastric antrum and pylorus tube. Gastric emptying time was calculated by analyzing the volume change of gastric antrum. Significant clinical effectiveness of G-POEM was observed. The GCSI score, including each subscale score, showed significant decrease after G-POEM. Before G-POEM, there was a negative correlation between GCSI score and the inner diameter of pylorus, as well as a positive correlation with the length of pyloric tube. The similar results were found in the scores of nausea/vomiting and postprandial fullness/early satiety subscales. No correlation was observed between GCSI score and the emptying time, nor between the emptying time and the parameters of antrum morphology. After G-POEM, no correlation was found between GCSI (including subscales) score, the emptying time, and the parameters of antrum morphology. Patients who exhibited as clinical non-responders often accompanied with GERD symptoms. After G-POEM, the score of GERDQ decreased significantly. Either before or after G-POEM, no correlation was noticed between GERDQ scores, the emptying time and the parameters of antrum morphology. The technique of G-POEM was demonstrated as a minimally invasive approach with the long-term efficacy and safety in therapying postoperative gastroparesis.

P901 Extended induction response over time in patients with moderately-to-severely active Ulcerative Colitis treated with mirikizumab in the LUCENT-1 and -2 trials

Abstract Background The safety and efficacy of mirikizumab (miri), an anti-IL-23p19 antibody, for moderately-to-severely active ulcerative colitis (UC) have been shown in Phase 3 trials (LUCENT-1 and -2; NCT03518086, NCT03524092).1 Extended induction with 3 additional intravenous (IV) doses of miri induced clinical response at Week (W)24 in more than 50% of patients who did not initially achieve clinical response to induction with miri at W12.2 Among the clinical non-responders, some had achieved partial response at W12 (Table 1). We assessed response over time in clinical non-responders at the end of induction who received extended induction with miri for an additional 12W. Methods In LUCENT-1, patients (N=1281) were randomly assigned 3:1 to receive miri 300mg or placebo IV at W0, W4, and W8. Patients not achieving clinical response with miri 300mg IV at W12 of LUCENT-1 (n=272) received extended induction treatment with open-label miri 300mg IV at W12, W16, and W20 (LUCENT-2). Symptomatic remission, symptomatic response, bowel urgency (BU) remission, and BU change from baseline at W16 and W20 are reported (definitions in Table 1) in addition to the previously disclosed outcomes at W24. For categorical variables, number and percentage of patients who are responders/remitters were presented. For continuous variables, mean change from baseline with standard deviation (SD) was used. Missing data were imputed as non-response. Results Among patients who were clinical non-responders to 12W of initial induction treatment (n=272), 53 (19.5%); 73 (26.8%); 101 (37.1%) achieved symptomatic remission and 144 (52.9%); 169 (62.1%); 197 (72.4%) patients achieved symptomatic response at W16, W20, and W24, respectively. Among miri induction non-responders with Urgency Numeric Rating Scale (NRS) score ≥3 at induction baseline (n=256), 10.9% achieved BU remission at W16, 14.8% at W20, and 19.9% at W24. There was a 1.8±2.4 (mean±SD) point reduction in Urgency NRS scores at W16, 2.1±2.5 reduction at W20, and 2.5±2.7 reduction at W24 (Table 1). Conclusion Among patients who were clinical non-responders to induction at W12, more than 50% achieved clinical response after 3 additional induction doses with miri. A proportion of patients benefited earlier from extended induction at W16 and W20, respectively, regarding symptomatic response and remission, and BU outcomes. The results demonstrate continued symptomatic improvement and further support the potential benefit of extended induction treatment.

DOP16 Safety of long-term ozanimod treatment for up to 4 years in patients with moderately to severely active Ulcerative Colitis: an interim analysis of the True North open-label extension

Abstract Background The 52-week, phase 3 True North (TN) study (NCT02435992) demonstrated the efficacy and safety of ozanimod (OZA), a highly selective sphingosine 1-phosphate receptor 1 and 5 modulator, in patients (pts) with moderately to severely active ulcerative colitis (UC). A prior analysis reported the long-term safety of up to 3 y of OZA in the ongoing TN open-label extension (OLE; NCT02531126; from TN baseline to OLE Week [W] 94). This analysis presents the cumulative long-term safety of OZA in TN and the TN OLE for an additional year (up to OLE W142). Methods The TN study design has been previously described. This analysis included all TN pts who entered the OLE from TN (clinical nonresponders at W10, lost response during maintenance, or completed maintenance at W52). Safety assessments were reported from the first dose of OZA either in TN or OLE up to OLE W142. Lab abnormalities, including absolute lymphocyte count (ALC) reductions, were reported. Exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY) were calculated for all treatment-emergent adverse events (TEAEs). Results A total of 823 pts entered the TN OLE (average age: 41.7 y; 59% male); 62% had left-sided UC disease. Total PY exposure to OZA at OLE W142 was 2536 y. Overall, the cumulative safety assessments did not significantly change with an additional year of OZA exposure from OLE W94 to W142 (Table). A decrease in EAIRs per 100 PY was observed in overall TEAEs (85.5 vs 87.6) and serious TEAEs (7.0 vs 7.4) at OLE W142 vs OLE W94, respectively. Notably, with an additional year of OZA exposure, TEAEs leading to treatment discontinuation remained at 2.5 EAIR/100 PY, and there were no new cases of bradycardia or atrioventricular block. One new TEAE each of herpes zoster, macular oedema, cystoid macular oedema, myocardial ischaemia, pulmonary embolism, and deep vein thrombosis were noted. COVID-19 TEAEs increased at OLE W142 (n=103; EAIR: 4.3/100 PY) from OLE W94 (n=66; EAIR: 3.0/100 PY). Reductions in ALC <500 cells/mm3 were common in the OLE (OLE W94, 54.0%; OLE W142, 56.1%); few pts had ALC <200 cells/mm3 (OLE W94, 5.3%; OLE W142, 6.5%), but these pts had no serious infections. No serious hepatic safety events were observed. One new death due to adenocarcinoma, which was unrelated to OZA, was reported. Conclusion The ongoing safety profile of OZA is consistent with previous analyses, with no new safety signals identified compared with previous UC analyses. Long-term use of OZA representing 2536 PYs of exposure continues to be well tolerated in pts with moderately to severely active UC.

P1014 Faecal loss of vedolizumab is associated with UC severity, lower serum vedolizumab levels and rates of clinical response – Results from the FAVOUR study

Abstract Background Infliximab is detectable in the faeces of patients with active UC and faecal loss is associated with more severe disease and with primary non-response. Detection of vedolizumab (VED) in faeces and its importance in patients with UC has not been investigated. We conducted a prospective, observational study of patients with UC commencing VED to investigate faecal VED loss as well as its impact on serum VED levels (SVL) and association with treatment outcomes. Methods The FAVOUR study recruited UC patients with moderate to severe UC commencing vedolizumab between April 2019 and May 2022. Patients were treated with 300mg VED IV at weeks 0, 2, 6 and 14. Trough SVL were measured at weeks 2, 6 and 14. Faecal samples at days 1, 4, 7 and at weeks 2, 6 and 14 were homogenised and centrifuged to produce supernatants which were analysed for faecal VED levels (FVL) using a commercially available ELISA (LISA TRACKER, Theradiag, France). Clinical (SCCAI) and biochemical disease activity (CRP and faecal calprotectin) were measured at each infusion. Endoscopy was performed at baseline and week 14 to measure endoscopic (UCEIS/Mayo) and histologic activity (NHI). Correlations were calculated using the Spearman correlation coefficient (r). Categorical variables were compared using Mann-Whitney U. Results 36 patients (median age 34 (range 18-73); 13 Female) were recruited, of whom 33 completed induction therapy (3 withdrew early and were considered non-responders). 26/36 (72%) achieved a clinical response (SCCAI≤5 and reduction of ≥2) and 18/36 (50%) achieved endoscopic remission (UCEIS≤2). Faecal VED was detectable in 80/203 (39%) samples. Statistically significant correlations were observed between FVL and markers of clinical, biochemical, baseline endoscopic and histologic disease activity at day 1, and weeks 2 and 6 (table 1). Week 14 clinical non-responders had higher FVL than responders at that time point (median 1.0 vs 0.0ug/mL, p=0.004) but not at other timepoints. A statistically significant negative correlation was observed between week 2 FVL and SVL measured at weeks 6 and 14 (table 1). SVL did not differ significantly between week 14 responders and non-responders at any time point. Conclusion Active colonic inflammation results in faecal loss of vedolizumab. This appears to correlate with lower SVL and rates of response to treatment. However, SVL were not observed to directly influence rates of response. It is possible that FVL may be a marker of disease activity or that faecal loss results in lower rates of drug exposure at a tissue level and negatively impacts rates of response by this mechanism.

Predictors of Higher Frequency of Atrial Fibrillation in Patients with Cardiac Resynchronization Therapy.

Background and Objectives: Cardiac resynchronization therapy (CRT) is one of the effective therapeutic options in the treatment of systolic heart failure (HF) with persistent symptoms. This prospective study was designed to determine whether CRT with biventricular pacing would reduce the risk of development of atrial fibrillation (AF) and to identify predictors for AF occurrence. Materials and Methods: The study population consisted of 126 patients, with a mean age of 63.8 ± 9.1 years, who were eligible for CRT with biventricular pacing. Inclusion criteria were left ventricular ejection fraction (LVEF) ≤ 35%, QRS duration ≥ 130 msec, and persistent HF symptoms of New York Heart Association (NYHA) II or III, despite optimal drug therapy. Patients were followed for a period of 24 months and were evaluated through clinical, electrocardiographic, and echocardiographic examination at baseline (prior to CRT implantation), as well as at 6 and 24 months post-implantation. At the end of follow-up, patients were divided into clinical responders and non-responders based on the following criteria: decrease in NYHA class ≥ I, increase in LVEF ≥ 10%, and reduction in QRS duration ≥ 20 msec. Results: At follow-up, CRT was associated with a significant increase in LVEF (20.6 ± 6.9% pre-implantation, 32.9 ± 9.3% 24 months after implantation; p < 0.001), reduction in left ventricular end-diastolic and end-systolic diameters, and decrease in QRS duration (167.6 ± 14.3 msec pre-implantation, 131.7 ± 11.7 msec 24 months after implantation; p < 0.001), while left atrial (LA) diameter was slightly increased (p = 0.070). The frequency of AF occurrence increased after two years of follow-up (52.4% to 56.9%, p < 0.001). Significant predictors of AF occurrence in our study population were response to CRT-AF more frequent in non-responders (B = 8.134; p < 0.001), LA diameter-AF more frequent with larger LA diameter (B = 0.813; p < 0.001), and coronary sinus (CS) lead position-AF more frequent with posterolateral in comparison with lateral CS lead position (B = 5.159; p = 0.005). Conclusions: The results of our study provide new data on AF predictors in patients with HF subjected to CRT. There remains a permanent need for new predictors, which might help in patient selection and improvement in response rate.

Odronextamab Monotherapy for the Treatment of Relapsed/Refractory (R/R) Follicular Lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL): Focus on Clinical Pharmacology and Pharmacometrics in the ELM-1 and ELM-2 Studies

Background Odronextamab is a CD20×CD3 bispecific antibody that binds CD20 on B-cells and CD3 on T-cells, triggering T-cell-mediated cytotoxicity of malignant B-cells. Odronextamab demonstrated clinically meaningful efficacy and generally manageable safety in patients (pts) with R/R FL and DLBCL in the Ph 1 ELM-1 (NCT02290951; Bannerji R, et al . Lancet Haematol. 2022) and Ph 2 ELM-2 (NCT03888105) studies (Kim TM. ASH. 2022; Kim WS. ASH. 2022). Here, assessments of pharmacokinetics (PK), pharmacodynamics (PD), and exposure-response (E-R) analyses for efficacy and safety are presented, to support posology for the treatment of R/R FL and DLBCL. Methods Pts enrolled in ELM-1 and ELM-2 received IV odronextamab step-up doses of 0.7, 4, and 20 mg in Weeks (Wks) 1-3 of Cycle (C) 1 (21-day/cycle), odronextamab QW (FL: 80 mg; DLBCL: 160 mg) during C2-4, then odronextamab Q2W (FL: 160 mg; DLBCL: 320 mg) until disease progression or unacceptable toxicity. Pts who achieved a durable complete response for ≥9 months transitioned to Q4W dosing. After odronextamab infusion, serum samples were collected over time, odronextamab serum concentrations measured, and data analyzed using descriptive and population PK methods. Blood samples were collected to measure T-cells, T-cell activation and proliferation markers (e.g. HLA-DR, Ki67), peripheral CD19 + B-cells, and cytokines. E-R for efficacy was assessed with trough concentration at time of first efficacy assessment (C trough at Wk 12) and best overall response using logistic regressions. E-R for safety was assessed with odronextamab concentrations at the time of a safety event and safety events including any grade (Gr) and Gr ≥3 treatment-emergent AEs (TEAEs) via multivariate analyses. Results The PK of odronextamab were characterized in 507 pts and were similar between different ethnic populations across B-cell non-Hodgkin lymphoma types. Concentration-time profiles were similar with step-up doses in pts with FL and DLBCL. Exposure in pts with DLBCL was 2-fold higher than in FL during C2-4, in line with the 2× higher dose. PD profiles were similar in pts with FL and DLBCL. Rapid, pronounced, and prolonged B-cell depletion in blood was observed following infusion. Early T-cell activation and proliferation was observed, with T-cell expansion higher in clinical responders vs. nonresponders. Transient cytokine release was mainly observed in C1 and was infrequent in subsequent cycles. In pts with FL, the probability of clinical response increased with odronextamab exposure and the largest response (89%) was achieved at exposures consistent with the median C trough of 80 mg QW at Wk 12, supporting use of 80 mg QW for FL. Exposures associated with 80 mg QW in C2-4 were maintained or exceeded with subsequent 160 mg Q2W maintenance doses. In pts with DLBCL, the probability of clinical response increased with odronextamab exposure, but less steeply than for FL. The largest response (57%) was achieved at exposures consistent with the median C trough of 160 mg QW at Wk 12, supporting use of 160 mg QW for DLBCL. Exposures associated with 160 mg QW were maintained or exceeded with subsequent 320 mg Q2W maintenance doses. Exposure-safety analysis showed consistent results in FL and DLBCL. Among multiple factors evaluated that had potential to be associated with TEAEs, odronextamab exposure was not associated with any Gr or Gr ≥3 TEAEs, including cytokine release syndrome and infections, over time. Conclusions PK analyses showed predictable concentration-time profiles through step-up dosing, at treatment doses, and during maintenance. PD analyses showed durable and complete depletion of B-cells; T-cell activation, proliferation, and expansion; and transient cytokine release, consistent with the mechanism of action of odronextamab. In comparison with DLBCL, clinical response increased with odronextamab exposure faster for FL and can reach a higher response at 80 mg QW. Therefore, a higher odronextamab dose of 160 mg QW is needed to achieve maximal response for DLBCL. The studied regimens showed clinically meaningful activity and acceptable tolerability, and the risk of any Gr or Gr ≥3 TEAEs is not increased from low to high odronextamab exposures. Comprehensive PK, PD, exposure-efficacy, and exposure-safety analyses demonstrated that the selected odronextamab dose regimens have favorable efficacy and generally manageable safety profiles for the treatment of R/R FL and DLBCL.

Alterations to the Hidradenitis Suppurativa Serum Proteome with Spleen Tyrosine Kinase Antagonism: Proteomic Results from a Phase 2 Clinical Trial

Hidradenitis suppurativa is a disease in great need of novel therapies. Given the heterogeneous nature of the disease and the variable response to therapies, biomarkers are essential to predict response to therapies and increase our understanding of disease pathogenesis. Our recent phase 2 clinical trial of spleen tyrosine kinase antagonism using fostamatinib in hidradenitis suppurativa demonstrated a 75% clinical response, with the greatest benefit in individuals with elevated serum inflammation and IgG. In this study, we present results of an in-depth serum proteomic analysis in this patient cohort identifying downregulation of IL-12B as well as B-cell-associated proteins CCL19 and CCL20 and IFN-γ-mediated proteins CXCL10 and CX3CL1. Clinical responders demonstrated greater reduction in serum IL-17A, IL-6, IL-8, and CX3CL1 compared with clinical nonresponders. Baseline levels of CCL28 were associated with clinical response to fostamatinib therapy at week 12. Overall, this suggests that fostamatinib, by targeting B-cell receptor and Fc receptor activity in B cells, monocytes, and macrophages, has a significant molecular impact on the inflammatory serum proteome of hidradenitis suppurativa. In addition, potential therapeutic biomarkers may aid in patient selection for targeted therapy.

The Predictive Value of Circulating Exosomal PD-L1 in Cervical Cancer Immunotherapy

Programmed death ligand 1 (PD-L1) expression was wildly used as a predictor of immune Check-Point Inhibitors (ICIs) efficiency. However, emerging results showed that PD-L1 was of great heterogeneity in sampling time and site. Recently, some studies found that exosomal PD-L1(ExoPD-L1) was related to ICIs response. In this study, we aimed to explore the predictive value of ExoPD-L1 in ICIs treatment of cervical cancer (CC) for the first time. A total of 40 primarily diagnosed CC patients who accepted radical radiotherapy (RT) from March 2021 to October 2022 were included. The consecutive tumor sample were collected before and during RT. Another 37 advanced CC patients who accepted ICIs combination therapy from June 2020 to October 2022 were enrolled in this study. Blood samples were collected from each participant before and during treatment. Exosomes were derived by differential centrifugation, which was further identified by Western blot (WB) (CD9/TSG101/Calnexin), transmission electron microscope analysis and nanoparticle tracking analysis. ExoPD-L1 detection was conducted by enzyme-linked immuno-sorbent assay (ELISA). The knockout of PD-L1 was conducted via CRISPR/Cas9 assay and the overexpress of PD-L1 was conducted by lentiviral transfection. CD8+ T cells were extracted from murine spleen by CD8+ T Cell Isolation Kit. Immune cells and cytokines markers were detected by multicolor flow cytometry. The consecutive detection of PD-L1 showed a dynamic change during RT. Compared with the level before RT, PD-L1 expression elevated in most patients (87.5%, 35/40) after RT. And the responders (n = 18) had elevated ExoPD-L1 level at the first two circles in the ICIs combination therapy (P<0.001). Whereas the level of pre-treatment ExoPD-L1 couldn't stratified clinical responders and non-responders (P = 0.181). The median follow-up time was 14.13 months. The mPFS in increased group vs. decreased group: not reach vs.11.02 months (P = 0.025, HR: 0.218, 0.052-0.913). Continuous blood sampling of mice models also found that effective therapeutic intervention could increase ExoPD-L1 in the early stage. The combination of exosome inhibitor GW4869 and anti-PD-1 further inhibited tumor growth. Mice were injected with external ExoPD-L1OE and ExoPD-L1KO. The results showed that ExoPD-L1OE suppressed body immunity and promoted tumor growth. The results of flow cytometry showed that ExoPD-L1OE inhibited CD8+ T cells from releasing interferon-and granzyme B. And ExoPD-L1OE also suppressed the CD8+ T cells proliferation in murine spleen. The coculture of CD8+ T cells and exosomes in vitro also confirmed the above conclusion. Compared with unstable and impressionable tumoral PD-L1, ExoPD-L1 seems to be better predictor for the efficacy of immunotherapy in CC, which was with easy accessibility and continuation. Exosome PD-L1 played an immunosuppressive role by inhibiting the proliferation and functional factor release of CD8+ T cell.

Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis: QUASAR Phase 2b Induction Study

The QUASAR Phase 2b Induction Study evaluated the efficacy and safety of guselkumab, an interleukin-23p19 subunit antagonist, in patients with moderately to severely active ulcerative colitis (UC) with prior inadequate response and/or intolerance to corticosteroids, immunosuppressants, and/or advanced therapy. In this double-blind, placebo-controlled, dose-ranging, induction study, patients were randomized (1:1:1) to receive intravenous guselkumab 200 or 400 mg or placebo at weeks 0/4/8. The primary endpoint was clinical response (compared with baseline, modified Mayo score decrease ≥30% and ≥2 points, rectal bleeding subscore ≥1-point decrease or subscore of 0/1) at week 12. Guselkumab and placebo week-12 clinical nonresponders received subcutaneous or intravenous guselkumab 200 mg, respectively, at weeks 12/16/20 (uncontrolled study period). The primary analysis population included patients with baseline modified Mayo scores ≥5 and ≤9 (intravenous guselkumab 200 mg, n= 101; 400 mg, n= 107; placebo, n= 105). Week-12 clinical response percentage was greater with guselkumab 200 mg (61.4%) and 400 mg (60.7%) vs placebo (27.6%; both P < .001). Greater proportions of guselkumab-treated vs placebo-treated patients achieved all major secondary endpoints (clinical remission, symptomatic remission, endoscopic improvement, histo-endoscopic mucosal improvement, and endoscopic normalization) at week 12. Among guselkumab week-12 clinical nonresponders, 54.3% and 50.0% of patients in the 200- and 400-mg groups, respectively, achieved clinical response at week 24. Safety wassimilar among guselkumab and placebo groups. Guselkumab intravenous induction was effective vs placebo in patients with moderately to severely active UC. Guselkumab was safe, and efficacy and safety were similar between guselkumab dose groups. gov number: NCT04033445.

Effective treatment with the selective cytokine inhibitor BNZ-1 reveals the cytokine dependency of T-LGL leukemia

AbstractT-cell large granular lymphocytic leukemia (T-LGLL) is a clonal proliferation of cytotoxic T lymphocytes that can result in severe neutropenia, anemia, and bone marrow failure. Strong evidence from patients and mouse models demonstrate the critical role of interleukin-15 (IL-15) in T-LGLL pathogenesis. BNZ-1 is a pegylated peptide that selectively inhibits the binding of IL-15 and other γc cytokines to their cellular receptor complex, which has demonstrated efficacy in ex vivo T-LGLL cells and transgenic mice in preclinical studies. We conducted a phase 1/2 trial of BNZ-1 in patients with T-LGLL who had hematocytopenias (anemia or neutropenia) and required therapy. Clinical responses were assessed using hematologic parameters (improvement in hematocytopenias) based on response criteria from the Eastern Cooperative Oncology Group 5998 T-LGLL trial. BNZ-1 demonstrated clinical partial responses in 20% of patients with T-LGLL with minimal toxicity and the maximum tolerated dose was not reached. Furthermore, T-LGL leukemic cells showed significantly increased apoptosis in response to BNZ-1 treatment as early as day 2, including in clinical nonresponders, with changes that remained statistically different from baseline throughout treatment (P < .005). We report first-in-human proof that T-LGL leukemic cells are dependent on IL-15 and that intervention with IL-15 inhibition with BNZ-1 in patients with T-LGLL shows therapeutic effects, which carries important implications for the understanding of the pathogenesis of this disease. This trial was registered at www.clinicaltrials.gov as #NCT03239392.

Are we ready for biomarker driven, radiation dose–adaptable de-escalation studies for HPV+ oropharyngeal cancer?

6084 Background: Plasma circulating tumor modified viral human papillomavirus (HPV) DNA (TTMV) is a sensitive and specific biomarker of HPV+ oropharyngeal squamous cell carcinoma (HPVOPC). Patients with unresectable locally advanced (LA) HPVOPC are currently treated with induction chemotherapy (IC) and standard (sd) or reduced dose (rd) of chemoradiation (CRT). Post IC TTMV can be used in the future to help assign patients to sdCRT or rdCRT. This approach may help to maintain high efficacy and minimize long-term side effects of CRT in HPVOPC. Methods: Patients with LA HPVOPC and High Risk (HR) features (radiographic ECE, T4 primary, &gt;N2c, and isolated lung metastases) were treated with 3 cycles of TPF IC followed by rdCRT to 5600 cGy with weekly carboplatin in responders, sdCRT in clinical non-responders and in M1 patients who also received SBRT to isolated biopsy proven lung metastases. Patients with &gt; 20 pack year smoking history were excluded. Patients were eligible for rdCRT if they had a significant clinical response to IC and were participating in the QB2 trial (NCT02945631). Results: Fourteen subjects had pre and post IC TTMV testing available for analysis. 9/14 subjects after IC received rdCRT to 5600 cGy with weekly Carboplatin. 2 subjects were removed from the QB study for clinically inadequate response, 1 withdrew consent and 2 were M1 and treated for cure. All 5 underwent sdCRT 7000 cGy. 13/14 patients had TTMV testing done prior IC, 1 subject had TTMV done after the start of cycle 1 of IC; all 14 of them had a pretherapy or (1 subject) immediate post infusion positive elevated TTMV test. 11/14 subjects developed negative TTMV after 1 or 2 cycles IC. 3/14 subjects after 1 cycle and additional 6/14 subjects after 2 cycles of IC developed negative TTMV. 3/14 subjects still had abnormal TTMV after 3 cycles of IC; 2/3 subjects underwent 7000 cGy. Remaining 1/3 had a negative repeat TTMV prior to CRT and underwent rdCRT with 5600 cGy. TTMV testing was done for all subjects after completion CRT and all were negative. All subjects in addition to standard surveillance had TTMV testing done during their surveillance visits. 2 subjects developed recurrent HPVOPC after CRT: 1 locoregional and 1 metastatic (elevated TTMV after IC; sdCRT). Conclusions: In contrast to NCCN guidelines, rdCRT in many academic institutions has become a standard for HPVOPC. We have demonstrated a prompt reduction of TTMV to 0 in a subset of patients receiving 1 cycle and in a majority after at least 2 cycles of IC. The small sample size of our study lacks the statistical power to demonstrate that the failing to attain negative TTMV after/during IC is associated with a poor prognosis and warrants more aggressive therapy. TTMV biomarker response may have important prognostic value in delivering primary therapy and warrants further larger and more structured studies.

Circulating exosomal PD-L1 to predict response with immunotherapy in patients with advanced cervical cancer.

e17514 Background: Programmed death ligand 1 (PD-L1) expression was wildly used to predict immune Check-Point Inhibitors (ICIs) efficiency. However, emerging results showed that PD-L1 was of great heterogeneity in sampling time and site. Recently, some studies found that exosomal PD-L1(ExoPD-L1) was related to ICIs response. In this study, we aimed to explore the predictive value of ExoPD-L1 in ICIs treatment of cervical cancer (CC) for the first time. Methods: 40 primarily diagnosed CC patients who accepted radical radiotherapy (RT) were included. The consecutive tumor sample were collected before and during RT. Another 37 advanced CC patients who accepted ICIs combination therapy were collected. Blood samples were collected from each participant before and during treatment. Exosomes were derived by differential centrifugation, which was further identified by Western blot (CD9/TSG101/Calnexin), transmission electron microscope analysis and nanoparticle tracking analysis. ExoPD-L1 detection was conducted by enzyme-linked immuno-sorbent assay (ELISA). The knockout of PD-L1 was conducted via CRISPR/Cas9 assay and the overexpress of PD-L1 was conducted by lentiviral transfection. CD8+ T cells were extracted from murine spleen by CD8+ T Cell Isolation Kit. Immune cells and cytokines markers were detected by multicolor flow cytometry. Results: The consecutive detection of PD-L1 showed a dynamic change during RT. Compared with the level before RT, PD-L1 expression elevated in most patients (87.5%, 35/40) after RT. And the responders (n = 18) had elevated ExoPD-L1 level at the first two circles in the ICIs combination therapy (P &lt; 0.001). Whereas the level of pre-treatment ExoPD-L1 couldn’t stratified clinical responders and non-responders (P = 0.181). The median follow-up time was 14.13 months. The mPFS in increased group vs. decreased group: not reach vs.11.02 months (P = 0.025, HR: 0.218, 0.052-0.913). Continuous blood sampling of mice models also found that effective therapeutic intervention could increase ExoPD-L1 in the early stage. The combination of exosome inhibitor GW4869 and anti-PD-1 further inhibited tumor growth. Mice were injected with external ExoPD-L1OE and ExoPD-L1KO. The results showed that ExoPD-L1OE suppressed body immunity and promoted tumor growth. The results of flow cytometry showed that ExoPD-L1OE inhibited CD8+ T cells from releasing interferon-γand granzyme B. And ExoPD-L1OE also suppressed the CD8+ T cells proliferation in murine spleen. The coculture of CD8+ T cells and exosomes in vitro also confirmed the above conclusion. Conclusions: Compared with unstable and impressionable tumoral PD-L1, ExoPD-L1 seems to be better predictor for the efficacy of immunotherapy in CC, which was with easy accessibility and continuation. Exosome PD-L1 played an immunosuppressive role by inhibiting the proliferation and functional factor release of CD8+ T cell.

Systems-based digital twins to help characterize clinical dose-response and propose predictive biomarkers in a Phase I study of bispecific antibody, mosunetuzumab, in NHL.

Phase I oncology clinical trials often comprise a limited number of patients representing different disease subtypes who are divided into cohorts receiving treatment(s) at different dosing levels and schedules. Here, we leverage a previously developed quantitative systems pharmacology model of the anti-CD20/CD3 T-cell engaging bispecific antibody, mosunetuzumab, to account for different dosing regimens and patient heterogeneity in the phase I study to inform clinical dose/exposure-response relationships and to identify biological determinants of clinical response. We developed a novel workflow to generate digital twins for each patient, which together form a virtual population (VPOP) that represented variability in biological, pharmacological, and tumor-related parameters from the phase I trial. Simulations based on the VPOP predict that an increase in mosunetuzumab exposure increases the proportion of digital twins with at least a 50% reduction in tumor size by day 42. Simulations also predict a left-shift of the exposure-response in patients diagnosed with indolent compared to aggressive non-Hodgkin's lymphoma (NHL) subtype; this increased sensitivity in indolent NHL was attributed to the lower inferred values of tumor proliferation rate and baseline T-cell infiltration in the corresponding digital twins. Notably, the inferred digital twin parameters from clinical responders and nonresponders show that the potential biological difference that can influence response include tumor parameters (tumor size, proliferation rate, and baseline T-cell infiltration) and parameters defining the effect of mosunetuzumab on T-cell activation and B-cell killing. Finally, the model simulations suggest intratumor expansion of pre-existing T-cells, rather than an influx of systemically expanded T-cells, underlies the antitumor activity of mosunetuzumab.

Combinatory analysis of immune cell subsets and tumor-specific genetic variants predict clinical response to PD-1 blockade in patients with non-small cell lung cancer.

Immunotherapy by blocking programmed death protein-1 (PD-1) or programmed death protein-ligand1 (PD-L1) with antibodies (PD-1 blockade) has revolutionized treatment options for patients with non-small cell lung cancer (NSCLC). However, the benefit of immunotherapy is limited to a subset of patients. This study aimed to investigate the value of combining immune and genetic variables analyzed within 3-4 weeks after the start of PD-1 blockade therapy to predict long-term clinical response. Blood collected from patients with NSCLC were analyzed for changes in the frequency and concentration of immune cells using a clinical flow cytometry assay. Next-generation sequencing (NGS) was performed on DNA extracted from archival tumor biopsies of the same patients. Patients were categorized as clinical responders or non-responders based on the 9 months' assessment after the start of therapy. We report a significant increase in the post-treatment frequency of activated effector memory CD4+ and CD8+ T-cells compared with pre-treatment levels in the blood. Baseline frequencies of B cells but not NK cells, T cells, or regulatory T cells were associated with the clinical response to PD-1 blockade. NGS of tumor tissues identified pathogenic or likely pathogenic mutations in tumor protein P53, Kirsten rat sarcoma virus, Kelch-like ECH-associated protein 1, neurogenic locus notch homolog protein 1, and serine/threonine kinase 11, primarily in the responder group. Finally, multivariate analysis of combined immune and genetic factors but neither alone, could discriminate between responders and non-responders. Combined analyses of select immune cell subsets and genetic mutations could predict early clinical responses to immunotherapy in patients with NSCLC and after validation, can guide clinical precision medicine efforts.

P296 MAGNIFI-CD index is appropriate for treatment monitoring in perianal Crohn’s Disease

Abstract Background Perianal Crohn’s Disease (pCD) is a frequent and debilitating complication of Crohn’s Disease (CD). Magnetic Resonance Imaging (MRI) is the imaging modality for diagnosis, classification, and treatment monitoring in pCD. To evaluate treatment response, a validated radiological index is mandatory. Recently, the MAGNIFI-CD index has been developed. The aim of our study was to validate the MAGNIFI-CD index; evaluating reliability, responsiveness and accuracy. Methods At two tertiary IBD referral centers, patients (≥16yrs) with complex pCD that had pelvic MRI before and 3-24 months after medical and/or surgical treatment were included. Two independent, blinded abdominal radiologists randomly scored total MAGNIFI-CD and its separate items. Two clinicians scored clinical outcomes (remission, response, non-response) using the “fistula drainage assessment” (FDA). Interobserver agreement (ICCs or weighted K), responsiveness (according to FDA; Wilcoxon signed rank test), and test accuracy (ROC analyses for the follow-up (FU) MAGNIFI-CD) were determined. Youden indices (YI) were used to choose optimal cut-off values for the FDA categories. Results Sixty-seven patients (median age 30 [IQR 23-47], 51% female) were eligible with mean CD and pCD duration of 7.0 yrs (SD 8.7) and 3.7 yrs (SD 4.3), respectively. 44% was biological naïve, 9% had defunctioning ostomy and 20% had proctitis. Baseline MAGNIFI-CD was 18 [IQR 9–20]. MAGNIFI-CD had an almost perfect ICC of 0.88 (95%CI 0.78-0.92); reliability of the separate items was moderate to substantial. Between baseline and FU MAGNIFI-CD a significant decrease was observed in responders and remitters (p&amp;lt;0.05), while a non-significant decrease (p=0.14) was seen in clinical non-responders. AUROCFU MAGNIFI-CD was 0.80 (SD 0.05) discriminating remission and non-response/response, YImax of 0.61 resulted in a cut-off value ≤10 with a sensitivity and specificity of 70% and 80%. The AUROCFU MAGNIFI-CD was 0.75 (SD 0.07) discriminating response/remission and non-response, YImax of 0.50 resulted in a cut-off value ≤14 with a sensitivity and specificity of 73% and 75%. Conclusion The MAGNIFI-CD index is a reliable radiological index supported by an almost perfect agreement. Given the moderate agreement, the item “dominant feature” would need additional training or better definitions. The index shows a robust responsiveness to clinical change and does not improve significantly in non-responders. The MAGNIFI-CD seems to be an acceptable to excellent test to accurately determine response or remission. We suggest a cut-off value of ≤14 for response and ≤10 for remission at follow-up MAGNIFI-CD. These results support that the MAGNIFI-CD is suitable for treatment monitoring in clinical trials.

P746 Identification of Altered Microbial Genera at Baseline in Adalimumab Clinical Remitters and an Absence of Change in Total Microbial Composition Post Induction Treatment in the SERENE UC Study

Abstract Background The gut microbiome plays an integral role in the pathogenesis of Inflammatory Bowel Disease (IBD). However, there have been a limited number of studies investigating the composition of the gut microbiome in anti-TNF-treated Ulcerative Colitis (UC) patients. The aims of this study were to 1) identify novel microbial baseline predictors of clinical response and remission to Adalimumab treatment, and 2) assess the impact of Adalimumab induction treatment on the gut microbiome of UC patients. Methods The SERENE UC study (NCT02065622) compared the efficacy of higher adalimumab dosing regimens to the standard regimen in patients with moderately to severely active UC. 16S rRNA gene sequencing was performed on 204 stool samples from 107 UC patients at baseline and Week 8. An ANOVA test followed by Tukey HSD was used to compare microbial content within (baseline) or across (baseline vs Week 8) visits between clinical remitters (n=16), clinical responders (n=38), and patients who failed to respond to Adalimumab treatment (n=53). Clinical response was defined as a full Mayo score decrease of ≥3 points and ≥30% from baseline, plus ≥1-point decrease in rectal bleeding score or absolute bleeding score ≤1 at Week 8. Clinical remission was defined as a full Mayo score ≤2 with no sub-score &amp;gt;1 at Week 8. Results There were no differences in alpha diversity in terms of richness and evenness when comparing samples from patients across response categories, or alpha and beta diversity when comparing paired samples from patients pre- and post-treatment. In addition, principal coordinate analysis of the microbiome did not highlight any clustering of the samples between response groups or visits. When stratifying patients by clinical response status at Week 8, we identified 4 genera that were significantly altered at baseline in the clinical remitters compared to the clinical responders and/or non-responders, including Dorea, Ruminococcus torques group, Subdoligranulum, and Collinsella. Unexpectedly, when comparing paired pre- and post-treatment samples within a response group, we failed to detect any significant changes on the total microbiome composition regardless of response status at Week 8. Conclusion These findings suggest that baseline microbial composition is significantly altered in UC patients who achieve clinical remission, but that Adalimumab treatment does not significantly alter the composition of the gut microbiome after 8 weeks of treatment. Future work is focused on achieving a deeper understanding of the gut landscape in UC patients treated with Adalimumab through 1) investigation of bacterial, viral, and fungal composition by metagenomics, and 2) integration of serum metabolomics data.

DOP43 Extended induction in the True North OLE study: ozanimod efficacy in biologic-naive and biologic-experienced patients

Abstract Background Prior exposure to biologics can influence response to subsequent lines of advanced therapies. Previous analyses showed that patients who did not achieve clinical response following 10 weeks of ozanimod treatment in the phase 3 True North (TN) study benefited from extended induction with open-label ozanimod in the TN open-label extension (OLE) study. As the impact of prior biologic exposure on outcomes with extended induction is unknown, the aim of this analysis was to evaluate that question. Methods Clinical nonresponders to ozanimod at TN Week (W) 10 entered the OLE (data cutoff: January 10, 2022, at which point the disposition was available until OLE W94 for all patients). Data were analysed in patients with and without prior biologic exposure at baseline. Disease activity was assessed at TN W0 (baseline) and at W10 (OLE entry). Symptomatic clinical response and remission were evaluated through OLE W94, and multiple clinical, endoscopic, and histologic endpoints were evaluated at OLE W46 and W94 using observed case (OC) and nonresponder imputation (NRI) analyses. Results A total of 220 patients with prior biologic information entered the OLE after not achieving clinical response at TN W10 (biologic-naive, n=122; biologic-experienced, n=98). Disease activity at baseline was generally consistent between biologic-naive and experienced patients. About half of the ozanimod W10 nonresponders in both groups achieved symptomatic clinical response by OLE W5, with a higher proportion of biologic-naive patients maintaining response until OLE W94 in both OC and NRI analyses (Figure 1). Higher proportions of biologic-naive patients also sustained symptomatic clinical remission until OLE W94 in both OC and NRI analyses. In OC analysis, a higher proportion of biologic-naive patients achieved all clinical, endoscopic, and histologic endpoints at OLE W46 compared with biologic-experienced patients; by OLE W94, however, the proportions of patients who achieved all clinical, endoscopic, and histologic endpoints were generally consistent, regardless of prior biologic exposure (Figure 2). As expected, a smaller proportion of patients achieved the efficacy endpoints in the NRI analysis, with proportions being higher in biologic-naive patients; response rates were sustained between OLE W46 and W94 in each group. Conclusion Both biologic-naive and -experienced clinical nonresponders to ozanimod at the end of induction demonstrated response to extended induction with ozanimod. Delayed response was durable for up to 2 years of continuous ozanimod treatment in both groups, with higher proportions achieved in biologic-naive patients.

P773 Extended induction in the True North open-label extension study: clinical outcomes of ~2 years of ozanimod treatment

Abstract Background Ozanimod is approved in the EU, US, and other countries for the treatment of moderately to severely active ulcerative colitis in adults. In the phase 3, 52-week, double-blind True North (TN) study, Week 10 clinical nonresponders to ozanimod could enter the open-label extension (OLE) to continue treatment. Previous analysis showed that approximately 50% of Week 10 nonresponders achieved symptomatic clinical response with extended induction during the OLE in as early as 5 weeks. The current analysis evaluated long-term clinical and symptomatic endpoints up to 2 years in this delayed responder subgroup. Methods Efficacy data were analysed for TN Week 10 ozanimod nonresponders who subsequently received open-label ozanimod in the OLE, both by whole subgroup and original study arms (double-blind [Cohort 1] and open-label ozanimod [Cohort 2]) (data cutoff: January 10, 2022). Endpoints included symptomatic clinical response, symptomatic clinical remission, total Mayo score, clinical response, clinical remission, and corticosteroid (CS)-free remission up to OLE Week 94 (104 weeks of continuous ozanimod treatment). Data were evaluated using observed case (OC) and nonresponder imputation (NRI) analyses. Results A total of 226 nonresponders at TN Week 10 entered the OLE (Cohort 1, n=150; Cohort 2, n=76). Males comprised 67% of this subgroup, and mean (SD) age was 39.6 (13.6) years. Symptomatic clinical response (Figure 1), symptomatic clinical remission, and reduction in partial Mayo scores were observed as early as OLE Week 5 and were maintained through OLE Week 94. Minimal change in total Mayo score was observed from TN Week 0 (baseline) to TN Week 10 (OLE Week 0), but significant reductions from baseline occurred by OLE Week 46 (–4.2 [2.7]) and OLE Week 94 (–5.3 [2.6]). Overall, 62% of patients achieved clinical response, 26% achieved clinical remission, and 24% achieved CS-free remission at OLE Week 46; these increased to 74%, 35%, and 33%, respectively, by OLE Week 94 in the OC analysis (Figure 2). Data were similar between Cohorts 1 and 2. Conclusion Symptomatic response in ozanimod nonresponders was observed as early as 5 weeks after extended induction with ozanimod. Delayed response to ozanimod was maintained for up to 2 years as demonstrated by both symptomatic and objective endpoints. Even in those with delayed initial response, efficacy of ozanimod was durable.

P493 QUASAR Induction Study 1 Cumulative Response to Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis

Abstract Background Guselkumab (GUS), an IL-23p19 antagonist, had greater efficacy than placebo (PBO) in achieving clinical response and clinical remission at Week (Wk) 12 in the randomized, controlled Phase 2b QUASAR Induction Study 1 (NCT04033445) in patients with moderately to severely active ulcerative colitis (UC).1 Patients who were not in clinical response at Wk 12 received GUS treatment through Wk 24. Here, we report GUS cumulative efficacy and safety results for Induction Study 1. Methods Eligible patients had moderately to severely active UC (modified Mayo score of 5 to 9 with a Mayo endoscopy subscore ≥2) at baseline. Patients were randomized 1:1:1 to IV GUS 200mg, 400mg, or PBO at Wks 0, 4, and 8. Patients who were not in clinical response to IV induction at Wk 12 received GUS treatment (PBO IV→GUS 200mg IV; GUS 200mg IV→GUS 200mg SC; GUS 400mg IV→GUS 200mg SC) at Wks 12, 16, and 20 and were evaluated at Wk 24 (Figure 1). Matching IV or SC PBO was administered to maintain the blind. Results Three hundred thirteen patients were randomized and treated at baseline. Demographic and disease characteristics at baseline were similar among the treatment groups, and approximately 50% had a prior inadequate response or intolerance to advanced UC therapy. At Wk 12, clinical response was achieved by 61.4% (62/101) and 60.7% (65/107) of patients randomized to GUS 200mg and GUS 400mg IV vs 27.6% (29/105) of patients randomized to PBO IV (both p&amp;lt;0.001). Of the patients in the GUS groups who were not in clinical response at Wk 12, 54.3% (19/35) in the GUS 200mg IV→200mg SC group and 50.0% (19/38) in the GUS 400mg IV→200mg SC group achieved clinical response at Wk 24. Clinical response at Wk 12 or 24 was achieved by 80.2% of patients who were randomized to GUS 200mg IV and 78.5% of patients who were randomized to GUS 400mg IV. For patients who received PBO IV→GUS 200mg IV, clinical response at Wk 24 (65.2%) was similar to Wk 12 clinical response following GUS 200mg IV induction (61.4%). The most frequent adverse events among all GUS-treated pts (n=274) were anemia (7.7%), headache (5.1%), worsening UC (4.4%), COVID-19 (3.6%), arthralgia (2.9%) and abdominal pain (2.6%) which are consistent with Wk 12 results. Conclusion Overall, approximately 80% of patients randomized to receive GUS achieved clinical response at Wk 12 or 24. Continued treatment with SC GUS allowed 50-54.3% of IV GUS Wk 12 clinical nonresponders to achieve clinical response at Wk 24. No new safety concerns for GUS were identified.