Introduction

The QUASAR program (NCT04033445) evaluated guselkumab (GUS), a dual-acting interleukin (IL)-23p19 subunit inhibitor that potently neutralizes IL-23 and binds to CD64 (a receptor on cells that produce IL-23), in patients (pts) with moderately to severely active ulcerative colitis (UC). Induction Week 12 (Week I-12) nonresponders to intravenous (IV) GUS received subcutaneous (SC) GUS through Week I-24.¹ Week I‑24 responders were eligible for maintenance therapy. Here, we present the efficacy and safety of maintenance SC GUS among GUS Week I-24 responders.

Aims & Methods

Pts who were not in clinical response (see Table for definition) at Week I-12 after IV GUS 200 mg or 400 mg received SC GUS 200 mg at Weeks I-12, I-16, and I-20. Those who were in clinical response at Week I-24 (GUS Week I-24 responders) received SC GUS 200 mg every 4 weeks during the maintenance study in a blinded fashion and were evaluated as part of the nonrandomized study population. Clinical, symptomatic, endoscopic, histologic, and patient-reported outcome measures at maintenance Week 44 (Week M-44) and safety throughout the maintenance study are reported for GUS Week I-24 responders.

Results

Overall, 123 of 203 (60.6%) Week I-12 nonresponders to IV GUS achieved clinical response at Week I-24 and entered the maintenance study phase. Induction baseline characteristics of GUS Week I-24 responders were: 74.8% had severe disease (modified Mayo score 7-9), 77.2% had a Mayo endoscopy subscore of 3, median C-reactive protein was 5.0 mg/L (upper limit of normal, 3 mg/L), and 59.3% had a history of inadequate response or intolerance to biologic or Janus kinase inhibitor therapy for UC. At Week M‑44, 67.5% of the pts maintained clinical response and 30.1% were in clinical remission. Additional efficacy outcomes are shown in the Table. The proportion of GUS Week I-24 responders in symptomatic remission (defined as a stool frequency subscore of 0 or 1 and not increased from induction baseline, and a rectal bleeding subscore of 0) at maintenance baseline (58.5%) was sustained through Week M‑44 (56.9%). Adverse events (AEs) were reported for 78.0% of GUS Week I-24 responders, serious AEs for 5.7%, and serious infections for 1.6%. No opportunistic infections or deaths occurred. No new safety concerns were identified.

Conclusion

In this refractory population of GUS Week I-24 responders, maintenance treatment with GUS provided clinical benefit across a range of clinically relevant efficacy endpoints. Safety results were consistent with the overall population and safety profile of GUS in its approved indications.

References

1. Bressler B, et al. Am J Gastroenterol. 2023;118(10S):806-807.

Disclosure

D. T. Rubin: research funding from Takeda; consultant to AbbVie, Altrubio, Allergan, Arena, Aslan, Athos, Bellatrix, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corp/Syneos, Connect, GalenPharma/Atlantica, Genentech/Roche, InDex, Ironwood, Iterative Scopes, Janssen, Lilly, Pfizer, Prometheus, Reistone, Takeda, and Techlab; and co-founder of Cornerstones Health.
A. Dignass: fees for participation in clinical trials, review activities (data monitoring boards, statistical analysis, endpoint committees) from Abivax, AbbVie, Bristol Myers Squibb, Dr Falk Foundation, Galapagos, Gilead, Janssen, and Pfizer; consultancy fees from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Dr Falk Foundation, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Roche, Sandoz, Stada, Takeda, Tillotts, and Vifor Pharma; payment for lectures/speaker’s bureaus from AbbVie, Biogen, CED Service GmbH, Celltrion, Falk Foundation, Ferring, Galapagos, Gilead, High5MD, Janssen, Materia Prima, MedToday, MSD, Pfizer, Sandoz, Takeda, Tillotts, and Vifor Pharma; payment for manuscript preparation from Abbvie, Falk Foundation, Janssen, Takeda, Thieme, and UniMed Verlag.
J. R. Allegretti: consultant for AbbVie, Adiso, Ferring, Finch, Iterative Scopes, Janssen, Merck, Pfizer, Roivant, and Seres Therapeutics; speaker for AbbVie, Bristol Myer Squibb, and Janssen; and research support from Janssen, Merck, and Pfizer.
Y. Rayyan: fees for participating in clinical trials for Janssen as principal investigator and payment from lectures including service on speaker’s bureaus from Janssen, AbbVie, and Amgen.
M. Saruta: grants or contracts from Mochida, Zeria Pharma, EA Pharma, Kissei, and EPS Corporation; and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from AbbVie GK, Janssen, Mitsubishi Tanabe Pharma, Takeda, EA Pharma, Gilead Sciences, and Kissei.
D. Balderramo: advisor/speaker fees from AbbVie, Janssen, Pfizer, Takeda, and Amgen; and travel/congress support from AbbVie, Janssen, Takeda, and Ferring.
B. Bressler: advisor/speaker for AbbVie, Bristol Myers Squibb, Ferring, Janssen, Merck, Novartis, Organon, Pfizer, Sandoz, and Takeda; advisor for Alimentiv, Allergan, Amgen, AMT, Bausch Health, Bristol Myers Squibb, Celgene, Celltrion, Eupraxia Fresenius Kabi, Genentech/Roche, Gilead, Iterative Scopes, Jamp, Merck, Microbiome Insights, Mylan, Pendopharm, Protagonist, and Viatris; research support from AbbVie, Amgen, Business Intelligence, Bristol Myers Squibb, Genentech/Roche, GlaxoSmithKline, Janssen, Merck, and Qu Biologic; and holds stock options in Qu Biologic.
L. Peyrin-Biroulet: consultant for AbbVie, Abivax, Alimentiv, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol Myers Squibb, Celltrion, Connect, Cytoki, Lilly, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech/Roche, Gilead, Gossamer Bio, GlaxoSmithKline, HAC-Pharma, IAG, InDex, Inotrem, Janssen, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM, ONO, OSE, Pandion, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, and Ysopia; grants from Celltrion, Fresenius Kabi, and Takeda; honorarium for lectures from AbbVie, Amgen, Arena, Biogen, Celltrion, Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Janssen, Medac, MSD, Pfizer, Sandoz, Takeda, Tillots, Viatris, and Vifor; and fees from AbbVie, Adacyte, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Nordic Pharma, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Sanofi, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, Ysopia, Abivax, Samsung, Ventyx, Roivant, and Vectivbio.
T. Hisamatsu: grant support from AbbVie, Daiichi-Sankyo, EA Pharma, JIMRO, Mitsubishi Tanabe Pharma, Mochida, Nippon Kayaku, Pfizer, and Takeda; consulting fees from EA Pharma, Janssen Research & Development, Gilead Sciences, Lilly, and Bristol Myers Squibb; and lecture fees from AbbVie, EA Pharma, Mitsubishi Tanabe Pharma, Takeda, Mochida, and Kissei.
S. Yarandi, K.-H. G. Huang, M. Germinaro, J. Zhan, and H. Zhang: employees of Johnson & Johnson and own company stock/stock options.

Introduction

Immune checkpoint Inhibitors (ICIs) such as Atezolizumab/Bevacizumab (ATEZO/BEV) and Tremelimumab/Durvalumab (STRIDE) have shown promising results compared to Sorafenib in treating patients with advanced HCC. However, with median follow-up durations of 18 months and 33 months in the IMbrave150 and HIMALAYA trials respectively, the long-term survival outcomes of these therapies remain unknown. This study aims to predict the long-term survival outcome of these therapies through a reconstructed individual participant data meta-analysis.

Aims & Methods

Medline and Embase databases were searched for relevant studies. We included Phase II – IV randomized controlled trials (RCTs) with Kaplan-Meier survival curves on the use of Sorafenib in treating advanced HCC. We identified studies relating to the use of ATEZO/BEV or STRIDE in patients with advanced HCC. The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). We extracted individual patent data using the methods outlined by Guyot et al¹ and conducted an aggregate pooling with the arcsine-transformed survival probabilities in a random effects model using MetaSurv to predict long-term survival outcomes at 12, 36 and 60 months follow-up. Restricted mean survival time (RMST) analysis was used to estimate the survival benefit of ATEZO/BEV or STRIDE versus Sorafenib at 60-months follow-up.

Results

A total of 29 RCTs were included, with 336, 393 and 5525 individuals treated with ATEZO/BEV, STRIDE and Sorafenib respectively. The median OS for patients on ATEZO/BEV, STRIDE and Sorafenib were 19.1 months (CI: 17.1 – 23.9) 16.4 months (CI: 14.5 – 20.4) and 10.8 months (CI: 10.5 – 11.2) respectively. The predicted 12-, 36- and 60-months survival for patients receiving ATEZO/BEV was 60.51% (CI: 59.32 – 61.88%), 27.08% (CI: 24.93 – 29.28%) and 18.21% (CI: 13.38 – 23.65%) respectively. The predicted survival at 12-, 36-, and 60-months for patients receiving STRIDE was 55.23% (CI: 53.95 – 56.49%), 21.36 (CI: 19.37% - 23.42%) and 13.36% (CI: 9.27 – 18.20%) respectively. Compared to Sorafenib, the mean survival of ATEZO/BEV and STRIDE were 4.68 months (CI: 2.40 – 6.95 months) and 3.25 months (CI: 1.16 – 5.34 months) longer respectively. RMST analysis revealed no significant difference in OS between ATEZO/BEV versus STRIDE at 12-, 36-, and 60-months. The median PFS was 6.90 months (CI: 5.80 - 8.30), 3.85 months (CI: 3.67 - 5.35), and 4.07 months (CI: 3.81 - 4.18) for ATEZO/BEV, STRIDE, and sorafenib respectively. At 44-months, ATEZO/BEV had a statistically significantly longer PFS of 2.92 months (CI: 1.21 – 4.63 months, p<0.01) compared to STRIDE.

Conclusion

Compared to Sorafenib, there is projected clinically meaningful increases survival of ATEZO/BEV and STRIDE relative to Sorafenib. In addition, an extended analysis of PFS to 44-months suggests a significantly longer PFS of ATEZO/BEV over STRIDE. Our study suggests that ICIs could be considered as first-line agents in treating advanced HCC. However, these data are based on historical survival data from sorafenib and there is still limited data for the respective ATEZO/BEV and STRIDE treatment regimes. There remains a need for further studies to better define the sequencing of therapies beyond the first-line setting.

References

1. Guyot P, Ades AE, Ouwens MJNM, Welton NJ. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. BMC Medical Research Methodology. 2012;12(1):9.

Introduction

Patients with ulcerative colitis (UC) often have unpredictable response over time. Using clinical parameters has proven useful, however, deeper understanding of the molecular and cellular mechanisms that influence therapeutic outcomes in head-to-head trials is lacking. Here we performed a large-scale transcriptomics analysis of tissue biopsies derived from moderate-to-severe UC patients treated with vedolizumab (VDZ) or adalimumab (ADA) in the VARSITY trial (Sands, 2019).

Aims & Methods

The aim of this study was to identify biomarkers of response to VDZ and ADA treatment. We performed bulk RNA sequencing of 954 biopsies collected using the flexible sigmoidoscopy from pre-treatment/baseline, week (w)14 and w52. Our dataset comprised complete longitudinal tissue sampling of n=151 non-responders, n=117 responders based on clinical remission at w52. We employed comparative analysis to pinpoint differentially expressed genes (DEG) and differential pathways for ADA and VDZ treated patients. We then employed systems network strategies to identify gene modules (Choobdar, 2019) associated with clinical parameters. Finally, we utilized multivariate trajectory model (Nagin, 2018) to characterise longitudinal patient trajectories based on study endpoints and integrated transcriptomics signatures to patient variable response (Schreiber, 2023).

Results

Variable baseline gene expression profile was associated with prior exposure to anti-TNFα, corticosteroid or immunomodulator treatment. DEG and gene-modules linked to VDZ response in tissue biopsies revealed inflammatory, fibrotic, epithelial, and neuronal pathways, including but not limited to JAK/STAT, G-Protein Coupled Receptor signalling, ECM interactions, oxidative phosphorylation, and neuroglial signatures. Importantly, these consistent gene and gene-module predictors of clinical remission were detected at pre- and post-treatment (w14 and w52) to VDZ. For ADA treated patients, no DEG and gene-modules were significantly associated with treatment-response at baseline after FDR correction. Upon relaxing stringency, we were able to find pathways such as neutrophil degranulation, MAPK signalling, and Fc-mediated immune regulation linked to ADA response.
Cell type contributions were in silico inferred with deconvolution analysis of bulk gene expression data. In agreement with the pathway analysis, we identified epithelial, plasma, stromal populations as baseline biomarkers of response to VDZ, while specific CD4+, CD8+ T cell subsets, follicular B cells and inflammation-associated fibroblasts were significantly elevated in non-responders compared to the responders to VDZ from baseline to post-treatment. In ADA non-responding patients, CD4+ T cells were significantly increased compared to responders at baseline and post-treatment. Gene-module predictors were linked to distinct patients' trajectories based on symptoms; the greatest correlations with transcriptomics findings were observed between our extreme responding groups from trajectory analyses.

Conclusion

We present first-of-a-kind analysis using large-scale clinical trial integrating longitudinal bulk RNA-seq analysis with clinical outcomes in response to two different therapies. For VDZ, as opposed to ADA, we were able to find strong baseline predictors also preserved after treatment. We hope that similar approaches could support clinical precision medicine applications to help patients achieve faster and lasting disease control.

References

Sands, BE, et al. N Engl J Med 2019;381(13):1215-1226.
Choobdar, S, et al. Nat Methods 2019;16(9):843-852.
Nagin DS, et al. Statistical Methods in Medical Research 2018;27(7):2015-2023
Schreiber, et al., United European Gastroenterology Journal 2023; 11 (Supplement 8)

Disclosure

All authors are employees and shareholders of Takeda.

Introduction

There has been a resurgence in the use of bismuth quadruple therapy (PPI, bismuth, tetracycline and metronidazole) in Europe with the commercialisation of a three-in-one single-capsule formulation, but the experience with this regimen is still limited.

Aims & Methods

To evaluate the effectiveness and safety of the three-in-one single-capsule in the European Registry on Helicobacter pylori Management (Hp-EuReg).
International, multicenter, prospective, non-interventional registry aimed to evaluate the decisions and outcomes of H. pylori management by European gastroenterologists (Hp-EuReg). All infected adult patients treated with 10-day single-capsule according to data sheet (3 capsules/6h) or alternative three times a day (4 capsules/8h) prescriptions were systematically registered at AEG-REDCap e-CRF until December 2023. Variables included: Patient’s demographics, previous eradication attempts, prescribed treatment, adverse events, and outcomes. Modified intention-to-treat (mITT) and per-protocol (PP) analyses were performed, and data were subject to quality review.

Results

Of the 70,683 patients included in the Hp-EuReg, 11,130 (16%) received single-capsule bismuth quadruple therapy. The majority of these patients were naïve (77%), with an average age of 51 years, 61% female and 14% with peptic ulcer. Overall, the single-capsule achieved a high eradication rate based on the mITT (92%) and PP (93%) analyses. Effectiveness (mITT) was higher when using the single-capsule as a first-line treatment (94%), but it had also high effectiveness as a rescue therapy, both in second-line (88%) or subsequent lines of therapy (3^rd-6^th lines: 84%) (Table 1). Compliance with treatment (>90% of drug intake) was reported in 97% of cases and was the factor most closely associated with the effectiveness of treatment. Adverse events (26%) were generally mild and transient; only 0.1% of patients reported serious adverse events, leading to the discontinuation of treatment in 1.7% of patients.

Conclusion

The 10-day treatment with single-capsule bismuth quadruple therapy achieves H. pylori eradication in approximately 90% of patients by mITT in real-world clinical practice, both as a first-line and rescue treatment, with a favourable safety profile.

Disclosure

Javier P. Gisbert has served as speaker, consultant, and advisory member for or has received research funding from: Mayoly, Allergan/Abbvie, Diasorin, Richen, Juvisé and Biocodex.
Olga P. Nyssen received research funding from: Mayoly, Allergan/Abbvie, Richen, Juvisé and Biocodex.