A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study

Türeci, Özlem; Şahin, Uğur; Schulze‐Bergkamen, Henning; Zvirbule, Zanete; Lordick, Florian; Koeberle, Dieter; Thuss‐Patience, Peter; Ettrich, Thomas Jens; Arnold, Dirk; Bassermann, Florian; Al-Batran, S-E.; Wiechen, Kai; Dhaene, Karl; Maurus, Daniel; Gold, Michael A.; Huber, Christoph; Krivoshik, Andrew; Arozullah, Ahsan M.; Park, J.W.; Schüler, Martin

doi:10.1093/annonc/mdz199

Cited by 163 publications

(164 citation statements)

References 19 publications

(21 reference statements)

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“…To best of our knowledge, the present study is the largest systematic investigation of claudin 18.2 protein expression in EAC (n=485) in addition to the first study to detect claudin 18.2 expression in corresponding regional lymph node metastases using a commercially available monoclonal antibody, which was also used in other studies on gastric cancer (18)(19)(20)30). The present study demonstrated detectable claudin 18.2 expression in up to 18.4% of EAC cases.…”

Section: Discussionmentioning

confidence: 49%

“…Claudin 18.2 is an interesting tight-junction protein that may be therapeutically modifiable and whose relevance is currently being tested in studies on gastric cancer (16,(18)(19)(20)(21)28). In these studies, the response to therapy is associated with the measurable presence of the protein in the tumor (16,(18)(19)(20)(21)30). This may make claudin 18.2 a relevant biomarker, as we have known for years with programmed death-ligand 1, HER2/neu or hormone receptors in breast carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…IMAB362, a novel antibody targeting claudin 18.2, has been investigated in various phase I and phase II studies for patients with gastric and/or gastro-esophageal junction cancer and has exhibited anti-tumor activity (16,(18)(19)(20)(21)28). Gastrointestinal toxicities were the most commonly observed treatment-associated adverse events (18)(19)(20)30).…”

Section: Discussionmentioning

confidence: 99%

“…no DS9800) was used for 5 min at 37˚C. The primary antibody detects the same isoform 2 of Claudin 18 as described in clinical studies previously (19,30). Normal gastric mucosa served as an internal control.…”

Section: Methodsmentioning

confidence: 99%

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Claudin 18.2 expression in esophageal adenocarcinoma and its potential impact on future treatment strategies

et al. 2020

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The incidence of esophageal adenocarcinoma (EAC) has rapidly increased, particularly in the Western world. Despite improvements in perioperative treatments, the overall survival of patients remains low. Claudin 18.2 is a tight junction protein that is exclusively expressed in the gastric epithelia. However, following malignant transformation, gastric cancer metastases maintain this expression. Therefore, claudin 18.2 is a promising target for immunotherapy. Previous clinical trials have revealed improved anti-tumor activity in patients treated with an anti-claudin antibody by investigating the expression of claudin 18.2 in tumor cells. However, there is currently very limited data on the importance of claudin 18.2 expression in EAC. The present study analyzed the distribution of claudin 18.2 using immunohistochemistry in 485 patients with EAC, including their lymph node metastases. Additionally, these results were associated with clinical and molecular data. Claudin 18.2 was detected in 89/485 patients (18.4%). No correlations between expression and clinicopathological data (sex, age, pT stage, lymph node metastasis and grading) were observed. However, significantly decreased claudin 18.2 expression was observed in tumor types with upregulated human epidermal growth factor receptor 2 expression (P=0.036). Additionally, neoadjuvant treatment did not have any significant impact on claudin 18.2 expression (P= 0.331). To the best of our knowledge, the present study is the largest systematic investigation of claudin 18.2 protein expression in EAC. The results obtained suggested that claudin 18.2 may serve as a promising therapeutic target in a substantial number of patients with EAC.

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Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Claudin 18.2 expression in esophageal adenocarcinoma and its potential impact on future treatment strategies

et al. 2020

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“…This antibody was demonstrated to mediate cancer cell death through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In several early clinical trials for the treatment of advanced gastric cancer (GC), zolbetuximab alone or in combination with standard chemotherapy significantly prolonged survival with acceptable safety and tolerability [8,9].…”

Section: Introductionmentioning

confidence: 99%

Identification of CLDN18 as a potential diagnostic biomarker and therapeutic target for pancreatic cancer based on multiomic analysis

Li¹,

Zhang²,

Hu³

2020

Preprint

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Background Claudin 18 (CLDN18) is a transmembrane protein localized in the apical regions to form a tight-junction complex. The expression of CLDN18 was restricted to normal lung and stomach tissues but was aberrantly activated in some types of cancers, and this molecule can serve as a promising target for targeted treatment. Methods The mRNA expression, genetic variations and prognostic values of CLDN18 in pancreatic cancer (PC) were analyzed using public data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Human Protein Atlas (HPA) databases and multiple online tools. The role of cyclic AMP-responsive element binding protein (CREB) and DNA methylation in regulating the expression of CLDN18 was determined by correlation analysis. Results The expression of CLDN18 was restricted to the lung and stomach in normal tissues, but was ectopically overexpressed in PC. CLDN18 mRNA expression was higher in cancers with advanced local invasion, later clinical stage, infiltrating duct or mucinous carcinoma types. Genetic variations of CLDN18 are rarely observed in PC. Correlation analysis revealed that CREB3L1, CREB3L3, and CREB3L4 were significantly positively coexpressed with CLDN18, and CLDN18 expression increased as methylation gradually decreased. The expression of CLDN18 was not observed to plays a role in predicting the survival of PC patients. Conclusions This data-driven study summarizes the expression features of CLDN18 in PC and demonstrates that it may serve as an ideal biomarker and therapy target for PC.

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Histological and mutational profile of diffuse gastric cancer: current knowledge and future challenges

et al. 2021

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Gastric cancer (GC) pathogenesis is complex and heterogeneous, reflecting morphological, molecular, and genetic diversity. Diffuse gastric cancer (DGC) and intestinal gastric cancer (IGC) are the major histological types. GC may be sporadic or hereditary; sporadic GC is related to environmental and genetic low-risk factors and hereditary GC is caused by inherited high-risk mutations, so far identified only for the diffuse histotype.DGC phenotypic heterogeneity challenges the current understanding of molecular mechanisms underlying carcinogenesis. The definition of a DGC-specific mutational profile remains controversial, possibly reflecting the heterogeneity of DGC-related histological subtypes (Signet-Ring Cell Carcinoma (SRCC) and Poorly Cohesive Carcinoma not otherwise specified (PCC-NOS)). Indeed, DGC and DGC-related subtypes may present specific mutational profiles underlying the particularly aggressive behaviour and dismal prognosis of DGC vs IGC and PCC-NOS vs SRCC.In this systematic review, we revised the histological presentations, molecular classifications, and approved therapies for gastric cancer, with a focus on DGC. We then analysed results from the most relevant studies, reporting mutational analysis data specifying mutational frequencies, and their relationship with DGC and IGC histological types, and with specific DGC subtypes (SRCC and PCC-NOS). We aimed at identifying histology-associated mutational profiles with an emphasis in DGC and its subtypes (DGC vs IGC; sporadic vs hereditary DGC; and SRCC vs PCC-NOS). We further used these mutational profiles to identify the most commonly affected molecular pathways and biological functions, and explored the clinical trials directed specifically to patients with DGC. This systematic analysis is expected to expose a DGC-specific molecular profile and shed light into potential targets for therapeutic intervention, which are currently missing.

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A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study

Cited by 163 publications

References 19 publications

Claudin 18.2 expression in esophageal adenocarcinoma and its potential impact on future treatment strategies

Claudin 18.2 expression in esophageal adenocarcinoma and its potential impact on future treatment strategies

Identification of CLDN18 as a potential diagnostic biomarker and therapeutic target for pancreatic cancer based on multiomic analysis

Histological and mutational profile of diffuse gastric cancer: current knowledge and future challenges

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