Final results of the FAST study, an international, multicenter, randomized, phase II trial of epirubicin, oxaliplatin, and capecitabine (EOX) with or without the anti-CLDN18.2 antibody IMAB362 as first-line therapy in patients with advanced CLDN18.2+ gastric and gastroesophageal junction (GEJ) adenocarcinoma

Schüler, Martin; Al-Batran, S-E.; Zvirbule, Zanete; Manikhas, George; Lordick, Florian; Rusyn, A.; Vinnyk, Yuriy; Vynnychenko, I.; Fadeeva, Natalia; Nechaeva, M.; Dudov, A.; Gotovkin, E.; Pecheniy, Alexander; Bazin, I.; Bondarenko, Igor; Melichar, Bohuslav; Huber, Christoph; Türeci, Özlem; Şahin, Uğur

doi:10.1093/annonc/mdw371.06

Cited by 17 publications

(18 citation statements)

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“…Other notable genes relatively upregulated in SCCs were keratins KRT14 and KRT17 ; DSC3 , a member of the desmocollin family (a component of intercellular desmosomes); FAT2 , an atypical cadherin found to be induced by ΔNp63α (isoform of TP63) and promote invasion in LUSC [ 16 ]; EGFR , a key growth factor receptor in many cancers; CCNA1 , which encodes for cyclin A1, a cell cycle regulator; and WNT3A , a member of the Wnt family of signaling proteins, which also may have a role in SCCs [ 17 ]. Upregulated in ADCs were glandular markers such as mucins MUC3A and MUC13 ; claudins (which modulate tight junction permeability) CLDN2 and CLDN18 , which has recently been targeted therapeutically in advanced gastric and gastroesophageal junction adenocarcinomas [ 18 ]; drivers of cell differentiation such as GATA6 ; hepatic nuclear factors such as HNF1B , FOXA2 , FOXA3 ; and SPINK1 (serine protease inhibitor Kazal-type 1), which has been associated with a number of gastrointestinal and genitourinary cancers [ 19 ].…”

Section: Resultsmentioning

confidence: 99%

Comparative transcriptomes of adenocarcinomas and squamous cell carcinomas reveal molecular similarities that span classical anatomic boundaries

Lin

Karakasheva

Lee³

et al. 2017

PLoS Genet

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Advances in genomics in recent years have provided key insights into defining cancer subtypes “within-a-tissue”—that is, respecting traditional anatomically driven divisions of medicine. However, there remains a dearth of data regarding molecular profiles that are shared across tissues, an understanding of which could lead to the development of highly versatile, broadly applicable therapies. Using data acquired from The Cancer Genome Atlas (TCGA), we performed a transcriptomics-centered analysis on 1494 patient samples, comparing the two major histological subtypes of solid tumors (adenocarcinomas and squamous cell carcinomas) across organs, with a focus on tissues in which both subtypes arise: esophagus, lung, and uterine cervix. Via principal component and hierarchical clustering analysis, we discovered that histology-driven differences accounted for a greater degree of inherent molecular variation in the tumors than did tissue of origin. We then analyzed differential gene expression, DNA methylation, and non-coding RNA expression between adenocarcinomas and squamous cell carcinomas and found 1733 genes, 346 CpG sites, and 42 microRNAs in common between organ sites, indicating specific adenocarcinoma-associated and squamous cell carcinoma-associated molecular patterns that were conserved across tissues. We then identified specific pathways that may be critical to the development of adenocarcinomas and squamous cell carcinomas, including Liver X receptor activation, which was upregulated in adenocarcinomas but downregulated in squamous cell carcinomas, possibly indicating important differences in cancer cell metabolism between these two histological subtypes of cancer. In addition, we highlighted genes that may be common drivers of adenocarcinomas specifically, such as IGF2BP1, which suggests a possible link between embryonic development and tumor subtype. Altogether, we demonstrate the need to consider biological similarities that transcend anatomical boundaries to inform the development of novel therapeutic strategies. All data sets from our analysis are available as a resource for further investigation.

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Section: Resultsmentioning

confidence: 99%

Comparative transcriptomes of adenocarcinomas and squamous cell carcinomas reveal molecular similarities that span classical anatomic boundaries

Lin

Karakasheva

Lee³

et al. 2017

PLoS Genet

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“…Data from a recent randomized phase II, open-label study was presented that assessed the safety and antitumor activity of IMAB362 in combination with standard of care chemotherapy, which includes immunogenic cell death inducers. 49-51 Addition of IMAB362 to chemotherapy highly significantly improved both overall and progression-free survival compared with chemotherapy alone and was generally well tolerated with largely manageable adverse events. In the subgroup of highly CLDN18.2-positive patients near-doubling of the median overall survival was observed.…”

Section: Antibodies Helper T-cell Physiologymentioning

confidence: 97%

CIMT 2017: Anniversary symposium - Report on the 15th CIMT Annual Meeting of the Association for Cancer Immunotherapy

Kranz

Beck

Grunwitz

et al. 2017

Human Vaccines & Immunotherapeutics

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“…A ray of hope on the horizon of targeted therapies in a first line setting is provided by the phase II FAST study, which showed a sufficient inhibition of the tight junction protein claudin 18.2 with the monoclonal antibody zolbetuximab (median OS 8.4 months with chemotherapy regimen EOX vs. 13.2 months with zolbetuximab; HR 0.51, 95% CI 0.36-0.73; p = 0.0001) [37]. Due to this finding, two large phase III trials investigating zolbetuximab with different chemotherapy backbones, either with CAPOX or FOLFOX, are currently ongoing and results are expected to be published in the next few years.…”

Section: First Linementioning

confidence: 99%

New Treatment Options for Advanced Gastroesophageal Tumours: Mature for the Current Practice?

Puhr

Preusser

Prager

2020

Cancers

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Several clinical trials attempted to identify novel treatment options for advanced gastroesophageal tumours in first, second and further lines. Although results of targeted therapy regimens were mainly disappointing, novel immunotherapy agents showed promising activity, which led to their approval in second and third lines in many countries. This review focuses on the results of recent clinical trials investigating novel agents including targeted therapies, immunotherapy components and chemotherapies and discuss their current impact as well as current approval status on the treatment armamentarium of advanced gastroesophageal tumours.

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Cited by 17 publications

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Comparative transcriptomes of adenocarcinomas and squamous cell carcinomas reveal molecular similarities that span classical anatomic boundaries

Comparative transcriptomes of adenocarcinomas and squamous cell carcinomas reveal molecular similarities that span classical anatomic boundaries

CIMT 2017: Anniversary symposium - Report on the 15th CIMT Annual Meeting of the Association for Cancer Immunotherapy

New Treatment Options for Advanced Gastroesophageal Tumours: Mature for the Current Practice?

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