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      Phase 1 multicenter, dose-expansion study of ARX788 as monotherapy in HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma

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          Summary

          ARX788 is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate with AS269 as cytotoxic payload. In this phase 1 multicenter dose-expansion clinical trial, patients with HER2-positive advanced gastric/gastroesophageal junction adenocarcinoma failing to respond to prior trastuzumab-based standard treatment were enrolled. Between July 15 th, 2019, and March 14 th, 2022, 30 participants were enrolled. Twenty-eight (93.3%) patients experienced at least one drug-related adverse event (AE) and 13.3% experienced grade 3 ARX788-related AEs. The confirmed objective response rate is 37.9% (95% confidence interval [CI]: 20.7%–57.7%) and the disease control rate is 55.2% (95% CI: 35.7%–73.6%). With a median follow up of 10 months, the median progression-free survival and overall survival are 4.1 (95% CI: 1.4–6.4) and 10.7 months (95% CI: 4.8–not reached), respectively. The median duration of response is 8.4 (95% CI: 2.1–18.9) months. ARX788 is well tolerated and has promising anti-tumor activity in patients with HER2-positive advanced gastric adenocarcinoma ( ChinaDrugTrials.org.cn: CTR20190639).

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          Highlights

          • •

            ARX788 is an anti-HER2 antibody-drug conjugate with AS269 as cytotoxic payload

          • •

            ARX788 is well tolerated and has promising anti-tumor activity in this phase 1b study

          • •

            Mutation rate of ERBB2 was higher in the responders than in the nonresponders

          Abstract

          Zhang et al. demonstrate the safety, efficacy, and survival of an anti-HER2 antibody-drug conjugate, ARX788, in patients with HER2-positive advanced gastric adenocarcinoma. They show that ARX788 is well tolerated and has promising anti-tumor activities for HER2-positive advanced gastric adenocarcinoma.

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          Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

          Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)
          This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
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            The Ensembl Variant Effect Predictor

            William McLaren, Laurent Gil, Sarah Hunt … (2016)
            The Ensembl Variant Effect Predictor is a powerful toolset for the analysis, annotation, and prioritization of genomic variants in coding and non-coding regions. It provides access to an extensive collection of genomic annotation, with a variety of interfaces to suit different requirements, and simple options for configuring and extending analysis. It is open source, free to use, and supports full reproducibility of results. The Ensembl Variant Effect Predictor can simplify and accelerate variant interpretation in a wide range of study designs.
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              Maftools: efficient and comprehensive analysis of somatic variants in cancer

              Anand Mayakonda, De-Chen Lin, Yassen Assenov … (2018)
              Numerous large-scale genomic studies of matched tumor-normal samples have established the somatic landscapes of most cancer types. However, the downstream analysis of data from somatic mutations entails a number of computational and statistical approaches, requiring usage of independent software and numerous tools. Here, we describe an R Bioconductor package, Maftools, which offers a multitude of analysis and visualization modules that are commonly used in cancer genomic studies, including driver gene identification, pathway, signature, enrichment, and association analyses. Maftools only requires somatic variants in Mutation Annotation Format (MAF) and is independent of larger alignment files. With the implementation of well-established statistical and computational methods, Maftools facilitates data-driven research and comparative analysis to discover novel results from publicly available data sets. In the present study, using three of the well-annotated cohorts from The Cancer Genome Atlas (TCGA), we describe the application of Maftools to reproduce known results. More importantly, we show that Maftools can also be used to uncover novel findings through integrative analysis.
              Article 0 comments Cited 1892 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Rui-Hua Xu
                Journal
                Journal ID (nlm-ta): Cell Rep Med
                Journal ID (iso-abbrev): Cell Rep Med
                Title: Cell Reports Medicine
                Publisher: Elsevier
                ISSN (Electronic): 2666-3791
                Publication date PMC-release: 15 November 2022
                Publication date Collection: 15 November 2022
                Publication date (Electronic): 15 November 2022
                Volume: 3
                Issue: 11
                Electronic Location Identifier: 100814
                Affiliations
                [1 ]Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
                [2 ]Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
                [3 ]Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, P.R. China
                [4 ]Department of Oncology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, P.R. China
                [5 ]Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, P.R. China
                [6 ]Bioinformatics Platform, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
                [7 ]Department of Medical Oncology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, P.R. China
                [8 ]Department of Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
                [9 ]Novocodex Biopharmaceuticals, Shaoxing, P.R. China
                Author notes
                [∗ ]Corresponding author xurh@ 123456sysucc.org.cn
                [10]

                These authors contributed equally

                [11]

                Lead contact

                Article
                Publisher Item ID: S2666-3791(22)00373-1 Publisher ID: 100814
                DOI: 10.1016/j.xcrm.2022.100814
                PMC ID: 9729820
                PubMed ID: 36384091
                SO-VID: fb9c4ca8-fb87-4a41-b8c4-ecacfd8bbd72
                Copyright © © 2022 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 16 July 2022
                Date revision received : 13 September 2022
                Date accepted : 17 October 2022
                Categories
                Subject: Article

                Keywords: gastric cancer,gastroesophageal junction,human epidermal growth factor receptor 2,arx788,antibody-drug conjugate
                Data availability:
                Keywords: gastric cancer, gastroesophageal junction, human epidermal growth factor receptor 2, arx788, antibody-drug conjugate

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