Research progress of antibody-drug conjugates therapy for HER2-low expressing gastric cancer

Yu, Miao; Liang, Yangyueying; Li, Longhui; Zhao, Lu; Kong, Fanming

doi:10.1016/j.tranon.2023.101624

Cited by 5 publications

(3 citation statements)

References 56 publications

(79 reference statements)

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“… 27 , 28 , 29 , 30 Furthermore, in the context of HER2 therapies, trastuzumab deruxtecan, a HER2‐targeted antibody–drug conjugate, demonstrated remarkable efficacy in patients with breast cancer characterized by HER2‐low expression. 31 , 32 , 33 , 34 A higher response rate of trastuzumab deruxtecan in patients with high ERBB2 expression by WTS and no HER2 IHC expression in a phase 2 study for breast cancer also supports our finding. 32 Nevertheless, there are no extensive studies on treatment effectiveness specifically in cases that are IHC negative but show high expression of WTS in some specific biomarkers.…”

Section: Discussionsupporting

confidence: 84%

“…Recent studies have reported the potential utility of WTS‐derived RNA expression in treatment prediction 27–30 . Furthermore, in the context of HER2 therapies, trastuzumab deruxtecan, a HER2‐targeted antibody–drug conjugate, demonstrated remarkable efficacy in patients with breast cancer characterized by HER2‐low expression 31–34 . A higher response rate of trastuzumab deruxtecan in patients with high ERBB2 expression by WTS and no HER2 IHC expression in a phase 2 study for breast cancer also supports our finding 32 .…”

Section: Discussionsupporting

confidence: 84%

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Whole‐transcriptome sequencing in advanced gastric or gastroesophageal cancer: A deep dive into its clinical potential

Hashimoto,

Nakamura,

Mishima

et al. 2024

Cancer Science

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Advanced gastric and gastroesophageal junction cancers (GC/GEJCs) harbor diverse molecular signatures, highlighting the need for intricate evaluations to identify potential therapeutic targets. Although whole‐transcriptome sequencing (WTS) has emerged as a useful tool for understanding these molecular intricacies, its clinical implications have yet to be fully elucidated. This study evaluated the correlation between immunohistochemistry (IHC) and WTS, compared their clinical significance, and identified potential therapeutic targets undetectable through IHC alone. We enrolled 140 patients with advanced GC/GEJC and assessed them using IHC for six pivotal biomarkers: claudin‐18 (CLDN18), human epidermal growth factor receptor 2 (HER2), multiple receptor tyrosine kinases (RTKs), and programmed death ligand 1 (PD‐L1). Concurrently, WTS was employed as part of the analyses in MONSTAR‐SCREEN‐2, a multicenter multiomics study. IHC analysis revealed 16.4% HER2, 39.3% CLDN18 (2+/3 + ≥75%), and 15.8% PD‐L1 (combined positive score ≥ 10) positivity, among other molecular markers. Significant correlations were observed between IHC and WTS for all six pivotal biomarkers. Among nineteen HER2 IHC‐positive patients treated with anti‐HER2 therapeutics, ERBB2 status in WTS was significantly associated with progression‐free survival (ERBB2‐high vs. ‐low: median 9.0 vs. 5.6 months, log‐rank p = 0.046). IHC‐based molecular profiling revealed significantly high expression of CLDN18 in RTK‐negative patients, with 78.4% positive for either CLDN18 or PD‐L1. Additionally, WTS revealed elevated expression of pivotal biomarkers in patients displaying negative targetable biomarkers via IHC. Our findings highlighted the significant correlation between IHC and WTS, reinforcing the clinical utility of WTS. A subset with IHC‐negative but WTS‐positive status may benefit from specific biomarker‐targeted therapies.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 84%

Whole‐transcriptome sequencing in advanced gastric or gastroesophageal cancer: A deep dive into its clinical potential

Hashimoto,

Nakamura,

Mishima

et al. 2024

Cancer Science

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“…Additional HER2 ADCs are being explored in HER2-positive GAC. RC48 is an ADC composed of hertuzumab, an anti-HER2 mAb conjugated to a microtubule inhibitor, monomethylauristatin E (MMAE) [26,27]. A phase 2 trial in ICH 2+/3+ advanced GAC patients in the refractory setting showed an ORR of 24.8%, median PFS of 4.1 months, and median OS of 7.9 months [25][26][27].…”

Section: Antibody Drug Conjugates (Adcs)mentioning

confidence: 99%

Human Epidermal Growth Factor Receptor-2 Gastric Adenocarcinoma: Expanding Therapy of a Recognized Target

Rogers,

Yamashita,

Sewastjanow-Silva

et al. 2023

Cancers

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Human epidermal growth factor receptor-2 (HER2) is a well-known cancer target. Many HER2-targeted agents are marketed and being investigated. Unfortunately, these therapies lack consistent responses and outcomes amongst different tumors. Questions remain as to why HER2 biology is different in different tumor types. Gastric adenocarcinomas (GACs) demonstrate both intra- and inter-tumor HER2 expression heterogeneity and show discordance amongst primary and metastatic disease sites. This creates barriers in determining HER2 agents’ effectiveness and contributes to the failure of some HER2-targeted agents in the treatment of HER2-positive advanced GACs. Trastuzumab deruxtecan, an antibody drug conjugate of trastuzumab with a topoisomerase inhibitor, was recently approved for the treatment of refractory HER2-positive advanced GAC patients. There are exciting and newer therapies under investigation. Examining resistance patterns (both adaptive and acquired) along with establishing a better understanding of the intra- and inter-tumor heterogeneity is necessary to ensure successful progress. Here we review the current status of HER2-targeted therapy in GACs. We additionally review newer therapies under investigation and their potential role in HER2 GACs.

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Incidence, clinicopathological features, and clinical outcomes of low HER2 expressed, inoperable, advanced, or recurrent gastric/gastroesophageal junction adenocarcinoma

et al. 2023

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Research progress of antibody-drug conjugates therapy for HER2-low expressing gastric cancer

Cited by 5 publications

References 56 publications

Whole‐transcriptome sequencing in advanced gastric or gastroesophageal cancer: A deep dive into its clinical potential

Whole‐transcriptome sequencing in advanced gastric or gastroesophageal cancer: A deep dive into its clinical potential

Human Epidermal Growth Factor Receptor-2 Gastric Adenocarcinoma: Expanding Therapy of a Recognized Target

Incidence, clinicopathological features, and clinical outcomes of low HER2 expressed, inoperable, advanced, or recurrent gastric/gastroesophageal junction adenocarcinoma

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