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Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial
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Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial
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Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial
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Journal Article
Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial
2024
Overview
Trastuzumab deruxtecan (T-DXd) showed statistically significant clinical improvement in patients with human epidermal growth factor receptor 2-positive (HER2
+
) gastric cancer in the DESTINY-Gastric01 trial. Exploratory results from DESTINY-Gastric01 suggested a potential benefit in patients with HER2-low gastric cancer. Spatial and temporal heterogeneity in HER2 expression or gene alteration, an inherent characteristic of gastric cancer tumors, presents a challenge in identifying patients who may respond to T-DXd. Specific biomarkers related to therapeutic response have not been explored extensively. Exploratory analyses were conducted to assess baseline HER2-associated biomarkers in circulating tumor DNA and tissue samples, and to investigate mechanisms of resistance to T-DXd. Baseline HER2-associated biomarkers were correlated with objective response rate (ORR) in the primary cohort of patients with HER2
+
gastric cancer. The primary cohort had 64% concordance between HER2 positivity and
HER2
(
ERBB2
) plasma gene amplification. Other key driver gene amplifications, specifically
MET
,
EGFR
and
FGFR2
, in circulating tumor DNA were associated with numerically lower ORR. Among 12 patients with
HER2
gain-of-function mutations, ORR was 58.3% (7 of 12). ORR was consistent regardless of timing of immunohistochemistry sample collection. Further investigations are required in larger studies.
Exploratory analyses of the DESTINY-Gastric01 trial show that baseline HER2-associated biomarkers in circulating tumor DNA or tissue samples were associated with therapeutic response in patients with HER2-positive tumors, and these analyses identify potential drivers of resistance.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Aged
/ Biomarkers, Tumor - genetics
/ Biomarkers, Tumor - metabolism
/ Biomedical and Life Sciences
/ Camptothecin - analogs & derivatives
/ Camptothecin - therapeutic use
/ Cancer
/ Circulating Tumor DNA - blood
/ Circulating Tumor DNA - genetics
/ DNA
/ Epidermal growth factor receptors
/ Female
/ Fibroblast growth factor receptor 2
/ Humans
/ Immunoconjugates - pharmacology
/ Immunoconjugates - therapeutic use
/ Male
/ Proto-Oncogene Proteins c-met - genetics
/ Proto-Oncogene Proteins c-met - metabolism
/ Receptor, ErbB-2 - metabolism
/ Receptor, Fibroblast Growth Factor, Type 2 - genetics
/ Receptor, Fibroblast Growth Factor, Type 2 - metabolism
/ Stomach Neoplasms - drug therapy
/ Stomach Neoplasms - genetics
/ Stomach Neoplasms - pathology
/ Trastuzumab - therapeutic use
/ Tumors
