Predictive biomarkers identified in HER2-positive and HER2-low advanced gastric cancer patients treated with Trastuzumab Deruxtecan

July 2021 Science Tobias Rawson
3D Illustration Concept of Human Digestive System Stomach Anatomy

Two potential, predictive biomarkers have been identified in a post-hoc analysis of the phase II DESTINY-Gastric01 study. Plasma ERBB2 copy number and HER2 extracellular domain  (HER2ECD) were both predictive of response to the antibody-drug conjugate Trastuzumab Deruxtecan (T-DXd) in both HER2 positive (HER2+) and HER2-low advanced gastric cancer.

Previous findings and study design

These post-hoc findings follow the results of the initial study, which reported a overall response rate (ORR) of 51.3%, compared to 14.3% in patients who received their physicians choice. The study enrolled patients with HER2- expressing advanced gastric or gastro-oesophageal junction adenocarcinoma, who had received at least 2 prior regimens, requiring one regimen to include fluoropyrimidine and a platinum agent. Patients were randomised 2:1 to receive T-DXd (N= 125) (6.4 mg/kg, 3-week cycle) or their physician’s choice of irinotecan or paclitaxel (N= 62). These patients were also required to have progressed on a trastuzumab-containing regimen and have evidence of disease (IHC3+ or IHC2+/ISH+). Additionally, this study also contained two exploratory cohorts who were required to be anti-HER2 treatment naïve. The first cohort (N= 20) was required to be IHC2+/ISH-, with the second cohort (N= 20) being IHC1+. Both of these cohorts received T-DXd. Tumour and liquid biopsy samples were taken and assessed for HER2-status, RNA sequencing (ERBB2 gene expression), as well as cell-free DNA (plasma ERBB2 amplification & copy number) and HER2ECD.

HER2ECD and ERBB2 copy number predict overall survival

When stratified by HER2ECD, both the primary and exploratory cohort saw better outcomes for patients above a prespecified concentration threshold. In the primary cohort, patients with a HER2ECD above 14.4 ng/mL had a median overall survival (mOS) of 14.3 months, compared to 10.0 months in patients below this threshold (HR[95%CI]: 0.56[0.33-0.95]). Similarly, patients in the exploratory cohort above a HER2ECD concentration above 11.6 ng/mL had a mOS of 10.1 months, compared to just 4.3 months in patients who did not exceed this value (HR[95%CI]: 0.37[0.17-0.80]). This is further supporting by the finding that in the exploratory cohort, patients above the threshold of 11.6 ng/mL had an ORR of 36.7%, which was higher than the ORR of all patients in the exploratory cohorts, at 27.5%. Similarly,

ERBB2 copy number was also found to be predictive of survival outcomes, as patients in the exploratory cohorts with a copy number above 6.0 achieved a mOS of 21.2 months, whilst those below this threshold had a mOS of 12.0 months (HR[95%CI]: 0.54[0.29-1.00]). In the primary cohort, patients above this threshold had an ORR of 75.8%- much higher than the ORR of all patients in the primary cohort (51.3%).


These biomarkers were correlative with ORR and mOS, impying that they may be of use in a clinical setting to predict which HER2+ and HER2- advanced gastric cancer patients might benefit from treatment with T-DXd. Further investigation of these experimental biomarkers is warranted as a result.


 Shitara K et al., Exploratory biomarker analysis of trastuzumab deruxtecan in DESTINY-Gastric01, a randomized, phase 2, multicenter, open-label study in patients with HER2-positive or –low advanced gastric or gastroesophageal junction adenocarcinoma. Presented at the 2021 ESMO World Congress for Gastrointestinal Cancer. Abstract no. O-14.