Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial

Trastuzumab deruxtecan (T-DXd) demonstrated significant clinical benefit in HER2-positive gastric cancer in DESTINY-Gastric01, with exploratory signals of benefit in HER2-low disease. Given spatial and temporal heterogeneity of HER2 in gastric tumors, identifying predictive biomarkers for T-DXd remains challenging. This exploratory analysis evaluated baseline HER2-associated biomarkers in circulating tumor DNA (ctDNA) and tumor tissue, and investigated potential resistance mechanisms. Baseline biomarkers were correlated with objective response rate (ORR) in the HER2-positive primary cohort. Concordance between HER2 positivity in tissue and ERBB2 plasma gene amplification was 64%. Amplifications in other key drivers in ctDNA (MET, EGFR, FGFR2) were associated with numerically lower ORR. Among 12 patients with HER2 gain-of-function (GoF) mutations, ORR was 58.3% (7/12). ORR was similar regardless of the timing of immunohistochemistry (IHC) sample collection. Further validation in larger studies is warranted.