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.

Kohei Shitara, Yung-Jue Bang, Satoru Iwasa, Naotoshi Sugimoto, Min-Hee Ryu, Daisuke Sakai, Hyun Cheol Chung, Hisato Kawakami, Hiroshi Yabusaki, Yasuhiro Sakamoto, Tomohiro Nishina, Koichiro Inaki, Yusuke Kuwahara, Naoya Wada, Fumitaka Suto, Takeo Arita, Masahiro Sugihara, Zenta Tsuchihashi, Kaku Saito, Akihito Kojima, Kensei Yamaguchi