DESTINY-Gastric01 Biomarker Analysis Reveals ctDNA and HER2 Heterogeneity Challenges in Gastric Cancer
Exploratory biomarker analysis from the phase 2 DESTINY-Gastric01 trial found only 64% concordance between tissue HER2 positivity and plasma ERBB2 gene amplification, underscoring the spatial heterogeneity challenge in gastric cancer. Co-occurring MET, EGFR and FGFR2 amplifications detected in ctDNA were associated with lower response rates to trastuzumab deruxtecan. These findings highlight the potential of liquid biopsy to capture tumour heterogeneity and identify resistance mechanisms that tissue biopsy may miss.
The original study
Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial.
- Authors
- Shitara K, Bang YJ, Iwasa S, Sugimoto N, Ryu MH, Sakai D, et al.
- Journal
- Nature medicine
- Type
- Journal Article, Clinical Trial, Phase II, Randomized Controlled Trial
- PMID
- 38745009
Original abstract
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.