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.

^{在 DESTINY-Gastric01 试验中，曲妥珠单抗 deruxtecan (T-DXd) 在人表皮生长因子受体 2 阳性 (HER2 +} ) 胃癌患者中显示出统计学上显着的临床改善。 DESTINY-Gastric01 的探索性结果表明对 HER2 低胃癌患者具有潜在益处。 HER2 表达或基因改变的空间和时间异质性是胃癌肿瘤的固有特征，这对识别可能对 T-DXd 产生反应的患者提出了挑战。与治疗反应相关的特定生物标志物尚未得到广泛探索。进行探索性分析以评估循环肿瘤 DNA 和组织样本中 HER2 相关生物标志物的基线，并研究 T-DXd 耐药机制。在 HER2 ⁺胃癌患者的主要队列中，基线 HER2 相关生物标志物与客观缓解率 (ORR) 相关。主要队列的 HER2 阳性率和HER2 ( ERBB2 ) 血浆基因扩增之间的一致性为 64%。循环肿瘤 DNA 中的其他关键驱动基因扩增，特别是MET、EGFR和FGFR2，与较低的 ORR 相关。在 12 名HER2功能获得性突变患者中，ORR 为 58.3%（12 名患者中的 7 名）。无论免疫组织化学样本采集的时间如何，ORR 都是一致的。需要在更大规模的研究中进行进一步的调查。