Application of HER2-Targeted Antibody-Drug Conjugates in the Treatment of Gastric Cancer: A Systematic Review of Pivotal Clinical Evidence

Abstract

Gastric cancer ranks fifth in the world in the incidence of cancer and the fourth in mortality rate, and HER2 positive accounts for about 15%-20% of advanced gastric cancer. After the HER2 positive first-line regimen was established with trastuzumab combined chemotherapy, there was a long-term lack of standard regimens in the second and posteriary lines. Antibody-drug conjugates (ADCs) realize the accurate delivery of "antibody navigation + chemotherapy warhead" through antibody coupling of high-efficiency cytotoxic loads and dissolving connectors, and produces a bystander effect by releasing the load to penetrate the tumor microenvironment. This study retrieved the 2010-2025 PubMed, Embase and Cochrane databases according to the PRISMA process, and included a total of 15 key phase II/III trials and reviews. The results showed that the median overall survival of trastuzumab deruxtecan (T-DXd) was 3.3 months longer than ramucirumab combined with paclitaxel in the second-line phase DESTINY-Gastric04 (14.7 vs 11.4, HR 0.70), with an objective response rate of 44.3% vs 29.1%; the response rate of DESTINY-Gastric01 in Asia phase II was 51% vs chemotherapy 14%; the response rate of RC48 single-arm phase II in China's original research was 24.4%, with a median overall survival of 7.9 months. Safety is mainly manifested in about 10% of interstitial lung disease and 51% of neutrophil reduction above grade 3. This study systematically portrays the therapeutic level and adverse event spectrum of HER2-ADC, and provides evidence-based support for back-line sequential decision-making and subgroup management.