Abstract 6581: DX126-262 combined with chemotherapy (Cisplatin and 5-Fu) demonstrates promising antitumor efficacy in HER2-positive gastric cancer

Abstract Gastric cancer is a common malignant tumor of the digestive system, and its morbidity and mortality rank among the top five in the world. Although significant progress has been made in cytotoxic chemotherapy, immunotherapy and targeted therapy in recent years, the long-term prognosis of patients with advanced or metastatic gastric cancer is still poor. Trastuzumab combined with chemotherapy is the first-line standard of care (SOC) for HER2-positive advanced or metastatic gastric cancer. Two ADC drugs targeting HER2, DS-8201 and RC-48, have also been approved for the treatment of gastric cancer. However, their limited clinical benefits and occurrence of adverse events still present a significant challenge. Therefore, minimizing the off-target toxicity and collateral damage while achieving significant chemotherapy efficacy has become the focus of gastric cancer treatment. DX126-262 is a novel HER2-targeting antibody-drug conjugate (ADC), generated by conjugating a Tubulysin B analogue to a recombinant humanized anti-HER2 monoclonal antibody through a linker containing branched hydrophilic polyethylene glycol, using thiol-maleimide chemistry to achieve drug antibody ratio (DAR) of 3. 8. Previous studies have confirmed that DX126-262 monotherapy showed excellent efficacy in HER2-positive gastric cancer NCI-N87 cells in vitro and in vivo. And the efficacy has also been demonstrated in clinical trials (now in phase II, CTR20211871). Based on above results, we intended to further explore whether combination therapy of DX126-262 with Cisplatin and 5-FU can improve the anti-tumor efficacy compared with SOC (Herceptin plus Cisplatin and 5-FU) or DS-8201 monotherapy. The triple-drug combination therapy demonstrated much better therapeutic efficacy than single drug (DX126-262, Cisplatin, 5-FU, Herceptin, or DS-8201) or double-drug combination (Cisplatin plus 5-FU) or SOC (Herceptin plus Cisplatin and 5-FU) on human gastric cancer cells in vitro and in vivo. Meanwhile, triple-drug combination therapy did not exhibit superimposed toxicity, judging by the body weight of mice and hemal biochemistry assays. These results suggested that DX126-262 plus Cisplatin and 5-FU might be a promising strategy for treatment of HER2-positive advanced or metastatic gastric cancer in clinic. Citation Format: Xiaobo Cai, Min Cao, Huihui Guo, Qingliang Yang, Xiangfei Kong, Yong Du, Zhicang Ye, Zhixiang Guo, Lingli Zhang, Lu Bai, Junxiang Jia, Yunxia Zheng, Yongxiang Chen, Miaomiao Chen, Wei Zheng, Jun Zheng, Wenjun Li, Yuanyuan Huang, Mengmeng Liu, Zhongliang Fan, Hangbo Ye, Yifang Xu, Binbin Chen, Meng Dai, Robert Y. Zhao. DX126-262 combined with chemotherapy (Cisplatin and 5-Fu) demonstrates promising antitumor efficacy in HER2-positive gastric cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6581.