Abstract LB212: Efficacy and safety of JS015 (an anti-dickkopf-1 antibody) in combination with standard of care in patients with gastrointestinal cancers

Abstract Background: Dickkopf-1 (DDK1) has been identified as an antagonist of the Wnt pathway, which plays a complex role in tumor development and metastasis. DDK1 inhibitors have been clinically studied and showed promising anti-tumor activities in gastrointestinal carcinoma. Here, we report the preliminary efficacy and safety data of JS015 in combination with standard of care in gastrointestinal patients from JS015-002 study (NCT06139211) and 2 IITs (ChiCTR2400091501 and ChiCTR2400088962) conducted in China. Methods: Patients with colorectal cancer that were not systematically treated (1L-CRC) or who had progressed after treatment with fluorouracil-based regimen (2L-CRC) received JS015 600 mg (intravenously) plus bevacizumab and chemotherapy, once every 2 weeks or 3 weeks, depending on chemotherapy schedules. Patients with gastric cancer that were not systematically treated (1L-GC) received JS015 600 mg plus toripalimab and chemotherapy, once every 3 weeks. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Results: As of the data cutoff (December 25, 2024), 36 patients with 2L-CRC, 6 patients with 1L-CRC, and 8 patients with 1L-GC were enrolled, with a respective median follow-up of 1.22, 1.41, and 1.38 months. In the efficacy analysis, among the 17 patients with 2L-CRC, 7 patients achieved a partial response (PR) and 8 patients had a stable disease (SD), producing an ORR of 41.2% (95% CI: 18.4%, 67.1%) and a DCR of 88.2% (95% CI: 63.6%, 98.5%); Among the 4 patients with 1L-CRC, there were 3 patients with PR and 1 patient with SD, producing an ORR of 75.0% (95% CI: 19.4%, 99.4%) and a DCR of 100.0% (95% CI: 39.8%, 100.0%); Among the 5 patients with 1L-GC, there were 3 patients with PR and 2 patients SD, resulting an ORR of 60.0% (95% CI: 14.7%, 94.7%) and a DCR of 100.0% (95% CI: 47.8%, 100.0%). Overall, the incidence of treatment-related adverse events (TRAEs) was 64.0% among those patients with CRC and GC. TRAEs were predominantly grade 1 or 2, and no grade 5 adverse events were reported. TRAEs of grade 3 or higher only occurred in 8 patients (8/50, 16.0%) among patients with 2L-CRC, including neutrophil count decreased (5/50, 10%), white blood cell count decreased (2/50, 4%), and aspartate aminotransferase increased, diarrhoea, and liver injury (1/50, 2.0% for each). Conclusion: JS015 combination therapy showed encouraging anti-tumor activities in patients with CRC and GC, with a favorable safety profile, supporting further investigations in a large population of patients with gastrointestinal carcinomas. Citation Format: Yong Gao, Ming Quan, Jianwei Yang, Xinjun Liang, Huiting Xu, Tao Zhang, Mingjun Zhang, Funan Liu, Lin Shen, Jingdong Zhang, Caixia Wang, Yiye Wan, Weiwei Wang, Yuanyuan Yu, Jing Xu, Chengbo Jia, Zexi Li, Huajun Li, Jin Li. Efficacy and safety of JS015 (an anti-dickkopf-1 antibody) in combination with standard of care in patients with gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB212.