Abstract 3038: Preclinical evaluation of combination therapy of HJ-037 with anti-PD-1 antibody treating KRASG12C mutated tumors

Abstract Background: The development and clinical application of KRASG12C inhibitors have made significant progress in recent years and some groundbreaking clinical results have been reported. However, overcoming resistance of KRASG12C-OFF covalent blockade remains a key focus in the fight against KRASG12C mutated cancers. Combination therapy may be one of the best treatment strategies to overcome the resistance. Methods and Results: HJ-037 is an orally available, potent, and highly selective covalent KRASG12C inhibitor, which showed significantly superior inhibitory activities against NCI-H358 and Mia PaCa-2 cells to current marketed KRASG12C inhibitors, and favorable safety profile was observed in pre-clinical study, providing a good safety foundation for its combination with PD-1 inhibitor. In a Colon Cancer CT26-mKRASG12C cell line subcutaneous syngeneic model, animals treated with HJ-037 plus anti-PD-1 antibody showed complete tumor regression without recurrence. A proof-of-concept clinical trial combining HJ-037 with PD-1 inhibitor is currently ongoing, and preliminary data shows a positive trend in efficacy and safety profile. Conclusions: Preclinical study results indicate that the combination therapy of HJ-037 with PD-1 inhibitor could enhance the intensity and duration of antitumor activity compared to monotherapy, with satisfactory safety, therefore possessing a better potential for the treatment of cancer patients harboring KRASG12C mutation. Citation Format: Na Guo, Xiangyu Yang, Longjun Yang, Fengtian Du, Huiqiao Ling, Ke Xue, Lina Zhang, Jianxin Ji, Zhigang Wu. Preclinical evaluation of combination therapy of HJ-037 with anti-PD-1 antibody treating KRASG12C mutated tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3038.