Abstract 6824: Efficacy and mechanism of surufatinib combination with PD-1 monoclonal antibody and chemotherapy for the treatment of pancreatic cancer with liver metastasis in animal models

Abstract Background: The phase 1b/2 study of surufatinib plus camrelizumab, nab-paclitaxel and S-1 (NASCA) as first-line therapy has demonstrated superior clinical efficacy compared with nab-paclitaxel and gemcitabine (AG) for metastatic pancreatic adenocarcinoma (PDAC) (NCT05218889), especially in patients with liver metastasis (LM). To delve deeper into the underlying mechanism behind NASCA's effectiveness in the LM group, we conducted animal experiments and utilized multiplex immunohistochemistry (mIHC) technology. Methods: Two animal models of pancreatic cancer (subcutaneous and LM) were established using KPC cells in C57BL/6 mice. The animals were then randomly assigned to receive placebo, AG, NASCA, and PD-1 plus nab-paclitaxel and S-1 (AS). Human primary pancreatic lesions (PL) and LM lesions were collected, and organ-specific differences were analyzed by using mIHC. Results: LM changes the effectiveness of NASCA in mice. NASCA outperformed than AG in subcutaneous model. In subcutaneous and LM model, NASCA and AG showed the comparable tumor regression to placebo in subcutaneous tumor, but better than AG in liver tumor. NASCA boosts anti-tumor efficacy in LM by improving immunosuppressive microenvironment. Flow cytometry of peripheral tissues revealed reduced MDSC and PDL1+ macrophages infiltration (p < 0.05) and increased NK and activated T cells infiltration (p < 0.05) in liver tumors with NASCA. Treg infiltration decreased in both subcutaneous and liver tumors from early (d5) to late (d14) treatment time points. Higher fractions of Treg cells were infiltrated in LM than PL by mIHC: A total of 59 patients with PDAC were enrolled to evaluated the organ-specific response of NASCA therapy. MIHC detected significantly higher fractions of FOXP3+ cells in stroma of LM compared with PL (p < 0.05). Patients with CD68+CD163- (percent) and FOXP3+ (percent) in stroma may benefit more from NASCA regimen. Conclusion: LM could alter the efficacy of NASCA in KPC mice through improving immunosuppressive microenvironment. The heterogeneity of mIHC is limited in LM and PL, but patients with CD68+CD163- and FOXP3+ in the stroma may benefit more from NASCA regimen, which may contribute to developing precise immunotherapy strategies for PDAC patients with LM. Citation Format: Mengjiao Fan, Ru Jia, Guanghai Dai. Efficacy and mechanism of surufatinib combination with PD-1 monoclonal antibody and chemotherapy for the treatment of pancreatic cancer with liver metastasis in animal models [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 6824.