Abstract 4618: Baseline and dynamic cytokines as biomarkers for first-line therapy in advanced hepatocellular carcinoma

Abstract Background: Hepatocellular carcinoma (HCC) causes significant cancer mortality. The preferred treatment for patients with advanced HCC is immune checkpoint inhibitors (ICIs), with or without the VEGF-inhibitor bevacizumab. The immune effects of bevacizumab are not well understood, and biomarkers are needed to guide therapy selection in advanced HCC. We serially evaluated circulating cytokines in patients with HCC treated with ICIs with or without bevacizumab. Methods: Circulating cytokines were evaluated in 57 advanced HCC patients treated with ICI-based therapy as standard of care at Sidney Kimmel Cancer Center from 2000-2024. A total of 36 patients received ICIs without bevacizumab (ICI-Only group), and 21 patients received the combination of an ICI with bevacizumab (ICI+Bev group). Serum was collected prospectively at baseline and at approximately 2 months after starting therapy. Cytokines were assessed using a Luminex panel of 33 cytokines. Patients were stratified by above- or below-median baseline cytokine levels and fold-change post-treatment. We evaluated the relationship between treatment group (ICI-Only versus ICI+Bev), cytokine changes, and clinical outcomes. Results: Across all patients, the median age was 65, 26% were female, and 60% were White. Baseline demographic characteristics were balanced between the ICI-Only and ICI-Bev treatment groups, except for a higher proportion of patients receiving prior systemic therapy in the ICI-Only group (75%) compared to the ICI+Bev group (14%). Compared to patients receiving ICI-Only, those receiving ICI+Bev exhibited reduced fold changes in multiple cytokines after 2 months of treatment, including sCD40L (p = 0.017), MIP-1b (p = 0.015), and MIG (p = 0.049). Across all patients, lower baseline levels of IL-8 (p = 0.017) and lower on-treatment levels of IL-1Ra (p = 0.008), IL-4 (p = 0.049), IL-8 (p = 0.021), IL-9 (p = 0.028), and IL-18 (p = 0.004) were associated with longer survival. In the ICI-Bev group, higher baseline IL-6 (p = 0.008) was associated with improved progression-free survival, while smaller post-treatment increases in IL-6 were associated with both improved PFS (p = 0.028) and objective response rate (p = 0.010). In contrast, in ICI-Only patients, lower baseline IL-8 (p = 0.012) and smaller post-treatment increases in IL-1Ra (p = 0.021) were associated with extended overall survival. Conclusion: Adding in bevacizumab to ICIs in advanced HCC may influence systemic cytokines, particularly those associated with innate immune populations. These findings suggest that bevacizumab may modulate innate immune responses and highlight the potential role of specific myeloid-related cytokines as biomarkers to identify patients who could benefit from bevacizumab-based combination therapy. These exploratory results warrant prospective validation in independent patient cohorts to confirm their clinical significance. Citation Format: Xiyu Zhao, H. Catherine Wilbur, Mark Yarchoan. Baseline and dynamic cytokines as biomarkers for first-line therapy in advanced hepatocellular carcinoma [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 4618.