Efficacy and Safety of Ipilimumab Plus Anti-PD-1/PD-L1 Antibodies Combination Therapy in Advanced Hepatocellular Carcinoma Patients Progressing After Multiple Lines of Treatment: A Retrospective Multicenter Study

Su-Su Zheng,1 Jing-Fang Wu,1 Zhen-Zhen Zhang,1 Yan-Fang Wu,1 Yi-Jie Chen,2 Sheng Qian,3 Bo-Heng Zhang1,4,5 1Department of Hepatic Oncology, Xiamen Clinical Research Center for Cancer Therapy, Clinical Research Center for Precision medicine of Abdominal Tumor of Fujian Province, Zhongshan Hospital, Fudan University (Xiamen Branch), Xiamen, Fujian, 361015, People’s Republic of China; 2Department of General Surgery, Strait Hospital of Huaqiao University (The 910th Hospital of the Joint Service Support Force of the Chinese People’s Liberation Army), Quanzhou, Fujian, 362008, People’s Republic of China; 3Department of Interventional Radiology, Zhongshan Hospital, Fudan University (Xiamen Branch), Xiamen, Fujian, 361015, People’s Republic of China; 4The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, Shanghai, 200032, People’s Republic of China; 5Center for Evidence-Based Medicine, Shanghai Medical School, Fudan University, Shanghai, 200032, People’s Republic of ChinaCorrespondence: Bo-Heng Zhang, Email [email protected]: The combination of nivolumab and ipilimumab has demonstrated significant antitumor activity in first-line treatment for hepatocellular carcinoma (HCC) and in second-line treatment following progression on sorafenib. However, the efficacy and safety of ipilimumab plus anti-PD-1/PD-L1 antibodies combination therapy in advanced HCC patients who have progressed after multiple lines of treatment have not yet been reported.Materials and Methods: We conducted a multicenter retrospective study that included 33 HCC patients who had progressed after multiple lines of immune-targeted therapy and received ipilimumab combination therapy. All patients had received at least one line of immunotherapy based combination therapy (excluding those treated with anti-CTLA-4 inhibitors). The primary endpoints were overall survival (OS) and progression-free survival (PFS). Efficacy was assessed using RECIST 1.1, while adverse events were evaluated according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE 5.0).Results: Among the patients, 29 (87.9%) received ipilimumab combination therapy as third-line or later line therapy. The median OS for the entire cohort was 14.07 months (95% CI: 5.57 months - not evaluable), and the median PFS was 2.36 months (95% CI: 1.97– 5.64 months). Univariate survival analysis indicated that an NLR ≥ 3.1 and tumor size ≥ 63 mm are prognostic risk factors for OS (P=0.03 and P=0.027, respectively). Multivariate survival analysis revealed that an NLR ≥ 3.1 is the only independent prognostic risk factor for OS (P=0.048). The overall response rate (ORR) was 12.1%, and the disease control rate (DCR) was 48.5%. One patient experienced treatment-related death (3%), two had hyperprogression (6.1%), and three discontinued treatment due to adverse events (9.1%).Conclusion: Ipilimumab combination therapy in very late lines is a viable treatment option, although careful monitoring for adverse events is essential. Earlier application of this combination may potentially benefit patients more effectively.Keywords: advanced hepatocellular carcinoma, nivolumab, ipilimumab, immune checkpoint inhibitor, retrospective study