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.

Background: 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.