Efficacy of regorafenib following first-line immune checkpoint inhibitor failure in patients with advanced hepatocellular carcinoma: A multicenter retrospective study.

e16166 Background: Hepatocellular carcinoma (HCC) remains a significant global health challenge While immune checkpoint inhibitors (ICIs) have become standard first-line treatments, identifying effective second-line therapies remains an unmet need. This study evaluates the efficacy and safety of regorafenib as a second-line option in advanced HCC patients post-progression on ICI-based regimens. Methods: This retrospective study included advanced HCC patients from eight hospitals in China who received regorafenib after progression on first-line ICI therapies, alone or combined with ICIs. Propensity score matching (PSM) was used to ensure comparability between treatment groups. The primary endpoint was overall survival (OS), secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs). Results: A total of 149 patients were included: 113 in the combination therapy group (Rego-ICI group) and 36 in the regorafenib monotherapy group (Rego group). After PSM, there were 67 patients in the Rego-ICI group and 31 in the Rego group. The median age was 59.00 years. Most patients had HBV-related infection (83.9%), ECOG PS 1 (76.3%), and Child-Pugh class A (73.2%). In the first-line treatment, only 10.7% of patients received ICI combined with bevacizumab, the rest were combined with MKIs. After PSM, there were 67 patients in the Rego-ICI group and 31 in the Rego group. The Rego-ICI group showed significantly improved median PFS (4.0 vs. 3.0 months, HR : 0.62 [95% CI: 0.389-0.986]) and OS (19.0 vs. 11.0 months, HR = 0.475 [95% CI: 0.272-0.832]) compared to the Rego group. Differences in ORR and DCR were not statistically significant (ORR 19.4% vs. 9.7%, P = 0.226; DCR 64.2% vs. 48.4%, P = 0.139), but the Rego-ICI group showed better disease control. Multivariate Cox analysis identified regorafenib plus ICI treatment as a protective factor for both PFS and OS. Subgroup analysis showed OS improvement with Rego-ICI in older patients ( > 60 years), ECOG 1/2, BCLC C stage, AFP < 400 ng/mL, and those with vascular invasion and/or extrahepatic metastasis. PFS improvement with Rego-ICI was observed in subgroups with ECOG 1/2, ALBI 2/3, NLR < 3.64, and PLR ≥ 136.9. In the Rego-ICI group, patients with NLR < 3.64 had significantly longer OS than those with NLR ≥ 3.64 (20.0 months vs. 16.8 months, P = 0.036). Conclusions: Adding ICIs to regorafenib therapy significantly improves OS in advanced HCC patients post-progression on first-line ICI treatments, highlighting the potential of regorafenib plus ICIs as an effective second-line option. These findings provide a strong foundation for further prospective clinical research. Clinical trial information: ChiCTR2400091318 .