A Multicenter Retrospective Study: Impact of First-Line Treatment Strategies on second-Line Efficacy and Safety of Regorafenib with or Without PD-1 Inhibitors in Unresectable Hepatocellular Carcinoma

Amid the era of targeted-immunotherapy for hepatocellular carcinoma (HCC), the selection of second-line therapy following failure of diverse first-line regimens remains inadequately explored. This multicenter study aimed to assess how first-line treatment strategies impact the efficacy and safety of second-line regorafenib-either alone or in combination with PD-1 inhibitors-in patients with unresectable HCC (uHCC). Specifically, we focused on two key populations: patients who failed first-line tyrosine kinase inhibitor (TKI) monotherapy, and a rapidly expanding cohort who progressed after first-line TKI plus PD-1 inhibitor combination therapy, and to address the critical clinical dilemma of whether to continue immunotherapy in the second line. This retrospective study enrolled 288 uHCC patients from five centers, stratified into two cohorts based on first-line therapy: 126 patients with first-line TKI monotherapy (Pre-Monotherapy cohort) and 162 with first-line TKI+PD-1 combination therapy (Pre-Combination cohort). All received second-line regorafenib alone or with PD-1 inhibitors. Primary endpoints were overall survival (OS) and progression-free survival (PFS); secondary endpoints included progression-free survival (PFS),objective response rate (ORR), disease control rate (DCR), and safety. In the Pre-Monotherapy cohort, regorafenib plus PD-1 significantly improved outcomes versus regorafenib alone: mPFS (10.5 vs 4.7 months, p<0.001), mOS (18.9 vs 14.0 months, p=0.003), ORR (29.69% vs 4.84%, p<0.001), and DCR (89.06% vs 67.74%, p=0.004). In the Pre-Combination cohort, no significant differences were observed in PFS (9.2 vs 6.3 months, p=0.062), OS (16.2 vs 13.2 months, p=0.13), ORR (22.33% vs 15.25%, p=0.276), or DCR (82.52% vs 74.58%, p=0.227). Second-line regorafenib plus PD-1 inhibitors yields significant clinical benefits in uHCC patients who failed first-line TKI monotherapy. However, in those who progress following first-line TKI plus PD-1 inhibitor therapy, continuing immunotherapy in the second line confers no additional efficacy, underscoring the need to explore alternative strategies. This study provides the first evidence-based guidance for the unmet clinical scenario of "first-line targeted-immunotherapy failure", highlighting the importance of precision sequential therapy tailored to first-line regimens.