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.

Purpose: 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. Patients and Methods: 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. Results: 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). Conclusion: 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.