Efficacy and safety of regorafenib combination with PD-1 inhibitors vs. regorafenib monotherapy in second-line treatment for patients with unresectable hepatocellular carcinoma after failure of different first-line treatments: A multicenter retrospective real-world study.

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4088 Background: Regorafenib is the first oral targeted drug as a second-line agent in patients with unresectable hepatocellular carcinoma (HCC) who progressed on sorafenib treatment.There is a lack of data to validate the second-line therapy after progression of targeted-immune combination therapy. Our aim was to investigate the efficacy and safety of regorafenib alone or in combination with a programmed death-1 (PD-1) inhibitor in second-line treatment for patients who have failed tyrosine kinase inhibitor (TKI) in combination with PD-1 or TKI monotherapy, respectively. Methods: A total of 288 patients were enrolled in this multicenter, retrospective study. These patients received regorafenib with or without PD-1 inhibitor (Sintilimab/Camrelizumab/Pembrolizumab) as second-line therapy after failure of TKI (sorafenib/lenvatinib) or such TKIs combined with PD-1 inhibitor (Sintilimab/Camrelizumab/Pembrolizumab). The primary study endpoint was the evaluation of overall survival (OS), while secondary study endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and treatment safety. Results: In the first line treatment, 126 patients received TKI and 162 patients received TKI plus PD-1. In the TKI cohort, the Reg-PD-1 group exhibited markedly higher ORR (29.69% vs 4.84%; p<0.001) and DCR (89.06% vs 67.74%; p=0.004), as well as longer median PFS (10.5 vs 4.7 months; p<0.001) and median OS (18.9 vs 14.0 months; p=0.03) compared to the Reg monotherapy group.There was no significant difference in PFS, OS, ORR, and DCR between the two groups in the TKI plus PD-1 cohort.The incidence of AEs was higher in the Reg-PD-1 group compared to the Reg group (81.25 % vs 58.06%; p=0.005) in the TKI cohort. And Reg-PD-1 group was comparable to Reg group (76.70% vs 66.10%; p=0.144) in the TKI Plus PD-1 cohort. Conclusions: Regorafenib plus PD-1 may enhance efficacy in uHCC patients who failed first-line TKI therapy. However, in patients who have progressed after first-line TKI plus PD-1 therapy, using regorafenib alone or in combination with PD-1 in second-line therapy does not show a significant difference in efficacy.These findings have significant implications for the selection of second-line treatment strategies for HCC patients, indicating that the combination of regorafenib and PD-1 might not provide additional benefits in certain patient subgroups. Outcomes in the two cohorts. Outcomes TKI TKI plus PD-1 Reg(n=62) Reg-PD-1 (n=64) P value Reg (n=59) Reg-PD-1 (n=103) P value CR 2 3 - 3 2 - PR 1 16 - 6 21 - SD 39 38 - 35 62 - PD 20 7 - 15 18 - ORR 4.84% 29.69% ＜0.001 15.25% 22.33% 0.276 DCR 67.74% 89.06% 0.004 74.58% 82.52% 0.227 PFS(m) 4.7 10.5 ＜0.001 6.3 9.2 0.062 OS(m) 14.0 18.9 0.03 13.2 16.2 0.13

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