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已发表论文
一项多中心回顾性研究：一线治疗策略对不可切除肝细胞癌二线使用瑞戈非尼联合或不联合 PD-1 抑制剂疗效及安全性的影响
Authors Ma W, Li Y, Lu Y, Liang Z, Yu H, Han J, Liu J, Wang W, Peng C, Cheng J
Received 7 May 2025
Accepted for publication 12 August 2025
Published 16 September 2025 Volume 2025:12 Pages 2123—2137
DOI https://doi.org/10.2147/JHC.S456712
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr David Gerber
Weihong Ma,1,2,* Yinyin Li,1,* Yinying Lu,1,2 Zhipeng Liang,3 Hongli Yu,1,2 Jie Han,1,2 Jiaqi Liu,1,2 Wenjing Wang,1,2 Caiyun Peng,1 Jiamin Cheng1
1Senior Department of Hepatology, The 5th Medical Center of the PLA General Hospital, Beijing, People’s Republic of China; 2Chinese PLA Medical School, Beijing, People’s Republic of China; 3Guizhou Medical University, Guizhou, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Jiamin Cheng, Email chengjiamin300@163.com Caiyun Peng, Email 1419567156@qq.com
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.
Keywords: hepatocellular carcinoma, different first-line treatment, second-line treatment
1Senior Department of Hepatology, The 5th Medical Center of the PLA General Hospital, Beijing, People’s Republic of China; 2Chinese PLA Medical School, Beijing, People’s Republic of China; 3Guizhou Medical University, Guizhou, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Jiamin Cheng, Email chengjiamin300@163.com Caiyun Peng, Email 1419567156@qq.com
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.
Keywords: hepatocellular carcinoma, different first-line treatment, second-line treatment