Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.
World J Gastrointest Oncol. Nov 15, 2026; 18(11): 123385
Published online Nov 15, 2026. doi: 10.4251/wjgo.123385
Regorafenib combined with programmed death inhibitor after initial treatment failure in unresectable hepatocellular carcinoma
Fei Ma, Li-Yun Zheng, Dan-Jun Song, Zhong-Wei Zhao, Fei Cao, Wei-Yuan Hao, Jun-Qi Qiu, Dong Lu, Jia-Ping Zheng
Fei Ma, Dan-Jun Song, Fei Cao, Wei-Yuan Hao, Jia-Ping Zheng, Department of Interventional Therapy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou 310022, Zhejiang Province, China
Fei Ma, Jia-Ping Zheng, Graduate Training Base of Wenzhou Medical University, Zhejiang Cancer Hospital, Hangzhou 310022, Zhejiang Province, China
Li-Yun Zheng, Zhong-Wei Zhao, Department of Radiology, Zhejiang Key Laboratory of Imaging and Interventional Medicine, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, Zhejiang Province, China
Jun-Qi Qiu, Department of Gastroenterology, Pingyang County People’s Hospital Affiliated to Wenzhou Medical University, Wenzhou 325400, Zhejiang Province, China
Dong Lu, Department of Intervention, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, Anhui Province, China
Dong Lu, Department of Intervention, The Second Affiliated Hospital of Anhui Medical University, Hefei 230001, Anhui Province, China
Co-first authors: Fei Ma and Li-Yun Zheng.
Co-corresponding authors: Dong Lu and Jia-Ping Zheng.
Author contributions: Zheng JP conceptualized and designed the study; Lu D contributed to refining the study design, interpreting the findings, reviewing the relevant literature, and preparing the manuscript; Song DJ, Zhao ZW, Cao F, Hao WY, and Qiu JQ collected, accessed, and verified the study data; Ma F and Zheng LY contributed to the statistical evaluation and manuscript preparation; and all authors read and approved the final manuscript. Ma F was primarily responsible for the statistical analyses, evaluation of the study results, and preparation of the initial manuscript. Zheng LY contributed to interpretation of the analyzed data and manuscript revision. Both authors made comparable contributions to data interpretation, evaluation of the results, and manuscript preparation, supporting their designation as co-first authors. As co-corresponding authors, Zheng JP and Lu D made complementary contributions to the study. Zheng JP initiated the study, defined the study objectives, eligibility criteria, and data collection plan, supervised the research process, coordinated study implementation, and critically revised the manuscript. He established the overall analytical framework for comparing the real-world effectiveness of regorafenib monotherapy and regorafenib combined with programmed cell death-1 inhibitors as second-line treatment for unresectable hepatocellular carcinoma. Lu D contributed to refining the study design, interpreting the findings based on existing evidence, reviewing the literature, and preparing and revising the manuscript. Lu D also led the interpretation and discussion of subgroup findings in patients with prior first-line immune checkpoint inhibitor exposure. Their collaboration and complementary expertise were essential to the completion of the study and manuscript preparation, supporting their designation as co-corresponding authors.
AI contribution statement: Portions of this manuscript were edited using AI tools solely for language refinement. The authors carefully reviewed and verified all AI-assisted outputs and take full responsibility for the scientific content of the manuscript.
Institutional review board statement: This study was approved by the Institutional Ethics Committee of Zhejiang Cancer Hospital [approval No. IRB-2026-762 (IIT)].
Informed consent statement: The requirement for written informed consent was waived by the Institutional Ethics Committee of Zhejiang Cancer Hospital due to the retrospective nature of the study.
Conflict-of-interest statement: All authors declare that they have no conflict of interest to disclose.
Data sharing statement: No additional data are available.
Corresponding author: Jia-Ping Zheng, MD, PhD, Professor, Department of Interventional Therapy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Banshan East Road, Hangzhou 310022, Zhejiang Province, China.
zhengjp@zjcc.org.cn
Received: May 18, 2026
Revised: June 29, 2026
Accepted: July 16, 2026
Published online: November 15, 2026
Processing time: 164 Days and 3.6 Hours
BACKGROUND
Sorafenib and lenvatinib remain the standard first-line therapies for unresectable hepatocellular carcinoma (HCC); however, disease progression is nearly universal. Regorafenib has become a standard second-line agent based on the RESORCE trial. Immune checkpoint inhibitor (ICI), particularly programmed cell death-1 (PD-1) inhibitors, have further reshaped the therapeutic landscape. Preclinical studies have demonstrated that regorafenib may modulate the tumor immune microenvironment, thereby enhancing antitumor immunity. Nevertheless, robust real-world evidence evaluating the efficacy of regorafenib combined with PD-1 inhibitors after first-line failure remains limited.
AIM
To compare the clinical efficacy of regorafenib plus PD1 inhibitor vs monotherapy as a second-line treatment for patients with unresectable HCC.
METHODS
This study analyzed 140 advanced HCC patients who experienced disease progression after first-line therapy between February 2019 and August 2024. Patients were divided into two cohorts, the regorafenib plus PD1 inhibitor group [regorafenib plus PD1 inhibitor (RP) group, n = 101] and the regorafenib monotherapy group [regorafenib monotherapy (R) group, n = 39]. Clinical outcomes were evaluated using objective response rate, disease control rate (DCR), progression-free survival, and overall survival (OS). Subgroup analyses and multivariate Cox regression analysis were performed to identify prognostic factors.
RESULTS
The RP group achieved a higher DCR, with better control of both intrahepatic and extrahepatic lesions than the R group. Median PFS (5.4 months vs 2.7 months, P = 0.003) and OS (54.8 months vs 25.3 months, P = 0.041) were longer in the RP group. Patients with prior ICI exposure achieved longer OS with RP therapy (P = 0.006), whereas no significant OS difference was observed in ICI-naive patients. First-line treatment type (lenvatinib vs sorafenib) did not affect second-line outcomes. Multivariable analysis identified second-line PD-1 inhibitor therapy as an independent predictor of PFS, whereas no independent predictors of OS were identified.
CONCLUSION
For patients with unresectable HCC who fail first-line treatment, the combination of regorafenib and PD-1 inhibitors confers better survival benefits and disease control than regorafenib monotherapy.
Core Tip: This multicenter retrospective study provides real-world evidence supporting regorafenib plus programmed cell death-1 (PD-1) inhibitors as second-line therapy for unresectable hepatocellular carcinoma after first-line treatment failure. Combination therapy improved disease control and prolonged progression-free and overall survival. Notably, survival benefit was mainly observed in patients with prior immune checkpoint inhibitor exposure, whereas first-line targeted therapy (lenvatinib or sorafenib) did not influence second-line outcomes. Second-line PD-1 inhibitor therapy independently predicted progression-free survival.
