Efficacy and safety of regorafenib as a first-line agent alone or in combination with an immune checkpoint inhibitor for advanced hepatocellular carcinoma: a retrospective cohort study
Original Article

Efficacy and safety of regorafenib as a first-line agent alone or in combination with an immune checkpoint inhibitor for advanced hepatocellular carcinoma: a retrospective cohort study

Jianfa Yu1, Yi Bai1, Zilin Cui1, Chuanliang Cheng2, Morten Ladekarl3,4, Kai-Chi Cheng5, Kai Siang Chan6, Hooman Yarmohammadi7, José L. Mauriz8,9, Yamin Zhang1

1Department of Hepatobiliary and Pancreatic Surgery, Tianjin First Central Hospital, Tianjin, China; 2Medical College of Nankai University, Tianjin, China; 3Department of Oncology, Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark; 4Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 5Department of Surgery, Kwong Wah Hospital, Hong Kong, China; 6Department of General Surgery, Tan Tock Seng Hospital, Singapore, Singapore; 7Division of Interventional Radiology, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 8Institute of Biomedicine (IBIOMED), University of León, León, Spain; 9Biomedical Research Networking Centre of Liver and Digestive Diseases (CIBERehd), Carlos III Health Institute, Madrid, Spain

Contributions: (I) Conception and design: J Yu; (II) Administrative support: Y Zhang; (III) Provision of study materials or patients: Y Bai; (IV) Collection and assembly of data: Z Cui; (V) Data analysis and interpretation: C Cheng; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Yamin Zhang, PhD. Department of Hepatobiliary and Pancreatic Surgery, Tianjin First Central Hospital, No. 24 Fukang Road, Tianjin 300192, China. Email: 13802122219@163.com.

Background: The RESORCE-III trial demonstrated that advanced hepatocellular carcinoma (HCC) patients who progressed on sorafenib and had second-line therapy with regorafenib improved overall survival compared with placebo. Later, immunotherapy with immune checkpoint inhibitors (ICIs) combined with antiangiogenetic antibodies has evolved as the preferred first-line treatment for fit patients. We aimed to explore the efficacy and safety of regorafenib as a first-line agent alone or in combination with ICIs in patients with advanced HCC.

Methods: We identified 50 patients with advanced HCC treated with regorafenib as a first-line agent. Two patients were lost to follow-up and excluded. Baseline factors, dosing, concomitant use of ICIs, toxicity and outcome of treatment were recorded from electronic medical records.

Results: Twenty-six patients received regorafenib as monotherapy and twenty-two received regorafenib + ICI in combination. In the total cohort, the median progression-free survival (mPFS) was 7.7 months and the median overall survival (mOS) was 16.7 months (P=0.02). Objective response rate (ORR) and disease control rate (DCR) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were 21% and 73%. In the regorafenib monotherapy group, mPFS was 5.9 months, and mOS was 13.9 months; in the combination group, mPFS was 7.8 months, and mOS was 23.6 months. ORR and DCR were 15% and 65% in the monotherapy group, and 27% and 82% in the combined treatment group, respectively.

Conclusions: Regorafenib used in combination with ICIs had a mild safety profile and resulted in improved response and an almost doubling of mOS compared to monotherapy, warranting further prospective evaluation in a randomized study.

Keywords: Hepatocellular carcinoma (HCC); first-line therapy; regorafenib; immune checkpoint inhibitor (ICI)

Submitted Apr 29, 2024. Accepted for publication Jun 24, 2024. Published online Jun 27, 2024.

doi: 10.21037/jgo-24-315

Highlight box

Key findings

• Regorafenib, alone or combined with immune checkpoint inhibitors (ICIs), demonstrates enhanced efficacy and survival in treating advanced hepatocellular carcinoma (HCC)with a manageable safety profile.

What is known and what is new?

• Regorafenib, a multi-kinase inhibitor, has demonstrated efficacy as a second-line treatment for advanced HCC after sorafenib therapy has failed, and is FDA-approved for this indication.

• This study positions regorafenib as a novel first-line therapy for advanced HCC, offering superior efficacy and survival when paired with ICIs, and underscores the predictive value of the CRAFITY score.

What is the implication, and what should change now?

• Implications suggest regorafenib as a potential first-line therapy for advanced HCC, necessitating validation through RCTs and possible revisions to treatment guidelines.

Introduction

Hepatocellular carcinoma (HCC) is the 5th and 7th most common cancer and the 2nd and 6th leading cause of cancer deaths worldwide in adult men and women, respectively (1,2). Hepatitis B virus (HBV) and hepatitis C virus (HCV) cause 60% and 33% of HCCs, respectively, in developing countries, compared to 23% and 20% in developed countries (3,4). Surgical resection remains an essential means of obtaining a cure for patients with early- to mid-stage HCC. However, even with R0 resection, the recurrence rate of the disease is still as high as 50% to 70% at 5 years after surgery (5). Like most tumors, HCC has no obvious symptoms in its early stages, so many patients have developed advanced disease by the time of initial diagnosis (6).

For over a decade, sorafenib was the only first-line agent approved for treating advanced HCC (7). In recent years, the therapeutic field has been rapidly evolving, with the approval of additional first- and second-line systemic therapies, most of which are targeted and immunotherapy (8). Regorafenib achieved notable success as a second-line treatment option for advanced HCC as a result of findings in the phase III RESORCE study, published in 2017. Treatment of patients progressing on sorafenib with regorafenib in second line showed a median overall survival (mOS) of 10.6 months and a mPFS of 3.1 months (9). The mOS from initiation of first-line treatment was 26 months for patients treated with sequential regorafenib after sorafenib (10).

In addition, there are many studies demonstrating good progress with regorafenib as a second-line agent in advanced HCC (11-13). Although regorafenib was initially approved as a second-line therapeutic agent, given the significant survival benefit it has shown in second-line therapy, we hypothesized that regorafenib may be equally effective in first-line therapy. Therefore, this single-institution, retrospective cohort study aimed to investigate the efficacy and safety of regorafenib as a first-line agent alone or in combination with immune checkpoint inhibitors (ICIs) in patients with advanced HCC. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-315/rc).

Methods

Study design and patients

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) (14). The study was approved by Science and Technology Ethics Committee of Tianjin First Central Hospital (No. 2023DZX08) and informed consent was taken from all the patients.

Our database was retrospectively established and prospectively maintained. We collected demographic, clinical and survival data from December 2018 to February 2022 from the electronic medical records of all patients with advanced HCC treated with regorafenib as first-line therapy alone or combined with ICIs at the Tianjin First Central Hospital, China. Baseline patient characteristics were collected within 1 week prior to initiation of regorafenib therapy.

The inclusion criteria were as follows: pathologically or clinically confirmed HCC (15); adult patients with advanced HCC not suitable for surgical resection; and regorafenib treatment used as first-line therapy for at least one 28-day course of treatment. Exclusion criteria were: participation in other interventional clinical studies during regorafenib dosing; and incomplete follow-up.

Treatment, toxicity and monitoring

Patients received a standard start dose of regorafenib 160 mg orally for the first 3 weeks and discontinued it for 1 week, making for a 5-week dosing cycle. Dose adjustments and interruptions were made at the treating physician’s discretion, depending on the type and severity of the adverse events (AEs). A dose reduction to 80 mg once daily, and to 40 mg in exceptional cases, was allowed, similar to the protocol of the RESORCE trial. Concurrent treatment with ICIs included atezolizumab, palivizumab, carrilizumab, and treprolizumab, but was not counted explicitly because some patients switched ICIs during the treatment. Treatment continued until disease progression, death or intolerable toxicity. The general monitoring strategy included physical examination, serum alpha-fetoprotein (AFP), contrast-enhanced computed tomography (CT) of the chest and abdomen, and contrast-enhanced magnetic resonance imaging (MRI) of the abdomen and pelvis. Laboratory and imaging tests were completed after every 2–4 cycles. Treatment-related AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE V5.0) (16).

Treatment response and survival

According to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (17), the objective response rate (ORR) was defined as the incidence of complete and partial response. The disease control rate (DCR) was the incidence of complete response, partial response, and stable disease. Progression-free survival (PFS) was defined as the time from initiation of regorafenib to confirmation of tumor progression or death or the last follow-up visit, whichever came first. Overall survival (OS) was defined as the time from initiation of regorafenib to death or the last follow-up visit.

CRAFITY score

Using two variables, AFP and C-reactive protein (CRP), to create the CRAFITY score, has shown to provide excellent prognostic stratification of HCC patients treated with tyrosine kinase inhibitors (TKIs) in combination with immunotherapy (18). CRP is a recognized marker of cancer-induced systemic inflammation (19). In the local tumor microenvironment, inflammation has multiple protumor effects, including the promotion of cancer cell proliferation, metastatic dissemination, angiogenesis, and suppression of adaptive immunity (20). AFP is a widely used serum biomarker in the treatment of HCC (21). Both expression of AFP and high absolute values of AFP at baseline are known negative prognostic factors (22).

Statistical analysis

Categorical data are described as number (percentage), and quantitative data are described as median (range). Categorical data were compared between the two groups using the chi-square test or Fisher’s exact test. The Mann-Whitney U test or Student’s t-test was used to compare quantitative data between two groups. The Kaplan-Meier method was used for PFS and OS curves, and the log-rank test was used to compare the two groups. All tests were bilateral, and P<0.05 was considered statistically significant. All statistical analyses were performed using SPSS Statistics version 22.0.

Results

Study patients and baseline characteristics

We identified, reviewed and collected information on at total of 50 patients. Two patients (4%) were lost to follow-up and excluded from further analyses. Of the 48 patients enrolled, 26 received regorafenib as monotherapy and 22 received regorafenib + ICI (Figure 1). Baseline characteristics are shown in Table 1. During the study period, 26 patients with advanced HCC receiving regorafenib as first-line therapy were enrolled, with a median age of 54 years (range, 38–74 years) and a sex ratio of 69% men to 31% women; 22 patients received regorafenib in combination with ICIs, with a median age of 53 years (range, 42–75 years) and 68% men. The two treatment groups were comparable as baseline clinical parameters were not significantly different.

Figure 1 Flow diagram of patient enrolment. HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor.

Table 1

The baseline characteristics of all regorafenib-treated patients and distributed according to treatment with monotherapy or in combination with ICIs

Variable Regorafenib (n=26) Regorafenib + ICI (n=22) N P
Age, years, median [range] 54 [38–74] 53 [42–75] – 0.65
Gender, n [%] >0.99
   Male 18 [69] 15 [68] 33
   Female 8 [31] 7 [32] 15
ECOG PS, n [%] 0.64
   0 10 [38] 8 [36] 18
   1 14 [54] 12 [55] 26
   2 2 [8] 2 [9] 4
Child-Pugh, n [%] 0.83
   A 15 [58] 12 [55] 27
   B 11 [42] 10 [46] 11
AFP, μg/L, median [range] 96.8 [1.2–1,210] 65.8 [8.2–1,210] – 0.36
ALT, U/L, median [range] 41.0 [10.9–160.6] 73.9 [18.5–177.6] – 0.22
AST, U/L, median [range] 39.0 [13.5–147.6] 42.0 [18.6–188.6] – 0.35
ALB, g/L, median [range] 37.3 [24.5–48.1] 39.1 [27.1–46.9] – 0.98
CRP, mg/L, median [range] 29.5 [3.9–113.4] 25.8 [2.6–118.3] – 0.35
Hepatitis B virus infection, n [%] 0.74
   No 6 [23] 6 [27] 12
   Yes 20 [77] 16 [73] 36
Liver cirrhosis, n [%] 0.48
   No 7 [27] 8 [36] 15
   Yes 19 [73] 14 [64] 33
BCLC stage, n [%] 0.68
   B 11 [42] 8 [36] 19
   C 15 [58] 14 [64] 29
Tumor diameter, n [%] 0.41
   <5 cm 10 [39] 6 [27] 16
   ≥5 cm 16 [61] 16 [73] 32
Tumor numbers, n [%] >0.99
   Single 3 [12] 3 [14] 6
   Multiple 23 [88] 19 [86] 42
Vascular invasion, n [%] 0.44
   No 17 [65] 12 [55] 29
   Yes 9 [35] 10 [45] 19
Extrahepatic metastasis, n [%] 0.56
   No 21 [81] 20 [91] 41
   Yes 5 [19] 2 [9] 7

AFP is the undiluted value. ICI, immune checkpoint inhibitor; ECOG PS, Eastern Cooperative Oncology Group Performance Status; AFP, alpha-fetoprotein; ALT, alanine transaminase; AST, aspartate aminotransferase; ALB, albumin; CRP, C-reactive protein; BCLC, Barcelona Clinic Liver Cancer.

Treatment efficacy

The efficacy evaluation is shown in Table 2. The ORR and DCR of the total cohort was 21% and 73%, respectively. The ORRs and DCRs were significantly higher in the combination group compared to monotherapy group (27% vs. 15%, P=0.51 and 82% vs. 65%, P=0.34, respectively).

Table 2

Treatment responses according to RECIST 1.1

Response Regorafenib (n=26) Regorafenib + ICI (n=22)
CR 0 1 (4%)
PR 4 (15%) 5 (23%)
SD 13 (50%) 12 (55%)
PD 9 (35%) 4 (18%)
ORR 4 (15%) 6 (27%)
DCR 17 (65%) 18 (82%)

RECIST, Response Evaluation Criteria In Solid Tumors; ICI, immune checkpoint inhibitor; CR, complete response; PR, partial response; SD, stable disease; PD, progress disease; ORR, objective response rate; DCR, disease control rate.

With a median follow-up of 20 months (range, 5–38 months), the mPFS in the total cohort of 48 patients was 7.7 months (95% CI: 5.9–10.4), with a 6-month PFS rate of 63% (95% CI: 50–79%) and a 12-month PFS rate of 20% (95% CI: 10–38%). The mOS was 16.7 months (95% CI: 14.3–23.6), the 12-month OS rate was 83% (95% CI: 72–95%), and the 24-month OS rate was 24% (95% CI: 13–45%).

When comparing treatment groups (Figure 2), the mPFS in the monotherapy group was significantly shorter, 5.9 months (95% CI: 5.6–10.3) than in the combination group, 7.8 months (95% CI: 7.3–14.5) (P=0.046). The mOS in the monotherapy group was 13.9 months (95% CI: 13.5–22.5), while the mOS in the combination group was almost twice as long, 23.6 months [95% CI: 16.6–not reached (NR)] (P=0.01).

Figure 2 Kaplan-Meier curves of PFS and OS in the regorafenib and regorafenib + ICI groups. (A) The mPFS of regorafenib and regorafenib + ICI was 5.9 and 7.8 months, respectively (P=0.046). (B) The mOS of regorafenib and regorafenib + ICI was 13.9 and 23.6 months, respectively (P=0.01). PFS, progression-free survival; OS, overall survival; ICI, immune checkpoint inhibitor.

The CRAFITY score significantly stratified the prognosis of patients in both the monotherapy and ICI combination treatment groups (P=0.02; P=0.03 (Figure 3).

Figure 3 Survival curves for CRAFITY score in the regorafenib and regorafenib + ICI groups. (A) Comparison of survival curves of patients with different CRAFITY scores in the regorafenib group (P=0.02). (B) Comparison of survival curves of patients with different CRAFITY score in the regorafenib + ICI group (P=0.03). CRAFITY, CRP and AFP in Immunotherapy; ICI, immune checkpoint inhibitor; CRP, C-reaction protein; AFP, alpha-fetoprotein.

Regorafenib dose was reduced early in most (87.5%) patients. However, the distribution of initial and final daily stable doses of regorafenib for the monotherapy and ICI combination treatment group were similar (P=0.69; P=0.65, respectively) (Figure 4). Analyses of associations between dosing of regorafenib and outcome, indicated improved PFS and OS with higher doses (see Appendix 1).

Figure 4 Distribution of the initial daily stable dose* (A) and final daily stable dose (B) of the 26 patients in the regorafenib group and the 22 patients in the regorafenib + ICI group. *, stable daily dosing was defined as maintaining the same dose for at least one whole treatment cycle (28 days), and if the patient’s stable daily dose varied between treatment cycles, the initial stable daily dose and the final stable daily dose were both counted. The initial dose of regorafenib was 160 mg in all 48 patients. ICI, immune checkpoint inhibitor.

Adverse events

The incidence of treatment-related AEs was similar (35% vs. 36%, P=0.89) in the monotherapy and ICI combination groups, with only one grade III/IV AE in the monotherapy group and no grade III/IV AEs in the combination treatment group (Table 3). We found improved OS (P=0.04), but not PFS (P=0.36) in patients with hand/foot skin reactions compared to patients without (Figure 5).

Table 3

Treatment-related adverse events according to CTC

Adverse event All grades Grade III/IV
Regorafenib Regorafenib + ICIs Regorafenib Regorafenib + ICIs
Hand-foot skin reaction 6 (23%) 5 (23%) 1(4%) 0
Anorexia 3 (12%) 4 (18%) 0 0
Nausea 2 (8%) 3 (14%) 0 0
Diarrhea 4 (15%) 1 (5%) 0 0
Hypertension 2 (8%) 0 0 0
Fatigue 2 (8%) 5 (23%) 0 0
Neutropenia 1 (4%) 1 (5%) 0 0
Thrombocytopenia 2 (8%) 2 (9%) 0 0
Rash 5 (19%) 4 (18%) 0 0

ICI, immune checkpoint inhibitor; CTC, common terminology criteria.

Figure 5 Comparison of survival curves of patients with and without hand/foot skin reactions. (A) Comparison of PFS survival curves (P=0.36). (B) Comparison of OS survival curves (P=0.04). PFS, progression-free survival; OS, overall survival; HFSR, hand/foot skin reactions.

Discussion

Given the proven efficacy of regorafenib in second-line therapy and the potential benefit to first-line therapy, we selected regorafenib as first-line therapy. This decision was also influenced by current clinical practice and emerging research trends that support a reassessment of the existing treatment sequence. Our retrospective study evaluated the safety and efficacy of regorafenib as a first-line agent alone or in combination with ICIs in patients with advanced HCC. Sorafenib, has been shown to inhibit HCC proliferation and invasive ability (23) and is approved for first-line treatment of advanced disease (24). Compared to sorafenib, regorafenib possesses higher biological activity than the former and has more targets of action, inhibiting kinases associated with angiogenesis and tumorigenesis (25), such as vascular endothelial growth factor receptor VEGFR1-3, tyrosine-protein kinase receptors TIE and Ret, platelet-derived growth factor receptor PDGFR-β, basic fibroblast growth factor receptor FGFR-1/2, serine/threonine protein kinase Raf, and mitogen-activated protein kinase p38, thereby exerting antitumor effects (26-28). In addition, regorafenib can improve the tumor microenvironment; for example, regorafenib regulates macrophages and increases the proliferation and activation of CD8+ T cells to enhance antitumor immunity, and it can inhibit signal transduction and the STAT3 signaling pathway by increasing the cytolytic activity of NK cells, which eventually leads to apoptosis of HCC cells (29-31). Compared with lenvatinib, also an approved first-line drug for advanced HCC (32), regorafenib improves tumor immune microenvironment-related pathways through its targets TIE2, CSF1R and RAF to achieve immune enhancement and antitumor cell proliferation (33).

In this retrospective cohort study, we found a mPFS of 5.9 months in the monotherapy group and 7.8 months in the combination group, which compare favorably with the 2.8 months reported in patients with advanced HCC treated with first-line sorafenib in Asian patients (34,35). In addition, the mOS was almost twice as long in the combination group as in the monotherapy group (13.9 vs. 23.6 months), suggesting that ICI may act synergistically with regorafenib and warranting confirmation in a prospective randomized trial. We could reproduce the strong prognostic value of the CRAFITY score (22) and of hand/foot skin reactions developing during treatment (13).

Dose-response analyses suggested that a stable dose of 160 mg or regorafenib provides optimal efficacy, if tolerated. Hand/foot skin reactions are the most common side effect caused by TKI’s targeting vascular endothelial growth factor receptor (VEGFR) (36).

Although our study design did not directly compare regorafenib with standard of care (Lenvatinib or Atezolizumab/bevacizumab), we made indirect comparisons through a literature review and available clinical trial data. We found that while Lenvatinib and Atezolizumab/bevacizumab have been shown to be effective first-line treatment options, regorafenib may offer additional therapeutic advantages in certain patient populations, particularly in those who are resistant or intolerant to standard therapy (37). There are limitations to this study. First, the sample size of this study is relatively small, reducing its statistical power. Second, this was a retrospective study with some confounding factors and biases, including probable underreporting of AEs, and future prospective studies applying fixed protocols are needed to validate the findings. Comparisons of results with those of RCTs should therefore be done with reservations.

Conclusions

In conclusion, this retrospective, real-world study showed that regorafenib as a first-line agent alone or in combination with ICIs is active and seems to have a favorable safety profile. As the mOS of patients treated with regorafenib and ICI in combination was almost two years and approx. twice as long as compared to the monotherapy group, and the registered toxicity mild, further studies of the combination for first-line treatment of advanced HCC seems warranted.

Acknowledgments

Funding: This work was supported by The Tianjin Science and Technology Project (No. 19ZXDBSY00010 to Y.Z.).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-315/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-315/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-315/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-315/coif). M.L. reports research funding by Scandion Oncology A/S, Denmark. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Science and Technology Ethics Committee of Tianjin First Central Hospital (No. 2023DZX08) and informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

  1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424. [Crossref] [PubMed]
  2. Walter AJ, van de Klundert MA, Jung S. Many Ways to Communicate-Crosstalk between the HBV-Infected Cell and Its Environment. Pathogens 2022;12:29. [Crossref] [PubMed]
  3. Singal AG, Kanwal F, Llovet JM. Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy. Nat Rev Clin Oncol 2023;20:864-84. [Crossref] [PubMed]
  4. Li Q, Cao M, Lei L, et al. Burden of liver cancer: From epidemiology to prevention. Chin J Cancer Res 2022;34:554-66. [Crossref] [PubMed]
  5. Singal AG, Llovet JM, Yarchoan M, et al. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology 2023;78:1922-65. [Crossref] [PubMed]
  6. Rashed WM, Kandeil MAM, Mahmoud MO, et al. Hepatocellular Carcinoma (HCC) in Egypt: A comprehensive overview. J Egypt Natl Canc Inst 2020;32:5. [Crossref] [PubMed]
  7. Llovet JM, Castet F, Heikenwalder M, et al. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol 2022;19:151-72. [Crossref] [PubMed]
  8. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 2020;382:1894-905. [Crossref] [PubMed]
  9. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389:56-66. [Crossref] [PubMed]
  10. Finn RS, Merle P, Granito A, et al. Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: Additional analyses from the phase III RESORCE trial. J Hepatol 2018;69:353-8. [Crossref] [PubMed]
  11. Tu X, Yang J, Zheng Y, et al. Immunotherapy combination with regorafenib for refractory hepatocellular carcinoma: A real-world study. Int Immunopharmacol 2022;113:109401. [Crossref] [PubMed]
  12. Qiao L, He W, Wang G, et al. Regorafenib with immunotherapy versus regorafenib alone as second-line treatment for hepatocellular carcinoma: A multicenter real-world study. Cancer Med 2024;13:e7236. [Crossref] [PubMed]
  13. Yoo C, Byeon S, Bang Y, et al. Regorafenib in previously treated advanced hepatocellular carcinoma: Impact of prior immunotherapy and adverse events. Liver Int 2020;40:2263-71. [Crossref] [PubMed]
  14. World Medical Association Declaration of Helsinki. ethical principles for medical research involving human subjects. JAMA 2013;310:2191-4. [Crossref] [PubMed]
  15. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2018;68:723-50. [Crossref] [PubMed]
  16. Common Terminology Criteria for Adverse Events (CTCAE) Version 5. Published: November 27. US Department Of Health and Human Services.
  17. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. [Crossref] [PubMed]
  18. Scheiner B, Pomej K, Kirstein MM, et al. Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score. J Hepatol 2022;76:353-63. [Crossref] [PubMed]
  19. Lai H, Liu Y, Wu J, et al. Targeting cancer-related inflammation with non-steroidal anti-inflammatory drugs: Perspectives in pharmacogenomics. Front Pharmacol 2022;13:1078766. [Crossref] [PubMed]
  20. Mantovani A, Allavena P, Sica A, et al. Cancer-related inflammation. Nature 2008;454:436-44. [Crossref] [PubMed]
  21. Galle PR, Foerster F, Kudo M, et al. Biology and significance of alpha-fetoprotein in hepatocellular carcinoma. Liver Int 2019;39:2214-29. [Crossref] [PubMed]
  22. Yang Y, Ouyang J, Zhou Y, et al. The CRAFITY score: A promising prognostic predictor for patients with hepatocellular carcinoma treated with tyrosine kinase inhibitor and immunotherapy combinations. J Hepatol 2022;77:574-6. [Crossref] [PubMed]
  23. Li J, Yang F, Li J, et al. Postoperative adjuvant therapy for hepatocellular carcinoma with microvascular invasion. World J Gastrointest Surg 2023;15:19-31. [Crossref] [PubMed]
  24. Contreras L, Rodríguez-Gil A, Muntané J, et al. Broad Transcriptomic Impact of Sorafenib and Its Relation to the Antitumoral Properties in Liver Cancer Cells. Cancers (Basel) 2022;14:1204. [Crossref] [PubMed]
  25. Fondevila F, Méndez-Blanco C, Fernández-Palanca P, et al. Anti-tumoral activity of single and combined regorafenib treatments in preclinical models of liver and gastrointestinal cancers. Exp Mol Med 2019;51:1-15. [Crossref] [PubMed]
  26. An L, Liao H, Yuan K. Efficacy and Safety of Second-line Treatments in Patients with Advanced Hepatocellular Carcinoma after Sorafenib Failure: A Meta-analysis. J Clin Transl Hepatol 2021;9:868-77. [Crossref] [PubMed]
  27. Li Z, Wang J, Zhao J, et al. Regorafenib plus programmed death-1 inhibitors vs. regorafenib monotherapy in second-line treatment for advanced hepatocellular carcinoma: A systematic review and meta-analysis. Oncol Lett 2024;28:318. [Crossref] [PubMed]
  28. Marguier A, Laheurte C, Lecoester B, et al. TIE-2 Signaling Activation by Angiopoietin 2 On Myeloid-Derived Suppressor Cells Promotes Melanoma-Specific T-cell Inhibition. Front Immunol 2022;13:932298. [Crossref] [PubMed]
  29. Kelley RK, Mollon P, Blanc JF, et al. Comparative Efficacy of Cabozantinib and Regorafenib for Advanced Hepatocellular Carcinoma. Adv Ther 2020;37:2678-95. [Crossref] [PubMed]
  30. Wang D, Yang X, Lin J, et al. Comparing the efficacy and safety of second-line therapies for advanced hepatocellular carcinoma: a network meta-analysis of phase III trials. Therap Adv Gastroenterol 2020;13:1756284820932483. [Crossref] [PubMed]
  31. Chen J, Wang J, Xie F. Comparative efficacy and safety for second-line treatment with ramucirumab, regorafenib, and cabozantinib in patients with advanced hepatocellular carcinoma progressed on sorafenib treatment: A network meta-analysis. Medicine (Baltimore) 2021;100:e27013. [Crossref] [PubMed]
  32. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018;391:1163-73. [Crossref] [PubMed]
  33. Grothey A, Blay JY, Pavlakis N, et al. Evolving role of regorafenib for the treatment of advanced cancers. Cancer Treat Rev 2020;86:101993. [Crossref] [PubMed]
  34. Zarlashat Y, Abbas S, Ghaffar A. Hepatocellular Carcinoma: Beyond the Border of Advanced Stage Therapy. Cancers (Basel) 2024;16:2034. [Crossref] [PubMed]
  35. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25-34. [Crossref] [PubMed]
  36. Chen L, Wu Z, Yang L, et al. Nitric oxide in multikinase inhibitor-induced hand-foot skin reaction. Transl Res 2022;245:82-98. [Crossref] [PubMed]
  37. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389:56-66. Erratum in: Lancet 2017;389:36. [Crossref] [PubMed]
Cite this article as: Yu J, Bai Y, Cui Z, Cheng C, Ladekarl M, Cheng KC, Chan KS, Yarmohammadi H, Mauriz JL, Zhang Y. Efficacy and safety of regorafenib as a first-line agent alone or in combination with an immune checkpoint inhibitor for advanced hepatocellular carcinoma: a retrospective cohort study. J Gastrointest Oncol 2024;15(3):1072-1081. doi: 10.21037/jgo-24-315

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