Efficacy and safety of tyrosine kinase inhibitors combined with sintilimab and transarterial chemoembolization in patients with Barcelona Clinic Liver Cancer stage B/C hepatocellular carcinoma: a pooled analysis

Introduction

As indicated by the Global Cancer Observatory (GLOBOCAN) 2020 data, liver cancer had 905,677 new cases and caused 830,180 deaths globally in 2020, posing a severe threat to global health (1). Systemic therapies, such as immunotherapy, molecular-targeted therapy, chemotherapy, and transarterial chemoembolization (TACE), are appropriate for patients with unresectable hepatocellular carcinoma (HCC), of which less than 15% of patients can survive 5-year (1).

Sintilimab (Sin) has been approved for the treatment of many malignancies, such as advanced esophageal cancer and gastric cancer, in China. It has been shown that Sin exhibits robust anti-tumor activity by highly selectively blocking programmed death-1 (PD-1). Based on the findings of the ORIENT-32 study, Sin plus a bevacizumab biosimilar (IBI305) are superior to sorafenib in treating unresectable HCC (2).

Tyrosine kinase inhibitors (TKIs) are of utmost significance in improving the prognosis of patients with HCC. Sorafenib and lenvatinib, as first-line treatments, have synergistic effects with immunotherapy and play a pivotal role in treating unresectable HCC by promoting greater disease stabilization (3-5).

TACE plays a crucial role in treating HCC, as it induces tumor ischemia by embolizing the arteries that supply the tumor, leading to tumor cell death and necrosis (6).

Trials investigating TKIs, Sin plus TACE (TKIs-Sin-TACE) for the treatment of HCC in patients with Barcelona Clinic Liver Cancer (BCLC) B/C stage are currently registered and ongoing. Some of these trials have already reported results demonstrating that TKIs-Sin-TACE is safe and can extend overall survival (OS) and progression-free survival (PFS) (7-12). However, the sample sizes of these trials so far are relatively small. Furthermore, no systematic reviews have been conducted to date to demonstrate their clinical effects and treatment-related adverse events (TRAEs). Given these promising preliminary findings, it is crucial to conduct a pooled analysis of TKIs-Sin-TACE therapy for HCC in patients with BCLC stage B/C to further evaluate its clinical benefits and safety profile. We present this article in accordance with the PRISMA reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-431/rc) (13).

Methods

Data sources and search strategy

The population in this meta-analysis is patients with BCLC stage B/C HCC. The intervention is TKIs-Sin-TACE. There is neither a comparative group nor a control group. Primary outcomes were disease control rate (DCR) and objective response rate (ORR). Secondary outcomes were the rates of TRAEs ≥ grade 3, 10-month PFS, and 10- and 20-month OS.

PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched for potentially eligible studies up to October 1, 2024.The query included the following terms: (“Liver Neoplasms” or “Hepatic Neoplasms” or “Hepatic Neoplasm” or “Neoplasm, Hepatic” or “Neoplasms, Hepatic” or “Neoplasms, Liver” or “Liver Neoplasm” or “Neoplasm, Liver” or “Cancer of Liver” or “Liver Cancer” or “Cancer, Liver” or “Cancers, Liver” or “Liver Cancers” or “Hepatocellular Cancer” or “Cancers, Hepatocellular” or “Hepatocellular Cancers” or “Cancer of the Liver” or “Cancer, Hepatocellular”) and (“Sintilimab” or “anti-PD-1 antibody” or “IBI 308” or “IBI308” or “IBI-308”) and (“sorafenib” or “lenvatinib” or “tyrosine kinase inhibitors” or “TKIs”). This study isn’t registered.

Study selection and eligibility criteria

Two researchers (G.L.L. and J.M.T.) individually screened literature and assessed its eligibility as shown in Figure 1. Any discrepancies were resolved by consensus-building with the third reviewer (F.T.).

Figure 1 PRISMA flow chart.

The inclusion criteria for this study is listed as follows: (I) patients with HCC confirmed by histopathology or cytology; (II) patients with a clinical stage BCLC B or C; (III) patients with no history of systematic treatment before, such as chemotherapy, immunotherapy or TACE; (IV) studies with complete clinical outcomes such as ORR and DCR; (V) patients aged 18 years or older with mild to moderate liver dysfunction; (VI) studies published in English.

The exclusion criteria for this study are described as below: (I) cases involving metastatic hepatic carcinoma, biliary carcinoma, or gallbladder carcinoma; (II) studies of patients with history of systemic therapies before or during treatment; (III) studies of patients with Child-Pugh grade C or active bleeding; (IV) studies involving patients with BCLC stage A; (V) study types such as reviews, case reports, or meta-analyses; (VI) studies relating to cells or animals; (VII) studies lacking ORR or DCR; (VIII) duplicate publications of the same clinical trial data; (IX) studies with high levels of bias.

Data extraction and quality assessment

Data were extracted from enrolled studies by G.L.L. and J.M.T. Disagreements were resolved by F.T. As outlined in Table 1, data included first author and year, country, sample size, age, male proportion, regimen, trial registration, and study design.

The Methodological Index for Non-Randomized Studies (MINORS) was used to evaluate literature quality and the levels of bias (14). In this index, items that are not reported receive 0 points, those with inadequate descriptions receive one point, and adequately described items receive two points. Studies whose scores are less than 50% of the maximum are categorized as the ones with high risk of bias and low quality, while those with scores exceeding 75% of the maximum are defined as having a low risk of bias and high quality (14).

Statistical analysis

Stata software (version 14) and R software with the metaprop packages were used to generate the combined rate with 95% confidence intervals (CIs). Heterogeneity exists when I² >50% and P<0.10. In this context, a sensitivity analysis was performed to examine the robustness and stability of the meta-analysis results, as well as to identify potential sources of heterogeneity. If potential sources of heterogeneity cannot be found, the aggregated rate was computed using a random-effects model. Publication bias was tested using funnel plots and Egger’s test (15). There was publication bias when the P value was less than 0.05 in Egger’s test and asymmetry was observed in the funnel plots.

Results

Results of study selection

Figure 1 shows that this search yielded a total of 838 studies initially considered for review (13). Studies that were excluded are listed below: 109 studies due to previous adjuvant therapy, 120 studies focusing on metastatic hepatic malignancy or intrahepatic bile duct carcinoma, 198 duplicate studies, 44 trial protocols, 192 articles consisting of reviews and case reports, 67 studies lacking ORR or DCR data, 71 studies involving cells or animals, and 31 high-bias studies. Consequently, a total of 6 high-quality, low-bias trials were enrolled in this meta-analysis.

Study characteristics

As summarized in Table 1, this pooled analysis was conducted on six studies involving a total of 336 patients. The clinical stages of these patients ranged from BCLC B to C. The intervention was the TKIs-Sin-TACE regimen (Table 1). The patients’ ages generally ranged between 25 and 75 years. The proportion of males varied from 80.2% to 88%. Two studies are prospective, while the remaining studies are retrospective.

Risk of bias

The quality assessment of the included studies using the MINORS criteria revealed the following scores: one study scored 12 points (14), one study scored 24 points (10), three studies scored 20 points (9,11,13), and one study scored 16 points (8). These scores indicate that the selected studies are of high quality and have low bias, thereby ensuring the robustness of the meta-analysis (Table 1 and Table S1).

Meta-analysis results

Efficacy of TKIs-Sin-TACE therapy for HCC in patients with BCLC stage B/C

In terms of ORR and DCR, six studies with 336 HCC cases were included (7-12). The combined ORR and DCR were 39% (95% CI: 26–55%) and 74% (95% CI: 60–84%), respectively (Figures 2-3 and Table 2). As manifested in Table 2, both had heterogeneity (ORR, I² =83.7%; DCR, I² =76.4%; both P<0.10).

Figure 2 Forest plot of ORR of TKIs-Sin-TACE. CI, confidence interval; ORR, objective response rate; TKIs-Sin-TACE, tyrosine kinase inhibitors combined with sintilimab and transarterial chemoembolization.

Figure 3 Forest plot of DCR of TKIs-Sin-TACE. CI, confidence interval; DCR, disease control rate; TKIs-Sin-TACE, tyrosine kinase inhibitors combined with sintilimab and transarterial chemoembolization.

Four studies involving 238 HCC patients reported the 10-month PFS rate (7,8,10,11). As presented in Figure 4 and Table 2, the pooled rate was 0.41 (95% CI: 0.30–0.54). Heterogeneity was also noted (I² =78.3%, P<0.10).

Figure 4 Forest plot of 10-month PFS of TKIs-Sin-TACE. CI, confidence interval; PFS, progression-free survival; TKIs-Sin-TACE, tyrosine kinase inhibitors combined with sintilimab and transarterial chemoembolization.

In the OS rate analysis, three studies involving 203 HCC patients were enrolled (7,10,11). As illustrated in Figures 5,6 and Table 2, the combined 10-month OS rate and 20-month OS rate were 0.73 (95% CI: 0.54–0.86) and 0.30 (95% CI: 0.16–0.49), respectively. Heterogeneity existed (10-month OS rate, I² =81.6%; 20-month OS rate, I² =87.3%; both P<0.10).

Figure 5 Forest plot of 10-month OS of TKIs-Sin-TACE. CI, confidence interval; OS, overall survival; TKIs-Sin-TACE, tyrosine kinase inhibitors combined with sintilimab and transarterial chemoembolization.

Figure 6 Forest plot of 20-month OS of TKIs-Sin-TACE. CI, confidence interval; OS, overall survival; TKIs-Sin-TACE, tyrosine kinase inhibitors combined with sintilimab and transarterial chemoembolization.

Safety of Sin-TACE therapy for HCC in patients with BCLC stage B/C

Regarding TRAEs ≥ grade 3, five trials with 278 HCC cases were involved (7,8,10-12). As exhibited in Figure 7 and Table 2, the cumulative incidence was 0.23 (95% CI: 0.12–0.42), demonstrating heterogeneity (I² =77.9%, P<0.10). The most common TRAEs ≥ grade 3 included hypertension (12.80%), abnormal liver function (3.57%), decreased neutrophil count (2.38%), and decreased platelet count (3.27%) (Table 3).

Figure 7 Forest plot of TRAEs of grade ≥3 of TKIs-Sin-TACE. CI, confidence interval; TRAEs, treatment-related adverse events; TKIs-Sin-TACE, tyrosine kinase inhibitors combined with sintilimab and transarterial chemoembolization.

Sensitivity analysis and publication bias

The funnel plots were symmetric, as displayed in the Figures S1-S6. No publication bias was detected according to Egger’s test (all P>0.05, Table 2). As demonstrated in the Figures S7-S12, all these cumulative pooled rates remained stable and robust in the sensitivity analysis, even when a study was omitted.

Discussion

BCLC Stage B/C HCC is generally unresectable or potentially resectable. This poses a prominent challenge for treatment due to its rapid progression and poor prognosis, making effective therapeutic strategies critical. This analysis aims to provide a more comprehensive understanding of TKIs-Sin-TACE therapy in patients with BCLC stage B/C HCC and to help physicians make evidence-based decisions in clinical practice.

Primary outcomes are ORR and DCR. Previous studies have shown that TACE combined with targeted therapy and immunotherapy is safe and effective for potentially resectable or unresectable HCC (16-20). The pooled ORR was 39%, which indicated that the TKIs-Sin-TACE therapy was highly effective in reducing tumor size. The combined DCR reached 74%, further confirming the effectiveness of the TKIs-Sin-TACE therapy in delaying disease progression. For 10-month PFS, the aggregated rate was 41%, meaning that the TKIs-Sin-TACE regimen provides preliminary clinical benefits and potential long-term disease control. Compared with the Sin-sorafenib and Sin groups, patients with unresectable HCC in the Sin-sorafenib-TACE group had longer median OS and PFS, as well as a higher DCR (8). This study shows that the 10-month OS rate was 73%, while the 20-month OS rate was 30%. A conclusion can be drawn that the TKIs-Sin-TACE regimen is effective for BCLC stage B/C HCC, regardless of its relatively higher costs. A cost-effective strategy is needed to promote its broader accessibility.

With regard to the safety of TKIs-Sin-TACE therapy, the severity and types of TRAEs were evaluated in this pooled analysis. The cumulative incidence rate of TRAEs ≥ grade 3 was 23%. Neither grade 5 TRAEs nor deaths due to TRAEs were reported. Autoimmune hemolytic anemia, which was grade 4, was effectively managed with glucocorticoids (12). Corticosteroids are the primary treatment for immune checkpoint inhibitor (ICI) hepatitis, with mycophenolate mofetil used as a secondary option for steroid-refractory cases (21). Abnormal liver function occurred in 3.57% of cases, which was also diagnosed as ICI hepatitis in this meta-analysis (22). It was effectively managed through treatment interruption, dose adjustment, hepatoprotective drugs, and symptomatic and supportive care. These safety data further support the potential application of TKIs-Sin-TACE therapy in clinical practice.

Programmed death-ligand 1 (PD-L1) expression has always been assessed by immunehistochemistry tests. It has been shown that pembrolizumab benefits patients with metastatic non-small cell lung cancer who have a PD-L1 tumor proportion score (TPS) of at least 50%, providing a durable, clinically meaningful long-term OS (23). HCC patients with PD-L1 TPS ≥1% had significantly longer median PFS and OS than those with PD-L1 TPS <1% (24). Sin, a highly selective PD-1 blocker, exhibits anti-tumor effects irrelevant of PD-L1 status. However, in patients with unresectable HCC, the correlation between PD-L1 expression and the efficacy of ICI remains uncertain (25). Future research could stratify outcomes based on PD-L1 expression levels, thereby making the findings more clinically relevant.

There are several limitations in this study. Firstly, retrospective or single-center trials introduce bias into the analysis. Secondly, no sources of heterogeneity were identified in the sensitivity analysis. A random-effects model was used to calculate the combined rates. Thirdly, all selected studies originate from China, inherently limiting the potential for generalizing the conclusions to global population.

Conclusions

Overall, this pooled analysis shows that TKIs-Sin-TACE regimen exhibits an efficacious and safe profile for Chinese patients with BCLC stage B/C HCC. Large-scale, global multicenter randomized controlled trials are needed to further validate these findings.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-431/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-431/prf

Funding: This study was supported by the Special Fund for Zhejiang Provincial Clinical Key Specialties, the Science and Technology Plan Project of Quzhou City (No. 2023 K198), and the Guiding Science and Technology Project of Longyou County (Nos. 2023079 and 2023088).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-431/coif). The 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.

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/.

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