Efficacy, safety, and biomarker analysis of TACE combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma: a real-world study

Abstract

Background

The integration of transarterial chemoembolization (TACE) with systemic therapy has demonstrated improved survival outcomes in patients with unresectable hepatocellular carcinoma (HCC). However, there is limited evidence evaluating the combination of TACE with the systemic regimen of anti-PD-1/L1 inhibitor plus lenvatinib. This study aims to assess the efficacy and safety of TACE combined with lenvatinib and sintilimab in unresectable HCC patients.

Methods

Unresectable HCC patients who received TACE in combination with sintilimab plus Lenvatinib as first-line treatment from 1 January 2020 to 31 March 2023 were included for the analysis. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were evaluated by modified Response Evaluation Criteria in Solid Tumors criteria. Exploratory biomarker analysis was conducted.

Results

The study included 70 patients with unresectable HCC, predominantly male and infected with Hepatitis B. The median follow-up duration for the whole cohort was 13.8 months (95% CI 11.08–16.7). The ORR was 61.4% (95% CI, 49.0%–72.8%) and the DCR was 68.6% (95%CI, 56.4%–79.2%). The median PFS was 13.2 months (95% CI 11.0-NA), with a corresponding 1-year PFS rate of 50.3% (95% CI 39.7%-65.5%). The median OS was not reached, and the 1-year OS rate was 89.3% (95% CI 81.4%–97.9%). The most common treatment-related adverse events (TRAEs) were fatigue 38.6% (27/70), hypertension 32.9% (23/70), and hand-foot syndrome 31.4% (22/70). Most TRAEs were mild-to-moderate and manageable. In addition, significant predictive value was found in alpha-fetoprotein levels (AFP), with patients showing a level of decrease post-treatment having better PFS.

Conclusion

The combination regimen demonstrated promising efficacy in treating unresectable HCC, accompanied by manageable safety profiles. Furthermore, the results of this investigation suggest that AFP holds promise as predictive biomarkers for this treatment strategy.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00262-024-03857-5.

Introduction

Primary liver cancer, notably hepatocellular carcinoma (HCC) which makes up about 75%–85% of such cases, is a prevalent cancer type and the third leading cause of cancer-related deaths globally [1]. Early-stage HCC patients, when diagnosed and treated timely, have a promising prognosis with over 70% survival rate over five years due to curative treatments. However, the majority of patients are identified at a more advanced stage, where these treatments are no longer viable [2]. For these patients, and also for those with intermediate-stage HCC, systemic therapies are the recommended approach, often combined with locoregional therapies in the latter group [3]. These systemic treatments have been effective in extending the median survival time for some patients. The introduction of targeted therapies such as tyrosine kinase inhibitors (TKIs), heralded a paradigm shift within the domain of treating HCCs [4, 5]. Immunotherapies like immune checkpoint inhibitors have also shown potential for HCC treatment trial. Atezolizumab plus bevacizumab and tremelimumab plus durvalumab have also been included as first-line treatments for advanced HCC [6, 7]. Despite recent advancements in systemic therapy, precise incorporation of these therapeutic strategies within the overall approach to managing HCC remains under investigation particularly in cases involving unresectable or advanced stage tumors.

Recently, it was proposed that all stages of hepatocellular carcinoma patients may benefit from systemic therapy mainly for TKIs combined with locoregional therapy [8]. The phase III LAUNCH trial comparing LEN-TACE versus LEN alone in advanced-stage HCC [7] showed that LEN-TACE significantly prolonged OS (HR = 0.45, p < 0.001) and PFS (HR = 0.43, p < 0.001) compared with LEN alone in advanced-stage HCC patients. This study demonstrated that locoregional therapy, which can reliably control intrahepatic lesions, in combination with systemic therapy prolongs OS even in advanced-stage HCC, as intrahepatic lesions are usually a prognostic factor. In addition, a phase III trial conducted in China comparing FOLFOX HAIC plus sorafenib with sorafenib alone showed that HAIC plus sorafenib significantly prolonged OS (HR = 0.35, p < 0.01) and PFS (HR = 0.33, p < 0.01) [9].

Immunotherapy as a systemic therapy combined with locoregional therapy potentially amplify anti-tumor effects synergistically. Locoregional therapy has been shown with an immunostimulatory effect and potentiated the effects of concurrent ICI therapy [10]. TACE may deliver localized control over tumor growth along with releasing antigens. Additionally, the modulation effect on immune system triggered by TACE may amplify the impacts of immunotherapies like sintilimab [11–13] given that the majority of HCC patients are generally identified at an advanced stage, which substantially restricts their therapeutic alternatives, while agents like lenvatinib might tackle residual disease thereby preventing distant metastasis. This suggests that RFA/TACE caused tumor antigen release followed by activation of cancer immunity cycles, resulting in infiltration of CD8 + T-cells into the tumor and inhibition of immunosuppressor cells, which may improve the response to ICIs [14].

While ongoing studies like the IMPACT trial (jRCTs051230037) are evaluating the combination of TACE with atezolizumab and bevacizumab, limited evidence is available on the safety and efficacy of combining immunotherapy with TKI and locoregional therapy. Therefore, this study aimed to assess the safety profile and effectiveness of the combination therapy comprising TACE, Lenvatinib and sintilimab in patients with unresectable HCC.

Method

Study design and patients

This single-center, retrospective study was conducted at the Fifth Medical Center of the PLA General Hospital. The study, approved by the hospital's ethics committee, spanned from 1 January 2020 to 31 March 2023. Inclusion criteria were individuals aged 18 to 80 years, clinically or histopathologically confirmed HCC at BCLC stages B or C, with at least one measurable lesion as per the modified Response Evaluation Criteria in Solid Tumours (mRECIST), considered unresectable either due to advanced-stage HCC, intermediate-stage HCC, or insufficient remnant liver volume following liver resection (< 40% for patients with liver cirrhosis; < 30% for patients without liver cirrhosis); had an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1 and a Child–Pugh score of class A or B. Exclusion criteria included patients with any malignancy other than HCC, a history of organ transplantation, previous treatments such as RFA, TACE, hepatic arterial infusion chemotherapy (HAIC), radiotherapy, or systemic therapies, those with prior systemic therapy or immunotherapy, a life expectancy under six months, and a history of autoimmune disease.

Treatment procedure

TACE: TACE was performed by interventional radiologists of our hospital with more than ten years of experience. The process began with a meticulous puncture of the femoral artery, followed by selective angiography of the celiac trunk and superior mesenteric artery using a specialized 5F catheter (RH catheter; Cook, Bloomington, Ind). Once these arteries were located, a 3F microcatheter (SP microcatheter; Terumo, Tokyo, Japan) was employed for selective catheterization of smaller or more challenging vessels. The embolization procedure involved the infusion of oxaliplatin (75 mg/m²), a chemotherapeutic agent, through the catheter directly into the tumor-feeding arteries. Oxaliplatin was selected as the chemotherapeutic agent due to its well-established efficacy in HCC treatment and its synergistic effects with targeting agents and immunotherapy [15, 16]. This was followed by the administration of a mixture of iodized oil (Lipiodol Ultrafluido; Guerbet, Aulnay-sous-Bois, France) and epirubicin (30–50 mg/m²), which served to embolize these arteries effectively, thereby cutting off blood supply to the tumor and delivering chemotherapy locally. The TACE procedure was repeated at intervals of 4–6 weeks, depending on the patient's response and tumor progression. Repeated TACE was considered when imaging studies showed residual viable tumors, with more than 50% of the baseline tumor volume, or for intrahepatic new lesions measuring > 10 mm which show arterial enhancement with venous washout, under the conditions that patients maintained adequate liver function (Child–Pugh class A or B) and performance status (ECOG PS 0 or 1). The detailed treatment schedule, including the timing of TACE and drug administration, was visually presented in Fig. 1.

Fig. 1.

Treatment schedule

Systemic Therapy: Lenvatinib was administered at full dose (12 mg for patients ≥ 60 kg, 8 mg for patients < 60 kg) starting two weeks before TACE, aiming to maintain a high relative dose intensity to enhance the therapeutic effect. Dose reductions were implemented based on patient tolerance and observed adverse events. The purpose of this pre-TACE lenvatinib treatment was twofold: to assess and ensure patient tolerability to the drug, particularly in the management of potential adverse events, and to normalize tumor neovasculature for a more effective TACE procedure. This normalization aimed at suppressing the post-TACE increase in hypoxia-inducing factors like VEGF and platelet-derived growth factor. Lenvatinib treatment was temporarily discontinued 2 days before each TACE session and resumed 3 days post-TACE to minimize potential drug-related complications during the procedure. Following the TACE procedure, patients were administered sintilimab at a dose of 200 mg intravenously. This was given on the first day of a 21-day treatment cycle, starting immediately after the TACE procedure. The combination of lenvatinib and sintilimab was intended to exploit the synergistic effects of targeted therapy and immunotherapy, potentially enhancing the overall therapeutic response against HCC.

Follow-Up visits

Patients were closely monitored with follow-up visits scheduled every 4–6 weeks post-initial TACE treatment. These visits included comprehensive assessments like chest CT, multiphase CT or MRI of the abdomen, and detailed laboratory tests (liver function tests, bilirubin, AST, ALT, albumin, γ-GT, PT, and serum AFP, AFPV levels). Definitions for OS and PFS were established, with specific criteria for determining disease progression.

Outcomes and evaluations

The primary study endpoints were ORR and PFS based on mRECIST. Secondary endpoints included OS, disease control rate (DCR), and safety. ORR was defined as the percentage of patients who had a best tumor response rating of CR and PR. Disease control rate (DCR) was defined as the percentage of patients who had a best tumor response rating of CR, PR and SD. OS was defined as the time from the first TACE treatment to death or the last follow-up. PFS was defined as the time from the first TACE treatment to disease progression or death from any cause. Disease progression was determined as untreatable (UnTACEable) progression, defined as the inability of a patient to further receive or benefit from TACE, due to reasons including intrahepatic tumor progression (25% increase vs baseline), the appearance of new lesions, vascular invasion, extrahepatic metastasis, or deterioration of liver function to Child–Pugh class C. Adverse events (AEs) were recorded and assessed based on Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The cut-off value of 400 ug/L for AFP was selected based on clinical evidence suggesting that levels above this threshold are indicative of more aggressive disease and are associated with poorer outcomes in HCC patients [17–19]. Patients were categorized into two groups based on the changes in their AFP levels from baseline to the first evaluation after treatment initiation: AFP-decrease group: This group included patients who exhibited a decrease in their AFP levels after the first treatment cycle compared to their baseline AFP measurement. AFP-increase group: This group comprised patients whose AFP levels increased after the first treatment cycle compared to their baseline AFP measurement. AFPV refers to AFP variation per volume, calculated as: AFPV = (Post-treatment AFP level—Baseline AFP level) / Baseline AFP level × 100%.

Statistical analysis

Data analysis was conducted using SPSS software (version 20.0) and GraphPad Prism (version 9.0). Continuous data were presented as median values with ranges, and categorical data were analyzed using chi-square and Fisher's exact tests. The Mann–Whitney U test was employed for continuous variables not normally distributed. PFS and OS were estimated using the Kaplan–Meier method and compared via the log-rank test. Prognostic variables were initially examined through univariate Cox regression analysis, with significant variables further analyzed using multivariate Cox regression to identify independent predictors for OS and PFS. Descriptive statistics were used to depict the AE landscape, ensuring a comprehensive evaluation of treatment effects. Significance was determined with a p-value threshold set at less than 0.05.

Results

Baseline patient characteristics

Totally 74 patients were identified in the current study between 1 January 2020 and 31 March 2023. 4 were excluded due to: diagnoses of intrahepatic cholangiocarcinoma (n = 2), an unexpected death (n = 1), and loss to follow-up (n = 1). Finally, this study included 70 patients for the analysis, with a median age of 57 years (range 26–73). The cohort was predominantly male (80%, n = 56), with ECOG PS 1 (94.3%, n = 66) and Child–Pugh Class A (82.9%, n = 58). Most patients had multiple hepatic lesions (75.7%, n = 53) and HBV infection (92.0%, n = 65), The cohort was almost evenly split between BCLC Stage B (47.1%, n = 33) and Stage C (52.9%, n = 37). Vascular invasion was observed in 27.1% of patients, while 15.7% had extrahepatic metastasis at baseline. Detailed baseline characteristics are shown in Table 1.

Table 1.

Baseline characteristics of patients

Baseline characteristics	N = 70
Age, years, median (IQR)	57.0(26–73)
Gender, n (%)
Male	56(80.0%)
Female	14(20.0%)
ECOG PS score, n (%)
0	2(2.9%)
1	66(94.3%)
2	2(2.9%)
Child–Pugh score, n (%)
A	58(82.9%)
B	12(17.1%)
BCLC stage, n (%)
B	33(47.1%)
C	37(52.9%)
Etiology, n (%)
HBV ( +)	65(92.9%)
HCV ( +)	3(4.3%)
Autoimmune liver disease	1(1.4%)
None	1(1.4%)
Baseline AFP, n (%)
> 400 ug/L	19(27.1%)
≤ 400 ug/L	51(72.9%)
Number of tumors, n (%)
single	17(24.3%)
multiple	53(75.7%)
Vascular invasion
yes	19(27.1%)
no	51(72.9%)
Extrahepatic metastasis
yes	11(15.7%)
no	59(84.3%)

Clinical outcomes and subgroup analysis

The median follow-up duration for the whole cohort was 13.8 months (95% CI 11.08–16.7). The ORR was 61.4% (95% CI, 49.0%-72.8%), comprising 37 PR and 6 CR (Table 2). Additionally, 5 participants exhibited SD, resulting in a DCR of 68.6% (95%CI, 56.4%-79.2%). The median PFS was 13.2 months (95% CI 11.0-NA) (Fig. 2A), with a corresponding 1-year PFS rate of 50.3% (95% CI 39.7%-65.5%). The median OS was not reached (Fig. 2B), and the 1-year OS rate was 89.3% (95% CI 81.4%-97.9%).

Table 2.

Efficacy of the treatment

	N = 70
CR	6
PR	37
SD	5
PD	22
ORR	43(61.4% 95%CI, 49.0%-72.8%)
DCR	48(68.6% 95%CI, 56.4%-79.2%)

Fig. 2.

Kaplan–Meier Survival Analysis for PFS and OS in Patients with uHCC. Kaplan–Meier curve representing (A) PFS for the entire study cohort and (B) OS for the entire study cohort (N = 70). (C) Stratified Kaplan–Meier curves for PFS based on AFP level changes. Red line indicates patients with AFP decrease (AFP-decrease; N = 33), green line shows patients with AFP increase (AFP-increase; N = 26), and blue line represents the entire cohort (All; N = 59). (D) Stratified Kaplan–Meier curves for PFS according to AFP variation per volume (AFPV) changes. Red line illustrates patients with AFPV decrease (AFPV-decrease; N = 20), green line for patients with AFPV increase (AFPV-increase; N = 16), and blue line for the entire subgroup (All; N = 36)

Exploratory biomarker analysis revealed a significant discrepancy between the AFP-decrease and AFP-increase groups (Fig. 2C). The AFP-decrease group exhibited a median PFS of 15.6 months (95% CI 11.0-NA). In contrast, the AFP-increase group had a median PFS of 11.0 months (95% CI 8.5-NA), resulting in a hazard ratio (HR) of 3.22 (95% CI 1.43–7.23) with p = 0.003. The 1-year PFS rate was notably higher in the AFP-decrease group at 68.8% (95% CI 53.5%-88.4%) compared to the AFP-increase group at 30.0% (95% CI 14.8%-60.8%). In addition, stratification based on AFPV changes revealed a substantial difference in median PFS: 19.7 months (95% CI 19.7-NA) for AFPV-decrease group versus 11.0 months (95% CI 9.6-NA) for AFPV-increase group, yielding an HR of 3.31 (95% CI 1.03–10.61) with p = 0.03(Fig. 2D). The 1-year PFS rate was notably disparate, with the AFPV-decrease group at 79.3% (95% CI 59.9%-100%) and the AFPV-increase group at 38.2% (95% CI 18.4%–79.3%).

Subgroup analyses indicated that patients with a tumor diameter less than 5 cm and no extrahepatic metastasis experienced significantly longer PFS (Supplementary Figure S1). Notably, when stratifying patients according to the BCLC staging system, individuals classified as BCLC-B stage demonstrated a markedly longer PFS compared to those in the BCLC-C stage (log-rank test, p < 0.05). These results underscore the importance of tumor burden and the extent of disease in predicting treatment response and survival benefits. Detailed numerical data supporting these observations, including hazard ratios and confidence intervals, are provided in Supplementary Table S1.

Safety results

A total of 70 subjects were included in the safety analysis. 57 (81.4%) subjects experienced at least one treatment-related TEAE, with the most common TRAEs (≥ 10%) being fatigue 38.6% (27/70), hypertension 32.9% (23/70), and hand-foot syndrome 31.4% (22/70), hypothyroidism 11.4% (8/70), skin rash 11.4% (8/70), and diarrhea 11.4% (8/70) (Table 3). Most of the TRAEs were of Grade 1/2 while 0.57% (4/70) patients experienced Grade 3/4 TRAEs. In one instance, rhabdomyolysis was identified and subsequently ameliorated following interventions with hemofiltration and corticosteroid therapy. Among three instances of hepatotoxicity, therapeutic measures facilitated improvement in two patients, who subsequently resumed their medication regimen; however, one patient succumbed to liver failure.

Table 3.

The incidence of TEAEs related the treatment

N = 70	Grade 1–2	Grade 3–4
Fatigue	27(38.6%)	0
Hypertension	23(32.9%)	1(1.4%)
Hand-foot syndrome	22(31.4%)	1(1.4%)
Hypothyroidism	8(11.4%)	0
Skin rash	8(11.4%)	0
Diarrhea	8(11.4%)	0
Neutropenia	5(7.1%)	1(1.4%)
Proteinuria	5(7.1%)	0
Abnormal liver function	4(5.7%)	2(2.9%)
Bleeding	4(5.7%)	1(1.4%)
Loss of appetite	4(5.7%)	0
Fever	4(5.7%)	0
Thrombocytopenia	3(4.3%)	0
Hyponatremia	1(1.4%)	1(1.4%)
Hypokalemia	0	1(1.4%)
Rhabdomyolysis	0	1(1.4%)

Discussion

Our study presents an analysis of a novel therapeutic approach combining TACE, lenvatinib, and sintilimab for the treatment of unresectable HCC. The ORR was 61.4% (95% CI, 49.0%-72.8%) and the DCR was 68.6% (95%CI, 56.4%-79.2%). A systematic review encompassing 15 studies with 741 patients treated with a triple regimen of TACE/HAIC, TKIs, and ICIs reported a CR rate of 12.4%, an ORR of 60.6%, and a DCR of 88.5%, closely paralleling our observations [20]. Furthermore, the median PFS of 13.2 months (95% CI 11.0-NA) in our study is aligning with findings from Ning et al., who observed a median PFS of 13 months [21].Moreover, A significant finding of our research is the prognostic value of AFP and AFPV in forecasting the results of treatment.

The integration of TACE with anti-angiogenic inhibitors has been underscored for its therapeutic potential [20, 22, 23]. Notably, findings from the TACTICS trial in Japan and the LAUNCH trial in China have demonstrated the superiority of this combination therapy over alternative treatments [24, 25]. The phase III LAUNCH trial, a multicentric study conducted across various centers in China, evaluated the combination of Lenvatinib with TACE on demand against conventional treatment modalities in patients presenting with advanced stages of HCC, characterized by extensive intrahepatic tumor load, portal vein thrombosis, and metastases beyond the liver [25]. This trial demonstrated a significant improvement in both mOS and mPFS within the cohort receiving combination therapy (mOS: 17.8 vs. 11.5 months, HR 0.45, p < 0.001; mPFS: 10.6 vs. 6.4 months, HR 0.43, p < 0.001). ORR assessed by mRECIST were markedly higher in the combination group (54.1% vs. 25.0%, p < 0.001). Notably, survival benefits were consistent across all examined subgroups, particularly in patients with substantial tumor burdens, including those with portal vein thrombosis (HR for OS, 0.35; 95% CI, 0.25–0.51), elevated AFP levels (≥ 400 ng/mL, HR for OS, 0.39; 95% CI, 0.26–0.61), multiple intrahepatic lesions (HR for OS, 0.43; 95% CI, 0.31–0.60), tumors exceeding 5 cm in diameter (HR for OS, 0.47; 95% CI, 0.33–0.66), and extrahepatic metastasis(HR for OS, 0.56; 95% CI, 0.38–0.82). Furthermore, the high ORR suggests the potential of this combination therapy as an effective downstaging modality, evidenced by 15.3% of participants in the Lenvatinib-TACE arm undergoing curative surgical resection post-downstaging, including two patients achieving complete pathological response.

Integrating TACE with the Lenvatinib plus ICI has shown some promising efficacy despite of no randomized phase III clinical trial completed. Recently, a retrospective study research targeting stage BCLC C HCC patients demonstrated that a combination of TACE with lenvatinib and a PD-1 inhibitor yielded superior outcomes and manageable side effects compared to TACE with lenvatinib alone [26]. Similarly, a comparative study revealed a marked improvement in both mPFS and mOS in patients receiving a regimen of TACE, Sorafenib, and ICIs compared to those treated solely with TACE and Sorafenib, showcasing mPFS of 16.26 versus 7.30 months (p < 0.001) and mOS of 23.3 versus 13.8 months (p = 0.012) [27]. The phase Ib KEYNOTE-524 study evaluated the efficacy of Lenvatinib combined with pembrolizumab in unresectable HCC patients, including those ineligibles for TACE, demonstrating promising antineoplastic activity (ORR by mRECIST: 46%, median PFS: 9.3 months, and median OS: 22 months) [28]. Following this, the phase III LEAP-002 trial [29] evaluating the combination of Lenvatinib and pembrolizumab in an advanced HCC cohort, revealing a mOS (21.2 months; 95% CI, 19.0–23.6) and mPFS (8.2 months; 95% CI, 6.3–8.3), alongside an ORR of 26.1%. The ongoing LEAP-012 trial (NCT04246177) aims to further elucidate the efficacy of combining Lenvatinib, pembrolizumab, and TACE, with outcomes anticipated to significantly influence future therapeutic paradigms for HCC.

The promising effectiveness of the tri-modality approach may stem from the following factors. The integration of TACE with anti-angiogenic and immune checkpoint inhibitors offers a formidable strategy against the inherent immunological defiance exhibited by tumors. The efficacy of immunotherapies may be augmented by the vascular normalization and immune modulation induced by anti-angiogenic drugs [30]. A noteworthy investigation utilizing murine models revealed the synergistic potential of Anti-PD-1 and VEGFR inhibition, showcasing a pronounced suppression in tumor progression and enhanced survival rates. This dual approach, by normalizing vascular structures and bolstering antitumor immunity, introduces a promising paradigm in oncological therapy [31]. Research conducted by Voron and colleagues elucidates that targeted therapeutic interventions can mitigate the upregulation of inhibitory receptors, a consequence of VEGF-mediated depletion of CD8 + T cells, denoting a pivotal stride in cancer treatment modalities [32]. Complementary studies further delineate the VEGF/VEGFR axis's capacity to attenuate dendritic cell functionality and differentiation, simultaneously fostering the proliferation of myeloid-derived suppressor cells (MDSCs) [33]. This pathway's complexity extends to direct implications on T cell exhaustion, contingent upon TOX dependency, thereby challenging conventional therapeutic strategies.

In addition, mechanistic investigations into the tumor microenvironment of HCC post-TACE have highlighted its role in precipitating immunogenic cell death [34]. TACE has also been shown to promotes tumor cell necrosis, antigen release, dendritic cell recruitment and activation, and result a shift from an immunosuppressive to an immune-supportive milieu [35]. This transformation, particularly when coupled with immunotherapy, primes the tumor environment for enhanced responsiveness to immunotherapeutic agents, culminating in improved treatment outcomes. Additionally, Lenvatinib's mechanism, primarily through the inhibition of angiogenesis and modulation of the tumor microenvironment's immunosuppressive features, synergizes with pembrolizumab to enhance immunotherapeutic responses against tumors [28, 36].

A notable aspect of our study is the prognostic significance of AFP and AFPV in predicting treatment outcomes. Our findings align with research by Wang et al., highlighting the role of immune-related biomarkers, including AFP, in HCC treatment [37]. The stratification of survival outcomes based on AFP levels provides a nuanced understanding of the therapy's effectiveness in relation to tumor markers, potentially guiding personalized treatment strategies. To further contextualize our findings, comparing them with additional relevant studies is beneficial. Yamashita et al. (2019) reported similar efficacy outcomes with lenvatinib, reinforcing its potential as a valuable component in HCC treatment [38]. Additionally, Kudo et al. provide a broader context for understanding the role of systemic therapies like lenvatinib and sintilimab in the HCC treatment landscape [39], a study that highlighted the potential of lenvatinib to drastically change the treatment landscape of HCC.

While our study contributes valuable data to the field, its retrospective design and single-center nature may limit the generalizability of the findings. Notably, most patients in this study were HBV-positive (92.9%, n = 65), reflecting the prevalence of HBV infection in Chinese HCC patients. Therefore, further research, particularly in HBV-negative populations, is needed to validate these results. Additionally, due to its retrospective nature, some key histological data, such as tumor grading and PD-L1 expression, were not consistently available for all patients, limiting our ability to analyze these factors comprehensively. Another limitation is the relatively short observation period for OS. As a result, the current OS data may not fully capture long-term outcomes. While the ORR and PFS provide valuable insights and are reported here, we acknowledge that a longer follow-up is needed to assess OS comprehensively. Future studies, ideally multicenter and prospective, could validate these results in a broader population. Exploring the molecular mechanisms underlying the observed responses and resistance to the combination therapy could provide deeper insights into optimizing treatment strategies for HCC.

In conclusion, our study supports the efficacy and safety of the TACE, lenvatinib, and sintilimab combination in treating unresectable HCC. The novel insights regarding the use of AFP as a biomarker and the detailed treatment protocol add significant value to the current understanding of HCC management. Future research should focus on expanding these findings through larger, multicenter studies and exploring the underlying biological mechanisms to further refine treatment approaches for HCC.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

AFP

Alpha-fetoprotein

AFPV

AFP variation per volume

BCLC

Barcelona Clinic Liver Cancer

CR

Complete response

DCR

Disease control rate

ECOG-PS

Eastern cooperative oncology group performance status

HBV

Hepatitis B virus

HCC

Hepatocellular carcinoma

HCV

Hepatitis C virus

ICIs

Immune checkpoint inhibitors

NASH

Non-alcoholic steatohepatitis

ORR

Overall response rate

OS

Overall survival

PD

Progressive disease

PFS

Progression-free survival

PR

Partial response

SD

Stable disease

TACE

Transarterial chemoembolization

TEAEs

Treatment-emergent adverse events

TKIs

Tyrosine kinase inhibitors

Authors contribution

Z.Z. and Y.G. formulated the research goals and aims, laying the foundation for the study's design. Z.Z., L.M., and H.L. developed the methodologies, ensuring the study's approach was scientifically robust. L.M., H.L., Y.J., P.Y., Z.W., L.C., B.S., Y.S., and J.Y. were responsible for gathering data, which included managing patient recruitment and coordinating facility usage. The data analysis and interpretation were handled by L.M., H.L., Y.J., Y.G., and Z.Z., involving statistical and computational analyses to draw meaningful conclusions from the data. L.M., H.L., Y.J., Y.G., and Z.Z. drafted the manuscript, presenting the study's findings. Manuscript review and editing were conducted by L.M., H.L., Y.J., Y.G., and Z.Z., ensuring the final manuscript was accurate and met scholarly standards. L.M., H.L., Y.J., J.Y., Y.S., and Z.Z. provided essential support, including data management and database construction. The project was overseen by Z.Z. and Y.G., who provided leadership and guidance throughout the research process.

Funding

The study was supported by the National Natural Science Foundation of China (NO. 92159305) and Capital’s Funds for Health Improvement and Research (2024–2-5062).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.

Informed consent

All patients have signed written informed consents before treatment.