The combination of HAIC with systemic therapy can provide superior efficacy compared to systemic therapy alone or local therapy alone for patients with advanced HCC complicated by vascular invasion, regardless of whether they have extrahepatic metastasis, with overall manageable safety. Currently, guidelines have recommended HAIC for HCC patients with unresectable primary tumors, PVTT type I/II/III/IV, and Child-Pugh A liver function, and recognize that its combination with sorafenib for patients with PVTT has superior efficacy compared to sorafenib monotherapy. However, more evidence is still needed regarding the efficacy of HAIC combined with lenvatinib and PD-1 inhibitors for patients with major vascular invasion (including PVTT/HVTT/IVCTT, etc.) and bile duct invasion. This study aims to further validate the efficacy and safety of lenvatinib and PD-1 inhibitors ± HAIC for HCC patients with major vascular invasion (including PVTT/HVTT/IVCTT, etc.) and bile duct invasion through larger sample size multicenter real-world data, with the goal of providing new evidence-based guidance for HCC treatment in clinical practice. This study is to evaluate the efficacy and safety of HAIC combined with lenvatinib and PD-1 inhibitors versus lenvatinib combined with PD-1 inhibitors in the first-line treatment of advanced hepatocellular carcinoma with major vascular or biliary invasion

Primary liver cancer is one of the most common malignancies worldwide, with approximately 75%-85% being hepatocellular carcinoma (HCC). According to national cancer incidence and mortality statistics released by the National Cancer Center, there were 367,700 new cases of liver cancer in China in 2022, ranking fourth in cancer incidence; deaths reached 316,500, ranking second in cancer mortality.

Most HCC patients are diagnosed at intermediate to advanced stages and are not suitable for curative treatments, including surgical resection, ablation, or transplantation. Among them, a considerable proportion of patients have major vascular or biliary tumor thrombi, resulting in poor overall survival prognosis. Based on biological behavior and anatomical features, HCC most commonly invades the portal vein, leading to portal vein tumor thrombus (PVTT), with an incidence of approximately 44%-62.2%. Once PVTT occurs, patients can rapidly develop intrahepatic and extrahepatic metastases, portal hypertension, jaundice, ascites, etc., with a natural overall survival (OS) of only 2.7-4 months. Additionally, HCC can also involve the hepatic veins, inferior vena cava, and bile ducts. Patients with such vascular invasion likewise have a poor prognosis, frequently developing life-threatening complications such as hepatic failure or tumor thrombus embolization within a short period. The median natural OS is approximately 3 months.

In recent years, systemic therapy for advanced HCC has made substantial progress. Representative regimens including targeted therapies (e.g., lenvatinib), combinations of targeted therapy with immunotherapy, and dual immunotherapy have significantly improved patient outcomes. However, even with systemic therapy, patients with HCC complicated by PVTT, hepatic vein tumor thrombus (HVTT), inferior vena cava tumor thrombus (IVCTT), or bile duct tumor thrombus continue to have poor prognoses. Accordingly, identifying effective first-line therapeutic strategies for advanced HCC with major vascular or biliary tumor thrombi is of great clinical importance.

1.1 Current Status of Systemic Therapy for Advanced HCC For patients with vascular invasion, such as PVTT, HVTT, or IVCTT, international practice, following the Barcelona Clinic Liver Cancer (BCLC) staging system, generally classifies these cases as advanced stage (BCLC stage C) and recommends systemic therapy as the first-line treatment. China Liver Cancer Staging (CNLC) defines HCC with imaging-visible tumor thrombus but without extrahepatic metastasis as CNLC stage IIIa, recommending more comprehensive treatment strategies including systemic therapy ± TACE, surgical resection, or radiotherapy; once extrahepatic metastasis occurs, it is classified as CNLC stage IIIb, with corresponding recommended regimens being systemic therapy, TACE, or radiotherapy.

Currently, for advanced HCC with vascular invasion and/or extrahepatic metastasis, first-line systemic antitumor therapy includes tyrosine kinase inhibitors (TKIs) such as sorafenib, lenvatinib, and donafenib, immune checkpoint inhibitors (ICIs) such as tislelizumab, and immune combination regimens such as atezolizumab + bevacizumab, sintilimab + bevacizumab biosimilar, and apatinib + camrelizumab.

Among them, lenvatinib is a novel oral angiogenesis inhibitor that primarily targets vascular endothelial growth factor receptors (VEGFR)-1-3, fibroblast growth factor receptors (FGFR)-1-4, platelet-derived growth factor receptor (PDGFR)-β, as well as the proto-oncogenes RET and KIT. In the global multicenter randomized controlled phase III REFLECT study comparing lenvatinib with sorafenib for advanced HCC, 954 eligible patients were randomly assigned to the lenvatinib group (n=478) or the sorafenib group (n=476). The median OS was 13.6 months in the lenvatinib group and 12.3 months in the sorafenib group, meeting the noninferiority survival endpoint (HR 0.92, 95% CI 0.79-1.06). According to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) assessment, all secondary endpoints were also significantly better in the lenvatinib group than in the sorafenib group: median progression-free survival (PFS) was 7.3 months versus 3.6 months (HR 0.64, P < 0.0001), and objective response rate (ORR) was 40.6% versus 12.4% (OR 5.01, P < 0.0001). Based on the REFLECT study, lenvatinib has been approved for first-line treatment of advanced HCC in multiple countries, including the United States, Japan, and China. In the REFLECT subgroup analysis of 288 Chinese patients (including mainland China, Taiwan, and Hong Kong), median OS was significantly longer with lenvatinib than with sorafenib by 4.8 months (15.0 months vs 10.2 months), suggesting that the Chinese population, characterized predominantly by HBV-related HCC, may be more suitable for lenvatinib treatment.

Programmed Death Protein 1 (PD-1) immune checkpoint inhibitors promote T cell activation and proliferation by blocking the negative regulatory signals generated by PD-1 and PD-L1 binding, thereby restoring the killing function of T cells in the tumor microenvironment and enhancing the body's anti-tumor immune response. In the field of advanced HCC treatment, multiple randomized controlled clinical studies have explored and validated the efficacy and safety of PD-1 inhibitors, including pembrolizumab and nivolumab, for first- and second-line treatment of advanced HCC. The CheckMate 459 study showed that, in previously untreated unresectable HCC, nivolumab numerically improved median OS (16.4 months vs 14.8 months, P = 0.0522) and ORR (15% vs 7%) versus sorafenib with a favorable safety profile. However, the OS difference did not meet the prespecified threshold for statistical significance, and there was no improvement in PFS (median 3.7 months vs 3.8 months). The RATIONALE-301 study showed that tislelizumab was non-inferior to sorafenib in OS, with median OS of 15.9 months and 14.1 months, respectively (HR 0.85, P=0.0398). Thus, PD-1 inhibitors as first-line treatment for advanced HCC can bring certain clinical benefits with good safety, but the overall value remains relatively limited.

On this basis, combination regimens for advanced HCC centered on PD-1 inhibitors plus targeted agents have advanced rapidly in recent years. Multiple clinical studies have confirmed that targeted therapy combined with immunotherapy further improves survival compared with monotherapy. The CARES-310 study evaluated the efficacy and safety of camrelizumab plus apatinib versus sorafenib for unresectable or metastatic HCC. Results showed that the combination group was significantly superior to the sorafenib group in PFS (median PFS 5.6 months vs 3.7 months, HR 0.52, P<0.0001), OS (median OS 22.1 months vs 15.2 months, HR 0.62, P<0.0001), and ORR (25.4% vs 5.9%, P<0.0001). The ORIENT-32 study enrolled 571 patients who were randomized 2:1 to receive sintilimab plus IBI305 (a bevacizumab biosimilar) or sorafenib. Results showed that compared to sorafenib, the sintilimab+IBI305 group had significant clinical benefit in OS (median OS NR vs. 10.4 months, HR 0.57, P<0.0001) , PFS (median PFS 4.6 months vs. 2.8 months, HR 0.56, P<0.0001), and ORR (24% vs. 8%, P<0.0001), with acceptable safety (grade 3 or higher treatment-related adverse events 34% vs 36%). Additionally, in the LEAP-002 study, lenvatinib plus pembrolizumab achieved a median OS of 21.2 months in the first-line treatment of advanced HCC. Although the difference versus the lenvatinib arm (median OS 19.0 months) did not meet the prespecified threshold for statistical significance, the combination still demonstrated encouraging clinical efficacy. The CS1003-305 study yielded similar findings. Nofazinlimab (a PD-1 inhibitor) plus lenvatinib, compared with placebo plus lenvatinib, showed a numerically meaningful improvement in median OS (21.6 months vs 18.5 months, HR 0.86, P = 0.145), along with improved ORR (33.1% vs 18.8%) and PFS (9.2 months vs 6.9 months). Overall, the combination of targeted agents and PD-1 inhibitors has further improved survival outcomes for patients with advanced HCC beyond monotherapy, with median OS exceeding 20 months and overall safety and tolerability remaining manageable.

However, the objective response rate of current systemic therapy alone remains relatively low, and evidence of efficacy in treating HCC patients with vascular invasion remains limited. According to published retrospective studies, median OS with sorafenib monotherapy in HCC patients with PVTT is only 3.1 to 6 months. In the REFLECT study, patients with high-risk features such as liver occupation ≥50%, definite bile duct invasion, or main portal vein invasion were excluded at enrollment, resulting in a lack of reference data on the efficacy and safety of lenvatinib in such patients. Moreover, lenvatinib monotherapy shows relatively limited efficacy in treating BCLC stage C HCC, with a median OS of 11.8 months versus 10.3 months for sorafenib.11 In the IMbrave150 study, the median OS of patients with macrovascular invasion at baseline treated with atezolizumab plus bevacizumab was only 14.2 months, while the median OS of advanced HCC patients with Vp4 type PVTT was only 7.6 months, indicating poor prognosis.

1.2 Research Progress of HAIC ± Systemic Therapy in Advanced HCC In unresectable HCC, the efficacy and safety of systemic therapy combined with local therapy such as transarterial chemoembolization (TACE) have been demonstrated in multiple studies, including LEAP-012, EMERALD-1, and CHANCE2201. Hepatic arterial infusion chemotherapy (HAIC), another commonly used interventional modality in addition to TACE, has shown substantial therapeutic activity in multiple clinical studies for advanced HCC, cholangiocarcinoma, gallbladder cancer, and colorectal liver metastases. Mechanistically, HAIC delivers high intratumoral concentrations of anticancer drugs with lower systemic toxicity, enabling rapid tumor debulking. Molecular targeted agents can synergize with HAIC to help overcome chemoresistance, interact with platinum transporters, increase vascular permeability in HCC, and enhance the local concentration of platinum agents. Chemotherapy-induced immunogenic cell death can further augment the antitumor activity of ICIs, achieving synergistic effects.

Multiple previous studies have indicated the efficacy and safety of systemic therapy combined with HAIC in advanced HCC. A retrospective study including 229 advanced HCC patients showed that HAIC combined with PD-1 inhibitors significantly improved OS (median OS 18.0 months vs. 14.6 months, HR 0.62, P=0.018), PFS (median 10.0 months vs. 5.6 months, HR 0.65, P=0.006), and disease control rate (83% vs 66%, P=0.006) compared to HAIC alone. At the 2021 ESMO Annual Congress, results were reported for the regimen of HAIC combined with apatinib and camrelizumab in advanced HCC. The 6-month PFS rate was 73.7%, the 12-month OS rate was 90.68%, and both median PFS and OS were not reached. The incidence of grade 3 adverse events was 69.23%. In a retrospective study conducted by Sun Yat-sen University Cancer Center, for advanced HCC patients, the lenvatinib + toripalimab + HAIC triple therapy (N=71) showed significantly prolonged PFS (11.1 months vs 5.1 months, P <0.001) and OS (not reached vs 11 months, P <0.001) compared to the lenvatinib monotherapy(N=86). Additionally, a meta-analysis including 17 clinical studies (7 studies of HAIC combined with TKIs including lenvatinib, 10 studies of HAIC combined with TKIs and ICIs) involving 3,070 subjects showed that advanced HCC patients receiving HAIC combined with systemic therapy had superior OS (HR, 0.52; 95% CI, 0.48-0.58), PFS (HR, 0.54; 95% CI, 0.46-0.63), ORR (RR, 2.20; 95% CI, 1.77-2.72), and DCR (RR, 1.21; 95% CI, 1.14-1.29) compared to systemic therapy alone. Although HAIC combined with systemic therapy led to an increased incidence of grade ≥3 adverse events, it was overall manageable. Notably, in subgroup analysis, HAIC combined with systemic therapy appeared to provide greater survival benefit for patients with PVTT compared to HCC patients without PVTT. For HCC with extrahepatic metastases, HAIC combined with systemic therapy also confers favorable survival benefits. In a retrospective study of 230 patients with extrahepatic metastases, after propensity score matching, HAIC plus targeted therapy and immunotherapy had significantly longer median OS and PFS compared with targeted therapy plus immunotherapy alone (median OS 27.0 months vs 9.0 months, P < 0.001; median PFS 8.0 months vs 3.0 months, P = 0.001). The ORR was doubled (67.3 percent vs 29.1 percent, P < 0.001), and the incidence of grade 3/4 adverse events did not increase significantly (P < 0.05).

1.3 Research Progress of HAIC ± Systemic Therapy in Advanced HCC with Vascular Invasion For advanced HCC patients with high-risk features such as major vascular invasion and bile duct invasion with relatively poor prognosis, HAIC or HAIC combined with systemic therapy has shown promising efficacy. Prior studies suggest that in advanced HCC patients with PVTT, the ORR of HAIC monotherapy can reach 48% to 71%, while combination with immunotherapy and other modalities can effectively reduce tumor volume, thereby improving long-term survival outcomes. In 2020, a retrospective study conducted by Peking University Cancer Hospital showed that compared with transarterial chemoembolization/transarterial embolization, HAIC infusion of oxaliplatin and 5-fluorouracil significantly prolonged survival time in HCC patients with PVTT, with median OS of 20.8 months and 4 months, respectively (P<0.001). Results from a phase III clinical study by Sun Yat-sen University Cancer Center showed that compared with sorafenib monotherapy, HAIC infusion of oxaliplatin and 5-fluorouracil (FOLFOX regimen) combined with sorafenib significantly prolonged survival time and improved ORR in HCC patients with PVTT, with median OS of 13.37 months and 7.13 months, respectively (P<0.001), and ORR of 40.8% and 3%, respectively (P<0.001). Another prospective phase II randomized controlled study from Peking University Cancer Hospital also confirmed that HAIC infusion of oxaliplatin and 5-fluorouracil (3cir-OFF regimen) combined with sorafenib significantly prolonged survival time compared with sorafenib monotherapy in HCC patients with major portal vein tumor thrombus (Vp3/Vp4), with median OS of 16.3 months and 6.5 months, respectively (P<0.001); meanwhile, ORR assessed by mRECIST was also significantly improved, at 50% and 3%, respectively (P<0.001).

In addition to combination with targeted agents alone, exploration of HAIC combined with targeted therapy and immunotherapy has also been conducted, showing considerable treatment response, survival improvement, and manageable safety. In a prospective phase II clinical study, HAIC combined with lenvatinib and toripalimab for advanced HCC achieved median PFS and median OS of 10.4 months and 17.9 months, respectively, with ORR reaching 63.9% (RECIST v1.1)/66.7% (mRECIST). In patients with high-risk features (defined as tumor invasion of the main portal vein and/or portal vein branches contralateral to the main involved lobe (Vp4), and/or bile duct invasion and/or tumor occupying ≥50% of the liver), median OS and median PFS were 17.4 months and 10.4 months, respectively, with median OS numerically much higher than that of atezolizumab plus bevacizumab in HCC patients with Vp4-type portal vein tumor thrombus in the IMbrave150 study. Regarding safety, 72.2% of patients experienced grade 3/4 adverse reactions. Similarly, in a retrospective study including HCC patients with high-risk features (Vp4, and/or bile duct invasion and/or tumor occupying ≥50% of the liver), compared with lenvatinib + PD-1 inhibitor, the HAIC + lenvatinib + PD-1 inhibitor group showed significantly prolonged median OS (19.3 months vs. 9.8 months, p <0.001) and median PFS (9.6 months vs. 4.9 months, p <0.001), with significantly improved ORR (RECIST 1.1: 64.1% vs.14.8%, p<0.001; mRECIST: 76.7% vs. 23.0%, P<0.001). Any-grade adverse events such as neutropenia, thrombocytopenia, ALT elevation, AST elevation, vomiting, and abdominal pain occurred at relatively higher rates in the HAIC + lenvatinib + PD-1 inhibitor group, but with appropriate hepatoprotective treatment, most patients' liver function could recover to pre-treatment levels. Against the background of preliminary validation of the efficacy of HAIC combined with targeted therapy and immunotherapy for advanced HCC (especially high-risk patients), a phase II study conducted by Peking University Cancer Hospital explored the efficacy and safety of HAIC + lenvatinib + PD-1 inhibitor versus lenvatinib + PD-1 inhibitor for first-line treatment of HCC with PVTT. Results showed that the 6-month PFS rates for the HAIC + lenvatinib + PD-1 inhibitor group and lenvatinib + PD-1 inhibitor group were 78.8% and 46.9% , respectively (P=0.013), with median PFS of 12.3 months and 5.9 months, respectively (P=0.001), median TTP of 15.1 months versus 6.2 months (P<0.001), and median OS of 29.0 months and 15.7 months, respectively (P=0.107). The incidence of adverse events was similar between the two groups, but the triple therapy group had a relatively higher incidence of grade 3/4 adverse events (51.5% vs 30.3%). These prospective results further suggest the clinical value of adding HAIC to lenvatinib + PD-1 inhibitor for treating patients with PVTT. Additionally, a retrospective study including 355 HCC cases with inferior vena cava and/or right atrial tumor thrombus suggested that after propensity score matching, patients receiving targeted therapy plus immunotherapy combined with HAIC had superior median OS compared to targeted therapy plus immunotherapy alone(18.0 months vs. 7.5 months, P<0.001) and HAIC alone (18.5 months vs. 7.1 months, P<0.001). Compared with targeted therapy plus immunotherapy (PFS: 9.5 months vs. 4.4 months; ORR: 47.0% vs. 21.3%, both P<0.001) and HAIC (PFS: 9.5 months vs. 4.4 months; ORR: 48.8% vs. 21.6%, both P<0.001), targeted therapy plus immunotherapy combined with HAIC had superior median PFS and ORR. However, there were no significant differences in OS, PFS, and ORR between the targeted therapy plus immunotherapy group and the HAIC group (all P<0.05). In terms of safety, the incidence of grade 3-4 adverse events in the targeted therapy plus immunotherapy combined with HAIC group, targeted therapy plus immunotherapy group, and HAIC group were 49.8%, 33.3%, and 35.0%, respectively, indicating that overall safety remains manageable alongside the enhanced efficacy of combination therapy.

In summary, the combination of HAIC with systemic therapy can provide superior efficacy compared to systemic therapy alone or local therapy alone for patients with advanced HCC complicated by vascular invasion, regardless of whether they have extrahepatic metastasis, with overall manageable safety. Currently, guidelines have recommended HAIC for HCC patients with unresectable primary tumors, PVTT type I/II/III/IV, and Child-Pugh A liver function, and recognize that its combination with sorafenib for patients with PVTT has superior efficacy compared to sorafenib monotherapy. However, more evidence is still needed regarding the efficacy of HAIC combined with lenvatinib and PD-1 inhibitors for patients with major vascular invasion (including PVTT/HVTT/IVCTT, etc.) and bile duct invasion. This study aims to further validate the efficacy and safety of lenvatinib and PD-1 inhibitors ± HAIC for HCC patients with major vascular invasion (including PVTT/HVTT/IVCTT, etc.) and bile duct invasion through larger sample size multicenter real-world data, with the goal of providing new evidence-based guidance for HCC treatment in clinical practice.

Inclusion Criteria:

• Age: 18-80 years, both genders;
• Diagnosed with hepatocellular carcinoma according to the Primary Liver Cancer Diagnosis and Treatment Guidelines (2019 edition) or pathological diagnosis;
• BCLC stage C with portal vein/hepatic vein/inferior vena cava/bile duct invasion, with or without extrahepatic metastasis;
• At least one measurable intrahepatic lesion according to RECIST 1.1 criteria;
• Received first-line lenvatinib + PD-1 inhibitor combination therapy or HAIC + lenvatinib + PD-1 inhibitor combination therapy between January 2020 to June 2024;
• ECOG PS score 0-1;
• Child-Pugh score: Class A or B (≤7); ALBI score: Grade 1-2.

Exclusion Criteria:

• Previous systemic therapy for HCC (including immune checkpoint inhibitors, tyrosine kinase inhibitors, anti-VEGF antibodies, etc.) and hepatic arterial chemotherapy;
• Received radiotherapy and other local treatments besides HAIC during treatment;
• Received other antitumor drug therapy during treatment;
• Previously diagnosed with fibrolamellar hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, cholangiocarcinoma, or other components by histology/cytology;
• Previously diagnosed with any other malignancy, except for basal cell or squamous cell skin cancer or cervical carcinoma in situ that has been curatively treated;
• Incomplete outcome data or missing key baseline characteristic data.

Patients with advanced HCC and portal vein/hepatic vein/inferior vena cava/bile duct tumor thrombi and treated by either HAIC+Lenva+PD1 or Lenva+PD1 from multiple centers in China