Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors and the fourth leading cause of cancer-related death worldwide (1). In patients with early-stage HCC, ablation, resection and transplantation have been recommended as curable therapies (2). Although unresectable disease may be treated by transarterial chemoembolization (TACE) and systemic therapy, most patients have a poor prognosis (3).

According to the Barcelona Clinic Liver Cancer (BCLC) staging and treatment strategy, TACE represents the standard treatment option for patients with intermediate stage HCC (4), being associated with longer survival compared with best supportive care (5). Meanwhile, only TACE hardly improves survival in advanced HCC (6, 7).

Lenvatinib has become a first−line systemic therapeutic option for advanced HCC (3, 4). In the phase III REFLECT trial (8), lenvatinib was non-inferior to sorafenib in overall survival (OS), showed greater objective response rate (ORR) and median progression-free survival (PFS), and conferred hepatic function in advanced HCC (9, 10).

Immune checkpoint inhibitors, as immunotherapeutic agents, have shown promising outcomes in patients with advanced HCC (11). In the KEYNOTE-240 study, although OS and PFS did not reach statistical significance, ORR and overall response were better than those of placebo, and some patients benefited from pembrolizumab (12). Sintilimab is a human immunoglobulin G4 (IgG4) monoclonal antibody that specifically binds to the PD-1 molecule on the surface of T cells, consequently blocking the tumor immune tolerance-inducing PD-1/programmed death-ligand 1 (PD-L1) pathway, re-activating the anti-tumor activities of lymphocytes, and inhibiting tumors. Sintilimab has been approved for marketing in December 2018, mainly for the treatment of recurrent or refractory classical Hodgkin lymphoma previously treated with at least two lines of chemotherapy. Sintilimab is also been applied for the treatment of various solid tumors in clinical practice, including lung cancer, liver cancer, and esophageal cancer, with notable safety and high efficacy.

Combination therapies have been researched for liver cancer, with favorable results (13), including PD-1 inhibitors plus lenvatinib, TACE plus Sorafenib and TACE plus Lenvatinib (14, 15). However, to date, TACE combined with lenvatinib plus sintilimab has not been studied for patients with unresectable HCC. Therefore, we conducted this retrospective study to assess the efficacy and safety of TACE combined with lenvatinib plus sintilimab in unresectable HCC.

Theraprutic options for unresectable HCC have been developed rapidly in recent years. Sorafenib was the only available systemic therapeutic over a decade ago, and lenvatinib has also become a first−line systemic therapeutic agent for advanced HCC after the REFLECT trial (18). Although immune checkpoint inhibitors alone do not achieve a very significant effect, the combination of immunotherapy and systemic therapy could be very satisfactory. In a phase Ib study, lenvatinib plus pembrolizumab showed promising results in patients with unresectable HCC (19). In this study the ORR reached 46.0% and 36.0% by the mRECIST and RECIST 1.1 criteria, respectively. Median DORs were 8.6 months by mRECIST and 12.6 months by RECIST v1.1. Median overall survival was 22 months. In the IMbrave150 trial (20), atezolizumab plus bevacizumab showed significantly better OS and PFS compared with sorafenib in patients with unresectable HCC. In this study, OS rates at 12 months were 67.2% and 54.6% with atezolizumab plus bevacizumab and sorafenib alone, respectively; median PFS times were 6.8 months and 4.3 months, respectively. Although the exact mechanism of this combination therapy is uncertain, it is possible that VEGF may play an important role in cancer immune evasion. VEGF can enhance immune-suppressive effects in the tumor microenvironment though 3 mechanisms (21), i.e., inhibition of DC maturation to reduce T-cell activation, reduction of T-cell tumor infiltration and increase of inhibitory cells such as myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs).

TACE is an effective treatment option for intermediate stage (multinodular, preserved liver function and ECOG PS=0) HCC (22–24). However, repeated TACE may lead to liver function impairment and even TACE resistance (25, 26), and TACE alone is unsatisfactory for patients in advanced stage (portal invasion or extrahepatic spread). Therefore, many studies have adopted TACE combined with systemic therapy for the treatment of unresectable HCC (27). TACE combined with sorafenib and lenvatinib, respectively, are commonly used in unresectable HCC (6, 28–30). The possible mechanism is that TACE induces angiogenesis and enhances the serum concentrations of VEGF because of local hypoxia, suggesting that VEGF may exert its greatest antiangiogenic effects before or after TACE (31). More importantly, recent studies found that pre-treatment with molecular targeted agents before TACE can normalize tumor vessels and upregulate VEGF, which may lead to a homogeneous distribution of lipiodol mixed anticancer drugs in the tumors (6). In this study, in order to obtain the best results, all patients received lenvatinib 2 weeks before TACE.

In present study, the ORR was 46.7% (28/60); CR and PR were observed in 4 and 24 patients, respectively. The DOR was 10.0 months (95%CI 9.0-11.0 months). PFS and OS were 13.3 months (95%CI 11.9-14.7 months and 23.6 months (95%CI 22.2-25.0 months), respectively. The median DOR, PFS and OS were longer than reported in previous trials combining PD-1 inhibitors and lenvatinib such as the IMbrave150 study (20) and other clinical trials (19). Therefore, this study showed that TACE combined with lenvatinib plus sintilimab is very effective in unresectable HCC.

This treatment was also safe as shown above. The most common treatment-related AEs were fatigue, hypertension, diarrhea, decreased appetite and Palmar-plantar erythrodysesthesia. In this study, 48%, 5.7% and 3.8% of patients had grade 3, 4 and 5 AEs, respectively. Totally 11.5% of patients discontinued any treatment component because of adverse events, and one individual died because of treatment related alimentary tract hemorrhage. The above results were comparable to those reported in previous studies examining combined treatments for unresectable HCC (19, 20, 32, 33), suggesting satisfactory safety and tolerability for this combination.

There were several limitations in this study. Firstly, this was a retrospective trial with a limited sample size, which may lead to potential bias. Besides, most patients in the current study had HBV infection, and prospective multicenter studies with other etiologies are required to validate these findings. Lastly, this was a one-arm study, without a control group. Randomized controlled trials of TACE combined with lenvatinib plus sintilimab versus lenvatinib plus sintilimab should be performed to confirm the efficacy and safety of this regimen.

In conclusion, the objective response rate, duration of response, progression-free survival and overall survival in this study were satisfactory, and adverse events were manageable. Therefore, TACE combined with lenvatinib plus sintilimab is very effective in unresectable HCC.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.

This study was sponsored by Medicine and Health Discipline Platform Project of Zhejiang Province (2018RC019), Medicine and Health Science Project of Zhejiang Province (2020KY483), Project of Hubei Chen Xiaoping Science and Technology Development Foundation (2020CXPJJH12000008-13) and Science Project of Beijing Medicine and Health Foundation (2020JWJKJJHKYJJ-LC19004).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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