Primary liver cancer is the sixth most common tumor in the world and the fourth leading cause of cancer-related death, of which 75% to 85% are hepatocellular carcinoma (HCC) (1). Chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (2). Additionally, HCC is often diagnosed at an advanced stage where only systemic treatment can be offered (3). Although many measures have been taken, the incidence of HCC has increased during the last decade globally and increases progressively with advancing age in all populations (4).

For a long time, there has been a lack of effective systemic therapy for advanced HCC. In the past decade, sorafenib was the only approved first-line agent for patients with unresectable or metastatic hepatocellular carcinoma (3, 5, 6). However, the benefits of sorafenib as the first-line standard treatment were limited. In the global and Asian phase III studies, compared with the placebo group, the median overall survival (OS) of patients in the sorafenib group was only extended by about 2 months, and the objective response rate (ORR) was only 2%-3.3%, and it often causes adverse events (7, 8). Targeted agents currently used in patients with HCC, such as sorafenib, regorafenib, and lenvatinib, are multikinase inhibitors, which have lower response rates and higher therapeutic resistance than targeted therapy agents in other cancers (9).

The emergence of immune checkpoint inhibitors (ICIs) provides hope for the treatment of hepatocellular carcinoma. ICIs are designed to block immunosuppressive receptors expressed on the surface of T lymphocytes such as cytotoxic T-lymphocyte-associated antigen 4, programmed death receptor-1 (PD-1), and the programmed death-ligand 1 (PD-L1) expressed on tumor cells and tumor-infiltrating immune cells (10). At present, immunotherapy, together with surgery, radiotherapy, chemotherapy and targeted therapy, has become the mainstay of the treatment of malignant tumors. Therapeutic monoclonal antibodies targeting PD-1 or PD-L1 have demonstrated notable clinical efficacy in the treatment of various advanced cancers, including non-small-cell lung cancer (NSCLC), melanoma, hepatocellular carcinoma et al. (11).

In this study, the existing literature on the treatment of HCC with PD-1 or PD-L1 inhibitors was retrieved, and a meta-analysis was conducted to provide evidence for the efficacy and safety of PD-1/PD-L1 inhibitors in the treatment of HCC.

We conducted this meta-analysis according to the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines (PRISMA) (12).

In recent years, the inhibition of PD-1 and PD-L1 pathway has emerged as one of the most potential therapeutic strategies in a variety of cancers, such as melanoma, lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, etc. (20). This meta-analysis analyzed the existing studies on the treatment of HCC with PD-1 or PD-L1 inhibitors. The results showed that for patients treated by PD-1 or PD-L1 inhibitors, RR, DCR, PFS, OS were 0.17 (0.15-0.19), 0.58 (0.55-0.61), 3.27 months (2.99-3.55), 11.73 months (10.79-12.67), respectively. Compared to the control group, treatment with ICIs significantly improved RR, PFS and OS, the OR and HRs were 3.11 (2.17-4.44, P<0.001), 0.852 (0.745-0.974, P=0.019) and 0.790 (0.685-0.911, P=0.001), respectively. However, no significant improvement in DCR was found in ICIs treatment in this meta-analysis, which may be due to the small number of RCTs or cohort studies included in this study.

Although immunotherapy has achieved certain results, the efficacy of treating some patients with ICI single drug is not ideal. Therefore, similarly to the treatment strategies that were commonly used against other malignant tumors, researchers are now exploring the use of a combination of immune checkpoint inhibitors with other treatments for HCC therapy (21). For example, Finn et al. combined pembrolizumab (a PD-1 inhibitor) with lenvatinib (a multikinase inhibitor) to treat unresectable HCC (uHCC), and found that lenvatinib plus pembrolizumab has promising antitumor activity in uHCC. Toxicities were manageable, with no unexpected safety signals (22). Xu et al. used apatinib and SHR-1210 (camrelizumab) to treat advanced HCC and results also showed manageable toxicity in patients with HCC (23). Other combinations include ICIs combination, ICIs combined with MTA (molecular targeted agents), ICIs combined with local/systemic therapy (21).

However, immunotherapy, as a drug class, boosts the body’s natural defense against cancer. These drugs have adverse effects, collectively known as immune-related adverse events, that represent immune effects on normal tissue that can result from misdirected stimulation of the immune system (24). There were also a lot of adverse events reported in the included studies, such as infection, rash, pruritus, reactive cutaneous capillary endothelial proliferation (RCCEP), increased aspartate aminotransferase (2, 6, 16).

There were also many deficiencies in this meta-analysis. Firstly, although 12 studies were finally included in this study, 8 of them were single-arm studies and only 2 were RCTs, and the lack of comparison data made it difficult to provide solid evidence of the efficacy and safety in the treatment of HCC with ICIs. Most of the studies included in this meta-analysis were single-arm studies, which only provided information on patients treated with ICIs, but did not have a control group for comparison. The direct merging of the single-arm studies data with the comparative studies data in the article might make the results of this meta-analysis unstable. At the same time, it was very difficult for us to perform the bias analysis due to the lack of studies with comparison data in this meta-analysis. Secondly, all the ICIs used in the included studies were PD-1 inhibitors (nivolumab, pembrolizumab, camrelizumab, cemiplimab and tislelizumab), so that the efficacy and safety of PD-L1 inhibitors in the treatment of HCC could not be analyzed, such as atezolizumab, durvalumab et al. Besides, the classification of HCC, the dosage and method of administration of ICIs were not identical, which could affect the reliability of the meta-analysis results. In general, there were still few studies on the treatment of HCC with PD-1 or PD-L1 inhibitors, especially the high-quality RCT studies that would reveal the efficacy and safety of PD-1 or PD-L1 inhibitors in the treatment of HCC. The good news is that there are a lot of studies going on right now, such as KEYNOTE-394 (25) (pembrolizumab plus best supportive care vs. placebo plus best supportive care), RATIONALE-301 (26) (tislelizumab vs sorafenib), etc. It is hoped that in the future, more objective and rich data can be obtained from these studies, so as to provide more useful evidence for the treatment of HCC by PD-1 or PD-L1 inhibitors.

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

XW conceived the idea for the study and assessed the quality of the manuscript. KF was responsible for data acquisition. SH and WJ performed the meta-analysis and co-drafted the manuscript. All authors contributed to the article and approved the submitted version.

National Natural Science Foundation of China (NO. 81501828).

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.