Introduction

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide, particularly in China, where HCC cases alone account for more than half of the estimated global total [1]–[4]. The overall survival of HCC varies considerably across the world, with Taiwan and Japan, where comprehensive surveillance programs afford early detection and curative therapy, having the best clinical outcomes. The outcomes in China, along with North America and Europe, however, are not as good. In these countries, greater than 60% of patients present to the hospitals with intermediate to advanced-stage HCC [5]. Unfortunately, to most of the late stage patients, only systemic and/or palliative treatment can be offered. The average survival time of these patients is usually less than 1 year [6]–[10].
Sorafenib is a multi-tyrosine kinase inhibitor (TKI) that inhibits proteins involved in angiogenesis and proliferation pathways implicated in the pathogenesis of HCC, such as vascular endothelial growth factor receptors (VEGFR), Raf-1 and B-Raf [11]. This drug was approved for advanced HCC treatment in 2007 following phase III SHARP trial [12]. It has been the only effective first-line systemic treatment option available for over a decade. It was not until recently that a few other TKIs such as lenvatinib[13], regorafenib[14] and cabozantinib[15] have been approved for first- and second-line HCC treatment. Although the use of TKIs has significant overall survival (OS) benefits over placebo, its effects are not easily sustained. Many of the treatment regimens have been limited by primary and secondary resistance to the drugs; or failed due to severe treatment related adverse events (TRAE) forcing the discontinuation of the therapy [11].
Immune checkpoint blocker therapy has demonstrated encouraging efficacy in multiple cancer types, particularly melanoma and lung cancers. A rapidly growing list of blocking antibodies to immune checkpoints has been approved for cancer treatment [16]. HCC, now generally considered as an immunogenic tumor, may also be a good candidate for such therapy [17]. Programmed cell death receptor-1 (PD-1) is a transmembrane molecule found to be expressed on the surface of T and B lymphocytes, natural killer T cells, activated monocytes and dendritic cells. PD-1 molecule negatively regulates T cell antigen receptor (TCR) signaling by interacting with specific ligands, namely PD-L1 and PD-L2 [18]–[20]. Aberrantly upregulated PD-L1 expression has been found on many tumor cells, which is likely to result in tumor induced immune suppression via PD-1 signaling, and in turn, favors the growth and expansion of tumor cells. Overexpression of PD-L1 has been demonstrated to be significantly associated with tumor aggression and postoperative recurrence in HCC [21], [22]. Disrupting the interaction between PD-1 and its ligands, using monoclonal antibody (mAb), prevents the activation of its downstream signaling pathways, and restores the host anti-tumor immunity[23]. Nivolumab and pembrolizumab are potent mAbs specifically targeting PD-1. CheckMate-040 (NCT01658878), a phase I study of nivolumab treating sorafenib-intolerant/refractory advanced HCC patients resulted in 20% objective response rate (ORR) and a promising 1 year OS rate of 62% [24]. Similarly in an open-label, no-randomized phase II study, KEYNOTE-224 (NCT02702401), pembrolizumab treatment has demonstrated an ORR of 16.3% and 77.9% 6-month OS [25]. Most other PD-1 inhibitor trials for advanced HCC are still at their patient recruitment or preliminary analysis stages; however, these findings were supported by an Austro-German international multicenter real world study of 65 patients. In this study, the objective response rate or nivolumab (n=34) was 15% and pembrolizumab (n=31) was 10%, resulted in an overall ORR of the 12% for this retrospective cohort of PD-1 inhibitor therapy [26].
There are three domestically developed PD-1 mAbs approved in China since 2016: two humanized PD-1 antibodies toripalimab (JS-001, Shanghai Junshi Bioscience Co. Ltd.)[27], camrelizumab (SHR-1210, Jiangsu Hengrui Medicine Co. Ltd)[28]; and sintilimab, a fully human PD-1 mAb (IBI308, Innovent Biologics and Eli Lilly and Company)[29]. Although these three drugs have been shown to be efficacious in several cancer types, so far only camrelizumab has been trial (NCT02989922) in HCC patients, the ORR was 13.8% and the six-month overall survival was 74.7% in this study of 217 patients [28]. The ORR is comparable to the typical 10-20% in other PD-1 therapy trials [24], [25], [28], [30]. However, being domestically developed, the most notable advantage of these drugs to Chinese patients is the significantly lower cost (approx. $17.5k, $17.0k and $13.9k USD respectively), a fraction of nivolumab (approx. $63k USD) and pembrolizumab (approx. $87k USD). It is important to note that China’s large population of HCC patients consists of members from vastly different socioeconomic backgrounds; the overall cost of a therapy is an important determinant in patients’ access to the appropriate treatments.
In China, more than 80% of HCC patients have a history of chronic hepatitis B virus (HBV) infection at the time of diagnosis. Persistent infection with HBV not only leads to chronic liver inflammation and drives the progression to HCC [31], it has also been shown to demonstrate many immunosuppressive properties. For example hepatitis B core antigen (HBcAg) is capable of induce in vivo secretion of IL-10, a potent immunosuppressive cytokine [32]. Here, we are the first group to report the safety and efficacy of these PD-1 inhibitor drugs in a real world treatment cohort of HBV associated HCC patients in China, aiming to reflect the treatment reality in HCC outside of clinical trial programs and to share our experience for developing countries where the majority of HCC cases are associated with chronic HBV infection [3].