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].