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Lee et al. Hepatoma Res 2018;4:51 I http://dx.doi.org/10.20517/2394-5079.2018.78 Page 11 of 18

not hampered by common mutations or neoantigen heterogeneity of tumor cells [28,73] . Therefore, immuno-
oncology agent is effective regardless of the response to prior therapies, and also a durable response can be
expected due to adaptive immunity to the cancer cells . However, the profile of AEs is completely different
[74]
from those of other cytotoxic and molecular targeting agents . The tolerability of immuno-oncology agents
[28]
generally depends on the severity of immune-related AEs (irAEs), although the majority of irAEs are mild
and manageable [20,75] .

Different clinical trials are currently underway to investigate the safety and efficacy of checkpoint inhibitors
for HCC immunotherapy as in monotherapy or in combination [Table 3] .
[28]

The PD-1/PD-L1 pathway
Higher intra-tumoral expression of PD-1/PD-L1 had been associated with significantly poorer PFS and OS
after hepatectomy as well as postoperative recurrence in HCC . It was shown that PD-1 immune checkpoint
[76]
inhibitor therapies have a strong therapeutic effect on patients with high levels of PD-L1 expression . This
[77]
could be due to the ability of the PD-1/PD-L1 pathway to act as an anti-apoptotic receptor on cancer cells
[Figure 1] [23,69] .

To date, two kinds of anti-PD-1 (nivolumab and pembrolizumab) and anti-PD-L1 (durvalumab, avelumab)
antibodies have been applied for clinical trials in HCC and nivolumab, pembrolizumab, and avelumab
are in development as monotherapy [20,28] . Two phase III studies are currently ongoing: a comparison of
nivolumab and sorafenib in the first line setting for advanced HCC (CheckMate 459), and a comparison of
pembrolizumab and a placebo in the second line setting for patients with advanced HCC who progressed
on sorafenib (KEYNOTE 240) [20,78] .

Nivolumab, a fully human IgG4 anti-PD-1 monoclonal antibody, was granted accelerated approval from U.S.
FDA on September 2017 for treatment of HCC patients who were previously treated with sorafenib. Approval
was based on findings in a phase I/II, open-label, non-comparative, dose escalation and expansion trial
(CheckMate 040) consisting of patients with HCC and Child-Pugh A cirrhosis . Between November 2012
[78]
and August 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the
dose-expansion phase). At the American Society of Clinical Oncology (ASCO) meeting in 2015, results of the
dose-escalation trial of CheckMate 040 were presented; 68% of patients had drug-related AEs, the complete
response (CR) rate was 5%, and the partial response (PR) rate 14%. The safety profile of nivolumab is generally
consistent with what was previously-reported in other tumor types. Twelve (25%) of 48 patients in the
dose-escalation phase had grade 3/4 treatment-related AEs. Autoimmune disease and hepatic dysfunction,
which were the AEs of initial concern, were not observed . In the 2017 ASCO meeting, final results of the
[20]
phase I/II CheckMate 040 study with nivolumab in advanced HCC showed favorable results with objective
response rate (ORR) 20% and disease control rate (DCR) 64% . The OS rate of the fixed dose of 3 mg/kg
[78]
nivolumab group at 12 months was 62%. Considering that a high proportion (66%) progressed on sorafenib
treatment, these outcomes appear to be extremely good. In addition, nivolumab was effective regardless of
prior sorafenib administration and viral status, indicating that nivolumab could be effective even in cases
refractory to sorafenib [20,28,78] . However, the ORR of HBV-positive cases was lower (14%) compared to non-
HBV cases (20%-23%) [28,78] . There was no significant association between PD-L1 expression in HCC and the
response to nivolumab [20,78] .

Another anti-PD-1 antibody, pembrolizumab, was associated with PR and prolongation of survival in a
patient with progressive metastatic HCC while being treated with sorafenib . The randomized, placebo-
[79]
controlled phase III KEYNOTE 240 study (NCT02702401) to compare the efficacy and safety of the
pembrolizumab with best supportive care for the treatment of advanced HCC after failure to sorafenib
is ongoing. Recently, findings from the KEYNOTE 224 study (NCT02702414), open-label phase II trial