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Shrestha et al. Hepatoma Res 2019;5:32 I http://dx.doi.org/10.20517/2394-5079.2019.24 Page 5 of 17

based on a phase II clinical study of HCC patients, Keynote-224 (NCT02702414) that reported an overall
[22]
response rate of 17% among 104 patients with 1 complete response and 16 partial responses . A clinical
study with 450 Asian HCC patients to evaluate efficacy and safety of Pembrolizumab or placebo with
[16]
best supportive care (NCT03062358) is ongoing . Another study is examining Pembrolizumab before
[16]
and after surgery or ablation to evaluate HCC recurrence (NCT03337841) . Recently, a phase III clinical
study Keynote-240 investigating Pembrolizumab plus best supportive care compared to placebo plus best
supportive care failed to meet its co-primary endpoints of overall survival and progression free survival in
413 patients with advanced HCC previously treated with systemic therapy . Similar to Nivolumab, there
[39]
are several ongoing trials of Pembrolizumab in HCC either as monotherapy or in combination with other
treatments.

Tislelizumab
[40]
Tislelizumab is also another human IgG4 against PD-1 . A phase I trial of Tislelizumab in 61 patients
[28]
with solid cancers including HCC confirmed the safety of this drug . In HCC, Tislelizumab is undergoing
two clinical studies, one is a phase II clinical study assessing safety, efficacy and pharmacokinetics of
the drug in 228 previously treated unresectable HCC patients (NCT03419897) and another is a phase
III clinical study that compares safety and efficacy of Tislelizumab with Sorafenib as first line systemic
treatment in 660 patients with unresectable HCC (NCT03412773) [28,41] .

Camrelizumab
Camrelizumab is a human IgG4 mAb against PD-1 which was reported to exhibit an anti-tumor response
in 58 patients with solid cancers including HCC in a phase I trial [42,43] . Currently, several clinical studies are
[40]
ongoing with Camrelizumab in HCC either alone or in combination with other treatments . A phase II/III
trial of Camrelibzumab reported a response rate of 13.8% and 6 month overall survival rate of 74.7% in HCC
[44]
patients previously treated with systemic treatment (NCT02989922) .

ICIS BLOCKING PD-L1
PD-L1 is the main ligand for PD-1 that is responsible for suppression of T-cell migration, proliferation and
secretion of cytotoxic mediators [45,46] . Studies have shown that higher expression of PD-L1 is associated with
poor prognosis in HCC patients [25,47-50] . A study reported that PD-L1 expression by neoplastic and intra-
[47]
tumoral inflammatory cells was associated with tumor aggressiveness .

Durvalumab
Durvalumab is an anti-PD-L1 antibody which has been approved for treatment of advanced or metastatic
[40]
urothelial carcinoma and non-small cell lung cancer . Durvalumab was reported with a 10% response
rate and median survival of 13.2 months in a cohort of 40 HCC patients in a phase I/II clinical study of
[51]
Durvalumab monotherapy for solid cancers including HCC (NCT01693562) .

Avelumab
Avelumab is a human IgG1 mAb targeting PD-L1 with ongoing trials for both monotherapy and
[40]
combination therapy in HCC . A phase II study of Avelumab is ongoing with 30 HCC patients previously
treated with Sorafenib (NCT03389126) .
[40]

ICI AS COMBINATION THERAPY IN HCC
Despite promising results from clinical studies of ICIs as monotherapy in HCC, only a small patient
population benefit from specific immune checkpoint blockade therapy . Thus, several combination
[52]
approaches have been utilized to improve the efficacy of ICI therapy. In HCC, the combination of
anti-CTLA-4 and anti- PD-1/PD-L1 along with combinations of ICIs with other immune and non-