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Page 4 of 17                                           Shrestha et al. Hepatoma Res 2019;5:32  I  http://dx.doi.org/10.20517/2394-5079.2019.24

               Table 1. Findings of initial clinical studies of immune checkpoint inhibitors in hepatocellular carcinoma
                Target        Immune checkpoint inhibitor Phase  Overall survival  Clinical trial number  Approval  Reference
                PD-1          Nivolumab             I/II  15 months dose escalation  NCT01658878  Approved  [20]
                              Pembrolizumab         II  12.9 months         NCT02702414  Approved    [22]
                CTLA-4        Tremelimumab          II  8.2 months         NCT01008358   Not approved  [35]
                PD-L1         Durvalumab            I/II  13.2 months      NCT01693562   Not approved  [51]
                PD-L1 and CTLA-4  Durvalumab + Tremelimumab  I/II  Not reported  NCT02519348  Not approved  [55]
                CTLA-4 and ablation Tremelimumab + ablation  12.3 months   NCT01853618   Not approved  [64]
               PD-1: programmed death protein-1; CTLA-4: cytotoxic T lymphocyte-associated protein-4; PD-L1: programmed death protein ligand -1


               Table 2. Current clinical trials of immune checkpoint inhibitors as monotherapy in hepatocellular carcinoma
                Target  Immune checkpoint inhibitor Phase  Clinical trial number  Design  Lines of therapy  End point
                PD-1       Nivolumab        III   NCT02576509    Nivolumab vs. Sorafenib  First-line therapy  OS
                           Nivolumab        III   NCT03383458    Nivolumab vs. placebo  Adjuvant therapy  PFS
                           Pembrolizumab    III   NCT03062358    Pembrolizumab vs. placebo Second-line therapy  OS
                           Pembrolizumab    II    NCT03337841    Pembrolizumab      Neoadjuvant therapy RFS
                           Tislelizumab     II    NCT03419897    Tislelizumab       Second-line therapy  ORR
                           Tislelizumab     III   NCT03412773    Tislelizumab vs. Sorafenib  First-line therapy  OS
                           Camrelizumab     II/III  NCT02989922  Camrelizumab       Second-line therapy  ORR/OS
                PD-L1      Avelumab         II    NCT03389126    Avelumab           Second-line therapy  ORR
               PD-1: programmed death protein-1; PD-L1: programmed death protein ligand -1; OS: overall survival; PFS: progression free survival; RFS:
               recurrence free survival; ORR: overall response rate

               and 3 out of 17 assessable patients showed partial responses (17.6%) and an additional 10 patients (58.8%)
               had stable disease resulting in time-to-progression of 6.48 months and overall survival of 8.2 months
               (NCT01008358) [35,36] . Tremelimumab is the only anti-CTLA-4 ICI which is undergoing a phase III trial as
               monotherapy in HCC as of September 2018 .
                                                    [28]

               ICIS BLOCKING PD-1
               PD-1, a key regulator of T-cell mediated immune response, is expressed by activated T cells, B-cells, natural
               killer cells, Tregs, myeloid-derived suppressor cells (MDSCs), monocytes and dendritic cells .
                                                                                             [37]

               Nivolumab
                                                                                           [11]
               Nivolumab is the first recombinant monoclonal human IgG4 antibody specific for PD-1 . Nivolumab is
               also the first FDA approved ICI for HCC based on the CheckMate 040 trial (NCT01658878) . The phase
                                                                                              [20]
               I/II study of CheckMate 040 trial with 262 treated patients and 202 patients with complete treatment
               reported a response rate of 20% with three complete responses and 39 partial responses in patients with
                                                                                               [20]
               advanced HCC and Child-Pugh A cirrhosis who progressed on or were intolerant to Sorafenib . There are
               several ongoing clinical trials for Nivolumab in HCC either as monotherapy or in combination. The success
               of earlier clinical studies of Nivolumab led to a phase III clinical trial CheckMate 459 (NCT02576509)
               examining Nivolumab as a first-line therapy in HCC and comparing the effects with Sorafenib in 726 HCC
                      [38]
               patients . However, a press release from Bristol-Myers Squibb recently announced that the topline results
               from the phase III clinical trial CheckMate 459 failed to meet its primary endpoint of overall survival.
               Nivolumab is also being studied as an adjuvant therapy after surgical resection or ablation therapy in
                                                                 [28]
               a second phase III trial CheckMate 9Dx (NCT03383458) . There are several ongoing clinical trials for
               Nivolumab in HCC either as monotherapy or in combination with other therapies.

               Pembrolizumab
               Pembrolizumab is another recombinant monoclonal human IgG4 antibody specific for human PD-1.
               Pembrolizumab gained approval for HCC patients previously treated with Sorafenib in November 2018
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