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Page 6 of 17 Shrestha et al. Hepatoma Res 2019;5:32 I http://dx.doi.org/10.20517/2394-5079.2019.24

Table 3. Current clinical trials of immune checkpoint inhibitors as combination therapy in hepatocellular carcinoma
Target Study design Clinical trial number Phase End point
Combination with other immune-based therapies
PD-1 and CTLA-4 Nivolumab + Ipilimumab NCT03682276 I/II ORR
Nivolumab + Ipilimumab NCT03510871 II
Nivolumab +/- Ipilimumab NCT03222076 II Safety
Nivolumab +/- Ipilimumab NCT03203304 I Safety
Tremelimumab vs. Tremelimumab + Durvalumab vs. NCT03298451 III OS
Sorafenib
Tremelimumab vs. Durvalumab vs. Tremelimumab + NCT02519348 II Safety
Durvalumab
PD-L1 and TIM-3 LY3300054 +/- LY3321367 NCT03099109 I Safety
PD-1 and LAG-3 REGN2810 +/- REGN3767 NCT03005782 I Safety/ORR
Combination with molecular targeted agents
PD-L1 and anti-VEGF Atezolizumab + Bevacizumab NCT02715531 I Safety/ORR
PD-L1 and anti-VEGF Atezolizumab + Bevacizumab vs. Sorafenib NCT03434379 III OS/ORR
PD-1 and TKI Pembrolizumab + Lenvatinib vs. Lenvatinib NCT03713593 III PFS/OS
PD-1 and TKI Pembrolizumab + Lenvatinib NCT03006926 I Safety/OR/DOR
PD-1 and TKI Camrelizumab (SHR-1210) + Apatinib NCT02942329 I/II OS
PD-1 and TKI Spartalizumab (PDR001) + Sorafenib NCT02988440 I Safety
PD-1 and c-MET Spartalizumab (PDR001) +/- Capmatinib (INC280) NCT02795429 I/II Safety/ORR
inhibitor
PD-1 and anti-TGF-β Spartalizumab (PDR001) +/- NIS793 NCT02947165 I Safety
PD-1 and FGFR4 Spartalizumab (PDR001) +/- FGF401 NCT02325739 I/II Safety/TTP/ORR
inhibitor
PD-1 and TKI Nivolumab +/- Lenvatinib NCT03418922 I Safety
PD-1 and TKI Nivolumab + Cabozatinib NCT03299946 I Safety/
Completion
PD-1 and anti-VEGF Nivolumab + Bevacizumab NCT03382886 I Safety
PD-1 and TKI Pembrolizumab + Regorafenib NCT03347292 I Safety
PD-1 and TKI Pembrolizumab + Sorafenib NCT03211416 I/II ORR
PD-L1 and TKI Avelumab + Axitinib NCT03289533 I Safety
PD-L1 and DNMT Durvalumab + Guadecitabine NCT03257761 I Safety/ORR
inhibitor
CTLA-4, PD-1 and Nivolumab + INCAGN01949 vs. Ipilimumab + NCT03241173 I/II Safety/ORR
anti-OX40 INCAGN01949 vs. Nivolumab + Ipilimumab +
INCAGN01949
PD-1 and anti- Pembrolizumab + Bavituximab NCT03519997 II ORR
phosphatidyl-serine
Combination with local therapies
PD-1 and ischemia Nivolumab + TACE NCT03143270 I Safety
PD-1 and radiation Pembrolizumab + TACE NCT03397654 I/II Safety
PD-1 and radiation Nivolumab + Y90 NCT03033446 II ORR
CTLA-4, PD-L1 and Tremelimumab + Durvalumab + Radiation NCT03482102 II ORR
ischemia
PD-1 and HSV Pembrolizumab +/-Talimogene Laherparepvec (T-VEC) NCT2509507 I Safety/ORR
oncolytic virus
PD-1: programmed death protein-1; CTLA-4: cytotoxic T lymphocyte-associated protein-4; PD-L1: programmed death protein ligand -1;
TKI: tyrosine kinase inhibitor, OS: overall survival; PFS: progression free survival; RFS: recurrence free survival; ORR: overall response rate;
TTP: time to progression

immune based treatment approaches are being studied. The combination therapies with ICI for HCC are
summarized in Table 3.

IMMUNE-BASED COMBINATION THERAPIES FOR HCC
The blockade of CTLA-4 and PD-1/PD-L1 is the most promising ICI combination therapy that could
enhance the anti-tumor effects in HCC. This combination blockade therapy has been very effective as an
immune dampener as CTLA-4 signaling prevents the initiation of a T-cell response, while the PD-1/PD-L1
axis limits T-cell activity in the TME .
[28]