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Monge Bonilla et al. Hepatoma Res 2020;6:68 I http://dx.doi.org/10.20517/2394-5079.2020.58 Page 7 of 14

It remains unknown whether virally-induced HCC is more prone to immune attack either secondary to the
presence of foreign viral antigens or an immune response to the virus, compared to non-viral associated
HCC. A recent pooled analysis assessed the efficacy of anti-PD1 or PDL1 in HBV infected HCC patients in
[86]
comparison to non HBV infected HCC patients . The results indicated that patients with HBV infection
achieved ORRs similar to their non-infected counterparts, and this was seen with single and multi-agent
treatment regimens. A lower disease control rate (DCR) was reported in HBV-infected HCC patients; stable
disease was more likely to be seen in non-viral HCC, but this observation was not statistically significant.
Drug efficacy evaluated as ORR and DCR of HCV-infected HCC patients compared to HBV positive
HCC and non-viral HCC was similar, and reached statistical significance. Although clinical activity was
observed for the most part in non-viral associated HCC patients, the interpretation of potential differences
in response based on viral aetiology remains limited by the small number of patients and would require
further evaluation with prospective, randomized, and double-blind clinical trials.

Given the profound immunomodulatory effect of the vascular epithelial growth factor (VEGF) pathway
and dominant presence of angiogenesis in HCC, there increasing interest in testing the anti-tumour efficacy
of ICIs in combination with anti-angiogenetic agents. For example, the anti-PD-L1 antibody atezolizumab
was studied in a phase Ib study in combination with bevacizumab in the first-line setting for advanced
[87]
HCC with Child-Pugh B liver disease . This study showed promising early findings, resulting in an ORR
[87]
of 34% with one CR . This led to the multicentre, open-label, randomized phase III trial IMbrave 150,
which evaluated this combination compared with sorafenib . This study enrolled 336 patients; 49% were
[88]
infected with HBV, 21% were infected with HCV, and 30% were non-viral in the combination cohort. In the
sorafenib cohort 165 patients were enrolled; 46% had HBV, 22% had HCV, and 32% did not have hepatitis
viral infections. The reported 12-month OS was 67.2% in the atezolizumab with bevacizumab group and
54.6% in the sorafenib cohort. Grade 3 or greater adverse events were reported in 56.5% of patients who
received at least one dose of the combination treatment, and in 55.1% of patients in the sorafenib cohort.
Interestingly, the subgroup analysis showed a superior OS benefit in patients with either HBV or HCV
[88]
infection treated with combination therapy . The FDA has approved the combination of atezolizumab and
bevacizumab for the treatment of patients with unresectable HCC as a first line treatment option [Table 1].
There are other reports using ICIs in combination with anti-angiogenic therapies including pembrolizumab
[90]
[91]
and lenvatinib , durvalumab with ramucirumab , nivolumab with ipilimumab and cabozantinib , as
[89]
[92]
well as avelumab with axitinib . There are on-going trials with the same strategy, including atezolizumab
and cabozantinib (COSMIC-312, NCT03755791), pembrolizumab with lenvatinib (LEAP-002,
NCT03713593), SHR-1210 and apatinib (NCT03764293), and sintilimab (anti-PD-1) with bevacizumab
biosimilar (ORIENT-32, NCT03794440).
The combined use of locoregional therapies such as ablation and transcatheter arterial chemoembolization
[93]
(TACE) could improve the effectiveness of immunotherapies against HCC . There are on-going phase III
trials evaluating the outcome of the combination of ICIs with these modalities. For example, durvalumab
and bevacizumab, or placebo with TACE in both intermediate HCC (EMERALD-1, NCT03778957) and
high-risk HCC (EMERALD-2, NCT03847428), pembrolizumab with stereotactic body radiation therapy
(NCT03316872), pembrolizumab following TACE (PETAL, NCT03397654) or Y90 (NCT03099564), and
nivolumab with Y90 (NCT03033446).

Other immune checkpoint molecules, such as LAG3, TIM-3, 4-1BB, CD40, and OX40, can also be
targeted and combined with PD-1/PD-L1 or CTLA-4 blockade in patients with HCC (NCT03005782,
NCT03099109, NCT03241173). Biphasic antibodies to target PD-1 and other immune checkpoints
concurrently are being studied as well (NCT03517488, NCT03752398).