Page 11 - Read Online

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

Table 2. Key immunotherapy trials
Drug name Trial number Phase Comments
Camrelizumab [72] NCT02989922 II Response rate 14%.
Median OS 14.4 months
(predominantly HBV-positive patients)
Tislelizumab NCT02412773 III Active recruiting
Pembrolizumab (Keynote 937) NCT03062358 III Active recruiting in Asia
Pembrolizumab (Keynote 394) NCT03062358 III Active accrual in Asia
Nivolumab (Checkmate 9DX) NCT03383458 III Currently recruiting
Nivolumab and Ipilimumab NCT03222076 II Currently recruiting
Cemiplimab [73] NCT03916627 II Currently recruiting
Tislelizumib NCT03412773 III Results pending
Durvalumab with tremelimumab and ablation [75] NCT02821754 I/II Response rate 20%
Median PFS 7.8 months
Durvalumab with tremelimumab NCT03298451 III Currently recruiting
(HIMALAYA )
PFS: progression-free survival; OS: overall survival

hepatitis . However, the subsequent phase III randomized control trial KEYNOTE-240 of pembrolizumab
[78]
as second line treatment in advanced HCC failed to show a statistically significant improvement in
progression-free survival (PFS) or OS. Even so, pembrolizumab showed a reduced risk of death by 22%
and an improved PFS compared with placebo. 25.9%, 15.5%, and 58.6% patients were affected by HBV,
HCV, or non-infected in the pembrolizumab treatment cohort, respectively, in comparison to 21.5%, 21%,
and 85% in the placebo cohort. A subgroup analysis indicated that patients with HBV infection treated
with pembrolizumab had a superior median OS compared to those treated with placebo; there was no
[79]
OS benefit in the group of HCV infected or non-infected patients . There are two on-going phase III
trials of pembrolizumab, including KEYNOTE-394, to evaluate pembrolizumab in Asian HCC patients,
and KEYNOTE-937 to evaluate pembrolizumab as an adjuvant therapy in HCC patients after curative
treatment.

Other PD-1 antibodies, including tislelizumab (BGB-A317), camrelizumab (SHR-1210) and cemiplimab
(REGN2810), also have shown anti-tumour activity in HCC, with response rates of 16.7% (all responders
were HBV infected) , 13.8% and 19.2% , respectively. Interestingly, in the trial of camrelizumab, 83%
[82]
[80]
[81]
of patients enrolled were infected with HBV. An increase in HBV titre was noted in 46 participants, but
the majority of these occurred after disease progression or after the last dose of treatment. Conversion
[81]
to HBsAg positive from negative status was not reported during the treatment . A phase III trial
(RATIONALE 301) of tislelizumab versus sorafenib as first-line treatment in patients with unresectable
HCC is currently underway (NCT02412773) [Table 2].

Durvalumab (MEDI4736) is an anti-PD-L1 monoclonal antibody. In a phase I/II trial of Child-Pugh class
A advanced HCC patients, durvalumab achieved an OS rate of 10.3% in 39 patients in the second line
[83]
setting. There was comparable ORR of 25% in patients with HCV infections and similar rates of TRAEs .
Furthermore, the combination of durvalumab with tremelimumab in patients with advanced HCC in the
second line setting showed an ORR of 20% (2 responders were HCV infected), median PFS of 7.8 months,
[84]
and median OS of 15.9 months amongst the 10 patients (7 HCV and 1 HBV infected) . However, the
other study reported this combination in advanced HCC showing no response in 9 patients with HCV
infection, 1 responder in 11 patients with HBV infection, and an ORR of 35% among 20 uninfected
[85]
patients with an overall ORR of 20% . The on-going phase 3 HIMALAYA study evaluating durvalumab
and tremelimumab compared with sorafenib or durvalumab monotherapy in the first-line setting in
unresectable HCC (NCT03298451) may provide further information regarding the response status of HBV-
or HCV-infected patients following anti-PD-L1 treatment.