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da Fonseca et al. Hepatoma Res 2019;5:37 I http://dx.doi.org/10.20517/2394-5079.2019.012 Page 7 of 13

did not vary across the different etiologies and the most common events were rash (23%), pruritus (21%)
and diarrhea (13%). Less than 2% presented serious adverse events of grade 3 or higher and no treatment-
related death was observed. The response rate by RECIST 1.1 was 15% and 20% in the dose escalation and
expansion cohorts, respectively, with a median duration of response in the expansion cohort of 9.9 months.
The median OS was 28.6 months in the population naïve to sorafenib and 15.6 months in the sorafenib-
[50]
experienced . Based on these results, nivolumab was granted accelerated approval by the US Food and
[51]
Drug Administration (FDA) in 2017 for patients previously treated with sorafenib . However, the phase
III trial CHECKMATE 459, which compared nivolumab to sorafenib in the first line was announced to be
[52]
negative by the company responsible for nivolumab development . The results of this trial were presented
in the European Society for Medical Oncology 2019 congress: the median OS was 16.4 months for
nivolumab and 14.7 months for sorafenib (Hazard ratio 0.85, 95% confidence interval 0.72-1.02, P = 0.0752),
[53]
with a response rate of 15% for nivolumab and 7% for sorafenib . Complete results are still pending to be
published.

Pembrolizumab, a monoclonal antibody that also targets PD-1, was shown to be active and safe in a phase
II trial. The KEYNOTE 224 enrolled 104 HCC patients with intolerance or progression after sorafenib to
receive pembrolizumab 200 mg every 3 weeks in a single arm design. The authors recorded a response rate
of 17% and 33% of the patients had stable disease. Grade 3 treatment-related adverse events were reported
[54]
in 24% of the patients, being that the most common were increased transaminasemia and fatigue . These
results substantiated the accelerated approval of pembrolizumab by the FDA in 2018 .
[55]
The KEYNOTE 240 trial, which was a phase III trial comparing pembrolizumab to placebo in the second-
line, were recently presented. The study included 413 patients who were randomized and analyzed for
a co-primary endpoint of PFS and OS. The median OS of the pembrolizumab arm was 13.9 months vs.
10.6 months for the placebo arm, what did not reach the pre-specified efficacy boundaries for statistical
significance . Therefore, the trial was not able to confirm the superiority of pembrolizumab over placebo,
[56]
even though the safety profile was manageable and the clinical difference between the two arms in terms
of median OS warrants a further exploration of the role of ICI in HCC.

ICIs combination with ipilimumab and nivolumab in patients with advanced stage disease previously treated
with sorafenib yielded a response rate of 31%, including 5% of complete responses, with a median duration
of response of 17.5 months. The study randomized patients into 3 arms: nivolumab 1 mg/kg and ipilimumab
3 mg/kg every 3 weeks for 4 cycles followed by nivolumab 240 mg every 2 weeks, nivolumab 3 mg/kg and
ipilimumab 1 mg/kg every 3 weeks for four cycles followed by nivolumab 240 mg every 2 weeks or nivolumab
3 mg/kg and ipilimumab 1 mg/kg every 6 weeks. The first arm experienced a median overall survival of
22.8 months, the second and third arms reached 12 and 13 months respectively. Overall, the combination
[57]
was well tolerated, with 37% of all patients experiencing grades 3-4 treatment-related adverse events .
Tremelimumab plus durvalumab was associated with 20% of grade 3-4 toxicities with no unexpected safety
signals in an analysis from an a phase I/II trial with 40 patients who progressed on or were intolerant
[58]
to sorafenib . An ongoing phase III trial (NCT 03298451) is actually recruiting patients in the first-line
setting to sorafenib vs. durvalumab vs. duralumab plus tremelimumab. Trials on immunotherapy are listed
in Table 1.

A focus is being placed on the potential benefit of ICI as an adjuvant treatment after resection or ablation.
In this sense, patients with high risk of recurrence are being enrolled in a phase III placebo-controlled trial
with nivolumab in the adjuvant setting. The primary endpoint of this study is recurrence-free survival
(NCT03383458). Similarly, pembrolizumab (NCT03867084) and durvalumab with or without bevacizumab
(NCT03847428) are also been tested in the adjuvant setting in other phase III trials in patients who
achieved complete response after resection or ablation.