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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 9 of 13

combination of ICI (anti-CTLA-4 and PD1/PD-L1) is also being evaluated in clinical trials, for example,
tremelimumab plus durvalumab (NCT 02119348) and ipilimumab plus nivolumab (NCT01658878).

Encouraging results of the combination of bevacizumab (an anti-VEGF antibody) with atezolizumab
(an anti-PD-L1 ICI) were reported in a phase Ib study that included 68 HCC patients. It was reported a
response rate of 34%, with 19 of the 23 responses lasting longer than 6 months. Grade 3-4 adverse events
[60]
were seen in 25% of the patients . This combination was granted a breakthrough designation therapy by
[61]
the US FDA in 2018 and a phase III trial aimed to evaluated atezolizumab and bevacizumab vs. sorafenib
is under recruitment (NCT0343479).

An open-label phase 1b trial that assessed the efficacy of lenvatinib plus pembrolizumab in 94 patients
has been recently reported. The combination induced a confirmed response rate of 26.9%, with a median
PFS of 9.69 months. Sixty percent of the patients had dose interruptions or reductions, 5 patients had
serious adverse events and there were 2 treatment-related deaths . Avelumab with axitinib also showed
[62]
encouraging activity in a trial with 22 patients, although a higher rate of grade 3 hypertension (50%) and
[63]
hand-foot skin reaction (22.7%) were reported . Table 2 summarizes main results on ICI in HCC.

CHALLENGES AND FUTURE DIRECTIONS
While final results on immunotherapy for HCC are awaited, some relevant issues are to be taken into
account when interpreting the available and upcoming data.

ICIs are associated with atypical patterns of response and progression. The traditional radiologic criteria
used to evaluate tumor response in oncology trials with cytotoxic chemotherapy may not be accurate
enough to detect clinical benefit or treatment failure with immune oncology agents. For example, a
radiological increasing in tumor burden without worsening in disease burden, called pseudoprogression,
can be explained by an immune-cell infiltration and do not represent treatment failure . Patients with
[64]
an initial progressive disease followed by a later radiologic response may experience a nonconventional
survival benefit comparing to those patients with the same initial behavior . Therefore, treatment with
[65]
ICI warrants specific radiologic criteria to assess benefit or the emergence of resistance.

Around 10%-30% of the patients with other solid tumors submitted to ICI treatment present long-term
disease control. This finding suggests the existence of a subgroup of patients that probably presents a
sensitive tumoral phenotype or a specific predictive biomarker. Mutational burden, tumor-infiltrating
lymphocytes and immune gene signatures are also being investigated as potential tools . For HCC, the
[66]
PDL-1 expression seems to be around 20%-25%, but no correlation between PDL-1 expression and better
response has been established so far .
[67]
Immune-related adverse events induced by ICIs are also a major concern in HCC. A wide range of events
are described in immunotherapy trials (dermatologic, endocrinologic, gastrointestinal and others), but
hepatotoxicity is of particular interest in this context. In clinical trials with anti-PD1 inhibitors, liver
enzymes elevations were typically mild. However, HCC patients often present underlying cirrhosis with a
limited liver reserve, what increase the risk of decompensation even in mild liver alterations.

In conclusion, the incorporation of immunotherapy in the HCC landscape is still under development.
[52]
[56]
The recently announced negative results of the phase III trials with pembrolizumab and nivolumab
somehow disappointed the initial hope placed in this strategy. Immunotherapy for HCC seems to be a
tougher road comparing to what we are experiencing with other tumors. However, huge effort is being
made in the search for predictive biomarkers and development of novel strategies to deliver better
outcomes for HCC patients.