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breakthrough therapy designation by FDA, since a phase Ib study presented at American Society of Clinical
Oncology (ASCO) 2018 was reported to show objective responses in 32% of patients. More than half of the
responders maintained their responses for at least 6 months. A combination trial of nivolumab plus sorafenib
(CheckMate-459) for first line therapy is currently in progress. Furthermore, combinations of kinase
inhibitors that target different or parallel growth pathways [EGFR, FGFR, hepatocyte growth factor receptor
(HGFR)/Met] seems similarly attractive for testing. In addition, it may be that sequencing might show
added anti-tumor activity rather than combinations, such as chemoembolization/sorafenib, SIRT/sorafenib,
sorafenib/regorafenib, immune checkpoint inhibitor (high responses)/multikinase inhibitor. Thus, the
field may look quite differently in 3 years than currently. The role of anti-viral or anti-inflammatory agents
(above section) may also turn out to be beneficial in selected patient subsets, with greater inflammatory
[50]
characteristics . Either way, HCC sub-phenotype identification may be important in matching individuals
to selected treatments. However, a final word of caution may be useful. A major phase III trial recently failed
to meet its end-points, even though patients were selected, based on their tumors having the putative target
[51]
(Met) for the agent being tested . However, given the high responses and their durability for immune
checkpoint inhibitors such as Nivolumab, one of them may become a preferred first line therapy, if ongoing
clinical trials support this idea.

DECLARATIONS
Authors’ contributions
The author contributed solely to the article.

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported in part by NIH (CA 82723) to Carr BI.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2019.

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