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Carr. Hepatoma Res 2019;5:3 I http://dx.doi.org/10.20517/2394-5079.2018.113 Page 5 of 10

Table 2. Current therapies for advanced stage hepatocellular carcinoma patients
First line
A. Chemoembolization or SIRT
B. Sorafenib or Lenvatinib
Second line
A. Regorafenib or Opdivo or Cabozantinib
B. Under FDA review: ramucirumab
Metastasis
Sorafenib or Lenvatinib
PVT
SIRT, Sorafenib, external beam irradiation
Combinations in development
A. Multikinase inhibitors plus chemoembolization or SIRT
B. Immune checkpoint inhibitors plus chemoembolization or SIRT
C. Kinase inhibitors targeting parallel growth pathways
D. Multikinase inhibitors plus immune checkpoint inhibitors

SIRT: selective internal radiation therapy; PVT: portal vein thrombosis; SBRT: stereotactic body radiation therapy

with fatigue, hypertension, hand-foot syndrome, slight elevation of transaminases and bilirubin occurring
after both drug treatments. The recommended regorafenib dose is 160 mg per day. The RESORCE trial
showed that it is possible to dose-reduce regorafenib and still obtain antitumor effects. Given the remarkable
structural similarity between sorafenib and regorafenib - one fluorine atom difference - it is surprising that
results for regorafenib were so positive in proven sorafenib-resistant patients. Both sorafenib and regorafenib
inhibit the insulin-like growth factor-1 (IGF-1) mediated growth pathway, and their actions in vitro are both
[35]
blocked by IGF-1. By contrast, their actions are augmented by IGF-1 receptor inhibition suggesting future
directions for enhancing their effects.

Nivolumab (opdivo)
FDA approved nivolumab, a programmed death receptor 1 (PD-1) immune checkpoint inhibitor, as
second line therapy for HCC patients who had failed prior sorafenib due to disease progression or
sorafenib intolerance, after tumor response and durability of those responses of the single arm phase Ib/
[36]
II CheckMate-040 trial . Results showed that 22 or 14% of 154 patients responded, regardless of their
programmed death receptor ligand 1 (PD-L1) status. Three of these patients had complete responses, with
91% of patients having responses lasting 6 months and 55% of patients having responses for more than a
year. Median duration of response was 16.6 months, with a rapid median onset of response at 2.8 months.
The 12 months OS rate was 59.9% and the median OS was 16.7 months. Serious adverse events occurred in
49% of patients and included pyrexia, ascites, back pains and abdominal pains and general deterioration.
Commonest toxicities were 38% of patients had fatigue, 36% musculoskeletal pain, 34% abdominal pain,
27% pruritus, 27% diarrhea, 26% rash and 23% cough. Thus, the toxicity profile is significant and somewhat
different from the multikinase inhibitors. The drug can cause immune-mediated colitis, hepatitis,
pneumonitis and endocrinopathies. The toxicity results of long-duration therapy are unknown, but may be
of concern. On the positive side, the mechanisms of this class of drugs are so different from TACE, SIRT and
other multikinase inhibitors, that they will be very attractive candidates for future drug combination trials.
A phase III comparison of nivolumab vs. sorafenib is ongoing.

Two new agents that have met their end-points in phase III trials in the second-line post sorafenib setting.
Ramucirumab (cyramza) is awaiting FDA evaluation and cabozantinib (cabometyx) in the Celestial trial has
just been FDA approved.

Cabozantinib (cabometyx)
Cabozantinib is a tyrosine kinase inhibitor, with targets including VEGF receptors 1, 2, and 3, MET, and
AXL, which are implicated in the HCC growth and sorafenib resistance. A phase III placebo controlled