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Giovanis et al. Hepatoma Res 2018;4:10 I http://dx.doi.org/10.20517/2394-5079.2018.21 Page 9 of 13

In September 2017 American Food and Drug Agency granted priority review to nivolumab for HCC and
approved it for patients who have previously been treated with sorafenib, at the dosage of 240 mg every
2 weeks. As a condition of accelerated approval, larger phase 3 randomized trials of nivolumab versus
sorafenib will be required to verify the clinical benefit of nivolumab for this indication. A randomized,
multicenter phase 3 study of nivolumab versus sorafenib as first-line treatment in patients with advanced
hepatocellular carcinoma (CheckMate 459) is ongoing with the goal to enroll 726 patients and the estimated
[60]
primary completion date is October 2018 .

DISCUSSION
Ten years after sorafenib introduction in HCC scenario, novel knowledge about this mature drug and the
availability of four new drugs are opening innovative therapeutic perspectives for patients suffering from
this disease.

Firstly, new evidences coming from clinical practice allowed a renovate use of sorafenib in first line setting.
In particular, an important recommendation is to remain in therapy for patients experiencing toxicity
during the first weeks of therapies. In fact, at the era of the studies SHARP and ASIA PACIFIC, those
patients experiencing important adverse events were considered unsuitable to sorafenib and were suggested
to permanently discontinue this therapy. Differently, at the present time, prospective and retrospective
data seem to indicate that most likely these patients could receive the major benefit to sorafenib. Indeed,
prospective studies and retrospective experiences identified toxicities as a probable marker of response to
the therapy. This suggest managing patients experiencing toxicities with an appropriate tolerable adverse
event protocol, proposing momentary suspensions followed by restart of therapy at lower doses with the aim
to generate drug-tolerance. Nevertheless, a small randomised clinical trial, comparing TACE plus external
beam radiotherapy (RT) versus sorafenib in patients affected by hepatocellular carcinoma with macroscopic
vascular invasion and Child-Pugh A liver function, demonstrated a superiority of the TACE-RT group over
sorafenib: at week 12, the PFS rate was 86.7% vs. 34.3%, with a higher rate of radiologic response (33.3% vs.
[61]
2.2%), a better time of progression (31 vs. 11.7 weeks), and an overall survival of 55 vs. 43 weeks .
The second innovative point of this new era is the solution to the historic unmet need due to lack of second
line therapies in HCC patients progressing to sorafenib. In the past 10 years the scanty opportunity for
these patients was the re-treatment with higher dose of sorafenib, or the participation in a clinical trial.
Presently, regorafenib is the only second line systemic therapy available worldwide in patients progressed on
sorafenib. First-line patients with a very severe intolerance to sorafenib unable to follow a tolerable adverse
event protocol may will benefit from the lenvatinib, once approved by Health Authorities, because proved
to be non-inferior to the standard of care sorafenib and presenting a different toxicity profile. Cabozantinib
and nivolumab could be valid second-line options that allow to reach the “embarrassment of riches” also for
treating intermediate and advanced stages HCC.

But these new therapeutic options open the dilemma on which second-line should be chosen. A first
speculative solution could evaluate survival data observed in pivotal trials of each therapy. Survival
benefit data refers that the sequence sorafenib-regorafenib is associated to 26 months, no data have been
reported for the sequences sorafenib-cabozantinib and sorafenib-nivolumab. Besides, while regorafenib was
evaluated only in patients with sorafenib progression, cabozantinib was studied in population generically
progressed to TKIs because CELESTIAL trial enrolled also patients treated with front-line drugs different
from the standard of care. Moreover, including in the trial a significant number of patients with two
previous regimens, cabozantinib could be evaluated as a third line therapy too. With the goal to achieve the
maximum lines of treatment, a possible sequence strategy may include the use of regorafenib in a second
line after progression to sorafenib, allowing to reach a third line of therapy with cabozantinib. The role of