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Page 4 of 7 Pelizzaro et al. Hepatoma Res 2021;7:36 https://dx.doi.org/10.20517/2394-5079.2021.24

[9]
[6]
Regorafenib , cabozantinib , and ramucirumab are all second-line treatments approved for patients
[7]
previously treated with sorafenib, which was the standard of care at the time RCTs were conducted.
Nowadays, the changed paradigm of first-line treatment after IMbrave150 trial makes all the
recommendation for second-line therapies characterized by low quality of evidence and weak strength,
being essentially Expert Panel opinions . A second-line therapy with a TKI after atezolizumab +
[11]
bevacizumab will probably work, in consideration of its different mechanism of action, but there is
uncertainty regarding the best molecule to administer (i.e., sorafenib, lenvatinib, cabozantinib, or
ramucirumab). Guidelines state that, after atezolizumab + bevacizumab, sorafenib or lenvatinib may be
offered, but also regorafenib or cabozantinib are reasonable options . After a first line with sorafenib or
[11]
lenvatinib, a second-line with another TKI (regorafenib or cabozantinib) or ramucirumab (in patients with
AFP ≥ 400 ng/mL) may be prescribed, with atezolizumab + bevacizumab as an alternative option . This
[11]
latter recommendation derives from the fact that it is likely that most patients considered for atezolizumab
+ bevacizumab in the second-line setting did not have access to this combination when they started first-
line treatment. However, it should be again considered that there are no studies evaluating the therapeutic
sequence, except if sorafenib is used as first-line. Moreover, the Expert Panel suggests to consider
pembrolizumab or nivolumab following first-line with sorafenib or lenvatinib (in appropriate candidates
[11]
who have contraindications to or cannot tolerate TKIs) . The FDA granted accelerated approval to
pembrolizumab after a first-line treatment with sorafenib following a phase II trial (Keynote 224)
[28]
demonstrating encouraging tumor response rate and durability of response . However, in the subsequent
phase III trial (Keynote 240), although confirming a high response rate (18%), pembrolizumab failed to
demonstrate an advantage in OS and PFS compared to placebo as per prespecified statistical plan . In a
[13]
second-line setting, nivolumab was approved by FDA following a phase I/IIb dose escalation and expansion
trial (Checkmate 040) demonstrating relevant response rates , but no phase III trial data are currently
[29]
available. In the Checkmate 459 trial , comparing nivolumab and sorafenib in first-line, despite the high
[12]
median OS in nivolumab treated patients (16.4 months), the statistically significant superiority over
sorafenib was not achieved (HR = 0.85; 95%CI: 0.72-1.02; P = 0.0752). Although one can agree on the
potential utility of pembrolizumab and nivolumab in the treatment of patients who have contraindications
to or cannot tolerate TKIs, currently there are no randomized data demonstrating a survival advantage for
these drugs. Therefore, the interpretation of these indications should be very cautious. In third-line, the only
available option is cabozantinib since in the CELESTIAL trial patients previously treated with one or two
[7]
other systemic therapy regimens were enrolled . No specific recommendation on third-line therapy has
been included in ASCO guidelines, but for the acknowledgement that it may be considered in healthy
[11]
patients with preserved liver function after multidisciplinary decision .
Despite all these recent relevant advances, a wide area of uncertainty and unmet needs still exists, especially
regarding the substantial lack of data to support treatment benefits in Child-Pugh class B patients. The only
successful registration trial which was not limited to patients with compensated liver disease was the
SHARP trial, but only 5% of sorafenib treated patients was Child-Pugh class B . In real-life clinical
[3]
scenarios, sorafenib is frequently prescribed regardless of liver function and safety seems not to be different
in mildly decompensated liver disease [30,31] , although these patients demonstrated worse survival . For other
[32]
drugs, very limited data in Child-Pugh class B patients are available [33-36] . In addition, high quality evidence
in the systemic treatment of HCC in patients with different comorbidities excluded from trials (i.e., solid
organ transplantation, HIV, autoimmune diseases, cardiovascular diseases, bleeding history, and
hemodialysis) is missing . In patients with recurrence of HCC after liver transplantation, retrospective
[37]
studies suggests that sorafenib and regorafenib are safe and moderately effective in this setting [38,39] . On the
other hand, the use of ICI after liver transplantation may be problematic, since the activation of the immune
system may lead to organ rejection, as demonstrated by the available case series . Therefore, TKIs probably
[40]
represent the therapy of choice in this category of patients. In the future, the identification of reliable