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Page 2 of 7 Pelizzaro et al. Hepatoma Res 2021;7:36 https://dx.doi.org/10.20517/2394-5079.2021.24

[2]
cells . In 2008 and 2009, for the first time, two randomized controlled trials (RCTs) showed that the TKI
[3,4]
sorafenib was able to prolong overall survival (OS) compared to placebo in patients with HCC . Following
this milestone in the treatments of patients with HCC, several other molecules (brivanib, linifanib, sunitinib,
and erlotinib) were compared against sorafenib in phase III trials, but failed to demonstrate a survival
benefit, either due to lack of effectiveness or unacceptable toxicity . Almost 10 years passed before
[5]
additional advances in systemic treatment for HCC were achieved. In 2017-2019, four RCTs demonstrated
positive results in first- and second-line setting with either TKIs (regorafenib, cabozantinib, and lenvatinib)
[6-9]
or a VEGFR-2 antagonist (ramucirumab) . An additional step forward in the management of unresectable
HCC patients was made last year with the positive result of the IMbrave150 trial, demonstrating a clear
survival benefit of the combination of an anti-programmed death ligand 1 (PD-L1) drug (atezolizumab) and
an anti-vascular endothelial growth factor (VEGF) molecule (bevacizumab), over sorafenib .
[10]
The landscape of systemic therapies for HCC is rapidly evolving and the significant expansion of treatment
possibilities in the last years make it difficult for clinicians to decide how to approach pharmacological
treatment for a patient with HCC. With the aim to provide a guidance to the selection of first-line and
subsequent second-line systemic therapies, the American Society of Clinical Oncology (ASCO) recently
published its recommendations [Table 1] .
[11]

Following the results of IMbrave150 trial, which demonstrated a dramatic improvement of OS in
atezolizumab + bevacizumab arm compared to sorafenib (HR = 0.58; 95%CI: 0.42-0.79; P = 0.0006) , the
[10]
combination therapy is recommended as the standard of care first-line treatment in patients with advanced
[11]
HCC, Child-Pugh class A and Eastern Cooperative Oncology Group performance status (ECOG-PS) 0-1 .
The remarkably better OS, progression free survival (PFS), and response rate results obtained with the
combination of atezolizumab + bevacizumab are groundbreaking, considering that previous trials with anti-
PD1 immune checkpoint inhibitorsICI alone (nivolumab and pembrolizumab) failed to show efficacy in
first- and second-line [12,13] . In phase II trials, bevacizumab monotherapy showed promising response rates
(about 14%) in patients with advanced HCC [14-16] , thus confirming the central role of angiogenesis in the
development and progression of liver cancer . The rationale behind the combination of bevacizumab and
[17]
[18]
ICI relies on the immunomodulatory effects of VEGF . Beyond promoting neovascularization, VEGF
produced in the tumor microenvironment is able to enhance the release of immunosuppressive cytokines
and to reduce the proliferation and activation of T lymphocytes [19-21] . In addition, through its effect on
angiogenesis, VEGF prevents the infiltration of antigen-activated CD8+ cells in the tumor tissue and creates
a microenvironment that inhibits their function . Therefore, the administration of VEGF inhibitors
[21]
reprograms the immunosuppressive tumor microenvironment toward immunostimulation, and the
[18]
administration of PD-1/PD-L1 antibodies under such conditions enhances antitumoral activity of T cells .
This may explain the high efficacy of combined therapy, which is also confirmed by the results of a phase Ib
trial that showed significantly longer PFS in the atezolizumab and bevacizumab group than in patients
receiving atezolizumab alone . The superiority of atezolizumab + bevacizumab over other first-line
[22]
treatment options (sorafenib, lenvatinib, and nivolumab), was recently confirmed in a systematic review
and metanalysis .
[23]
A major concern when using anti-VEGF drugs in cirrhotic patients is bleeding since upper gastrointestinal
bleeding is a common and life-threatening complication in these patients. In IMbrave150 trial the incidence
of upper gastrointestinal bleeding in atezolizumab + bevacizumab group was 7% compared to 4.5% in the
sorafenib group, despite the exclusion from the study of patients with untreated or incompletely treated
[10]
gastro-esophageal varices and high risk of bleeding . Although similar rates of fatal treatment emergent
adverse events were reported in the two arms, hemorrhage was more common in atezolizumab +