Page 70 - Read Online

Page 2 of 5 Fonseca et al. Hepatoma Res 2023;9:27 https://dx.doi.org/10.20517/2394-5079.2023.63

however, remains low, ranging from only 2% to 3%. In addition, some adverse events such as fatigue, hand-
foot reaction, diarrhea and arterial hypertension indicate the need for strict follow-up during treatment with
[4,5]
this drug .

In 2016, regorafenib (a tyrosine kinase inhibitor against VEGFR1-3, PDGFR, KIT RET, and RAF) showed a
significant increase in survival after progression with sorafenib, with a median survival of 10.6 months in
[6]
the regorafenib arm versus 7.8 months for placebo . An exploratory analysis showed that the sorafenib-
regorafenib sequence reached a median survival of 26 months, which reflects a significant advance in the
treatment of patients with advanced HCC .
[7]
Between 2016 and 2019, other drugs were introduced for the management of HCC after the results of
prospective randomized studies. Lenvatinib, another tyrosine kinase inhibitor, demonstrated non-inferiority
[8]
to sorafenib in the first-line setting and was incorporated as an option in this scenario . Cabozantinib, a
tyrosine kinase inhibitor against VEGFR, MET and AXL, increased the survival of patients with advanced
HCC after progression to sorafenib and became a second-line option . Finally, ramucirumab, a monoclonal
[9]
antibody against VEGFR-2, was associated with better survival in patients with AFP ≥ 400 ng/mL . Besides
[10]
the imaginary targets, there may be a general mechanism of action of tyrosine-kinase inhibitors aimed at
blocking a wide spectrum of pathways, which remain underexplored but can be addressed in the setting of a
[11]
personalized approach .
As of 2020, immunotherapeutic agents have also been incorporated into the management of advanced
HCC. The phase III study IMBRAVE150 included patients with advanced HCC to receive the combination
of atezolizumab (a PD-L1 inhibitor) with bevacizumab (a VEGF inhibitor) or sorafenib. The study
demonstrated a significant increase in overall survival, with a median survival of 19.2 months for the
[12]
experimental arm and 13.4 months for the control arm . In 2022, another combination of
immunotherapeutic agents demonstrated a benefit in overall survival in a phase III study with patients with
advanced HCC. In this study, patients who received the combination of durvalumab (a PD-L1 inhibitor)
and tremelimumab (a CTLA-4 inhibitor) had better median survival (16.4 months) compared to patients
[13]
who received sorafenib (13.8 months) . Therefore, combinations of immunotherapeutic agents have
become the standard choice in the first line of patients with advanced HCC.

The alternatives of systemic therapies for HCC are rapidly evolving and clinical decisions are challenging. In
order to offer guidance on the selection of first-line and subsequent second-line systemic therapies, the
American Association for the Study of Liver Diseases (AASLD) recently released recommendations, which
[14]
are summarized in Table 1 .
Several questions remain open in regard to the applicability of systemic treatment for HCC, most notably
the use in earlier stages aimed at preventing recurrence and the safety in populations underrepresented in
pivotal trials, such as patients with liver dysfunction or prior transplantation.

The pivotal trials restricted the inclusion of Child-Pugh A patients, while there is limited available data on
the use of systemic treatment in patients with liver dysfunction. A recent real-world study with 202 patients,
including 48 patients with Child-Pugh B treated with atezolizumab and bevacizumab, showed that these
patients had comparable rates of treatment-related adverse events to Child-Pugh A, and a median overall
survival of 6.7 months versus 16.8 months for Child-Pugh A patients . A meta-analysis evaluated different
[15]
studies of immunotherapy in patients with liver dysfunction and observed a median survival of 6.05
months, but concluded that the high heterogeneity across studies reflects the incapacity of the current