Hepatocellular carcinoma accounts for approximately 75% of all primary liver malignancies. Several hepatic diseases have been associated with the development of HCC, including hepatitis virus infection, liver cirrhosis, and nonalcoholic fatty liver disease (NAFLD), and some of these etiologies – especially the latter – have been suggested to play a role in modifying response to systemic treatments. HCC patients with Barcelona Clinic Liver Cancer (BCLC) 0/A and intermediate-stage BCLC B disease usually receive potentially curative approaches, such as radical surgery, liver transplantation, and locoregional treatments, such as chemoembolization, radiofrequency ablation, etc. On the contrary, patients with BCLC C HCC are treated with systemic treatments, including tyrosine kinase inhibitors. Over the last decade, we have witnessed the emerging of cancer immunotherapy, with immune checkpoint inhibitors (ICIs) revolutionizing the therapeutic landscape of an impressive number of hematological and solid malignancies. ICIs base their mechanism of action on the inhibition of immune checkpoint-related molecules, such as programmed cell death-1 (PD-1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and lymphocyte-activation gene 3 (LAG-3). Atezolizumab, pembrolizumab, nivolumab, and other ICIs have been assessed in HCC patients in several settings, reporting controversial and disappointing results as monotherapies. However, immune-based combinations have recently produced some paradigm shifts, following the results of the phase III IMbrave150 trial. This study compared the combination of the antiangiogenic agent bevacizumab plus the PD-L1 inhibitor atezolizumab versus sorafenib monotherapy, reporting statistically significant and clinically meaningful benefits in several clinical outcomes, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). These results have been also confirmed by the updated results of IMbrave150, highlighting a median OS of more than 19 months in patients receiving atezolizumab – bevacizumab. If HCC immunotherapy finally seems to have found its role in this setting in the form of combination approaches, questions remain and deserve scrutiny and discussion. Several novel agents and strategies are under assessment in this setting and have the potential to modify the therapeutic landscape of HCC.
In this special issue of Expert Opinion on Investigational Drugs, international experts in the field of HCC examine key approaches under active investigation in clinical and preclinical research. In particular, they present critical analyses and integrate their own perspectives on promising agents in clinical trials and the latest therapeutic strategies and drug targets. Keep watching this space; expert articles with a focus on HCC will continue to appear in later spring and summer issues of the journal.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Reviewers on this manuscript have no relevant financial or other relationships to disclose.