Abstract
Immune checkpoint inhibitors (ICIs) are the new frontier for the treatment of advanced hepatocellular carcinoma (HCC). Since the first trial with tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 inhibitor, increasing evidence has confirmed that these drugs can significantly extend the survival of patients with advanced hepatocellular carcinoma (HCC). As a matter of fact, the overall survival and objective response rates reported in patients with advanced HCC treated with ICIs are the highest ever reported in the second-line setting and, most recently, the combination of the anti-programmed death ligand protein-1 atezolizumab with bevacizumab—an anti-vascular endothelial growth factor monoclonal antibody—demonstrated superiority to sorafenib in a Phase III randomized clinical trial. Therefore, this regimen has been approved in several countries as first-line treatment for advanced HCC and is soon expected to be widely used in clinical practice. However, despite the promising results of trials exploring ICIs alone or in combination with other agents, there are still some critical issues to deal with to optimize the prognosis of advanced HCC patients. For instance, the actual proportion of patients who are deemed eligible for ICIs in the real-life ranges from 10% to 20% in the first-line setting, and is even lower in the second-line scenario. Moreover, long-term data regarding the safety of ICIs in the population of patients with cirrhosis and impaired liver function are lacking. Lastly, no biomarkers have been identified to predict response, and thus to help clinicians to individually tailor treatment. This review aimed to summarize the state of the art immunotherapy in HCC and, by analyzing a large, multicenter cohort of Italian patients with HCC, to assess the potential applicability of the combination of atezolizumab/bevacizumab in the real-life setting.
Highlights
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, with approximately 800,000 deaths per year and an estimated increase to more than 1 million deaths by 2030 [1]
Lenvatinib became an effective alternative to sorafenib as first-line therapy for hepatocellular carcinoma (HCC) in 2018, while regorafenib, cabozantinib, and ramucirumab only recently have been approved in the second-line setting [8]
Ramucirumab is an anti-VEGFR2 monoclonal antibody, and its utility in subjects with advanced HCC emerged from the double-blind, Phase III REACH-2 trial comparing ramucirumab versus placebo as second-line treatment in patients progressing on sorafenib and with baseline AFP ≥ 400 ng/mL [19]
Summary
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, with approximately 800,000 deaths per year and an estimated increase to more than 1 million deaths by 2030 [1]. The armamentarium for the systemic treatment of advanced HCC was limited to the anti-vascular endothelial growth factor (VEGFR), multi-target-tyrosine kinase inhibitor (TKI) sorafenib This drug determined a significant— though modest—survival benefit in two Phase III trials and remained the sole first-line treatment option for about 10 years, during which neither an alternative drug nor effective second-line therapies became available for patients who progressed during—or were intolerant to—sorafenib [6,7]. With the advent of second-line treatments, the survival of patients with advanced HCC has significantly improved, with a proportion (approximately 20%) of patients reaching survival times of about 2 years with the sequential use of sorafenib-regorafenib [9] These patients, belong to a small subgroup of patients who, maintaining an optimal liver function, are eligible for sequential treatment and tolerate the adverse effects of the anti-neoplastic agents [9]. We summarize the state of the art immunotherapy in advanced HCC, with a particular focus on the combination of atezolizumab plus bevacizumab, by assessing in a large cohort of Italian patients with HCC the potential applicability of this regimen to the real-life setting
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