Treatment of Hepatocellular Carcinoma with Immune Checkpoint Inhibitors and Applicability of First-Line Atezolizumab/Bevacizumab in a Real-Life Setting

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.

Cross-Resistance Among Sequential Cancer Therapeutics: An Emerging Issue

“…The first-line treatment of these patients is represented by the combination of anti-VEGF bevacizumb and anti-PD-L1 atezolizumab mAbs, that showed significant OS benefit over the multikinase inhibitor (MKI) sorafenib previously used in this setting, which was thereby approved by the FDA in 2020 (157). Data on efficacy and safety were subsequently confirmed by RWD analyses (158). Many therapeutic options are available for the second-line treatment of these patients, including a MKI, mAbs, or anti-PD1 agents such as cabozantinib, ramucirumab, nivolumab with or without the anti-CTLA4 ipilimumab (159).…”

The advanced development of molecular targeted therapy for hepatocellular carcinoma

“…Recently, the US FDA has approved combination treatment with atezolizumab plus bevacizumab as a breakthrough treatment for untreated advanced or metastatic HCC 152 . Studies have indicated that the ORR for combined immunotherapy is significantly higher than that for the single treatment with any ICI 153 – 156 . The US FDA has also approved the dual ICI treatment with nivolumab combined with ipilimumab, mainly for patients with HCC previously treated with sorafenib.…”

Feasibility of hepatocellular carcinoma treatment based on the tumor microenvironment

“…Atezolizumab (anti-PD-L1) and bevacizumab (vascular endothelial growth factor (VEGF) inhibitor) have been shown to be efficacious ( 86 , 87 ), and their combination has demonstrated antitumor activity and safety in a phase 1b trial in patients with unresectable hepatocellular carcinoma. In patients with unresectable hepatocellular carcinoma, atezolizumab and bevacizumab had better overall survival and progression-free survival than sorafenib ( 28 , 88 ), and the combination of atezolizumab + bevacizumab had longer progression-free survival than atezolizumab treatment alone ( 89 ).…”