Abstract
Hepatocellular carcinoma (HCC) remains the sixth most commonly diagnosed malignancy worldwide, still representing an important cause of cancer-related death. Over the next few years, novel systemic treatment options have emerged. Among these, immune checkpoint inhibitors (ICIs) have been widely evaluated and are under assessment, as monotherapy or in combination with other anticancer agents in treatment-naïve and previously treated patients. In particular, the approval of the PD-L1 inhibitor atezolizumab plus the antiangiogenic agent bevacizumab as front-line treatment for advanced HCC has led to the adoption of this combination in this setting, and the IMbrave 150 phase III trial has established a novel standard of care. However, several questions remain unanswered, including the identification of reliable predictors of response to ICIs in HCC patients. In the current paper, we will provide an updated overview of potentially useful predictive biomarkers of response to immunotherapy in advanced HCC. A literature search was conducted in September 2021 of Pubmed/Medline, Cochrane library and Scopus databases.
Highlights
Hepatocellular carcinoma (HCC) remains a lethal tumor with a 5-year survival rate of less than 20% for patients at all stages, accounting for more than 75% of all primary liver malignancies and resulting in 83 million deaths in 2020 [1, 2]
While results of immune checkpoint inhibitors (ICIs) monotherapy have been disappointing so far [15,16,17], the recently presented and published phase III IMbrave150 study comparing the programmed death ligand 1 (PD-L1) inhibitor atezolizumab plus bevacizumab versus sorafenib monotherapy as front-line treatment approach for advanced HCC patients has established a new standard of care [18,19,20]
These results are destined to mark a new era in this setting, and ICIs seem to have found their role in advanced HCC patients in combinatorial strategies [23]; the use of immunotherapy in HCC has been associated with several limitations in this setting [24]
Summary
Hepatocellular carcinoma (HCC) remains a lethal tumor with a 5-year survival rate of less than 20% for patients at all stages, accounting for more than 75% of all primary liver malignancies and resulting in 83 million deaths in 2020 [1, 2]. In the phase I/II CheckMate 040 study including 174 advanced HCCs with available PD-L1 status, a non-statistically significant difference was reported between PD-L1 positive and PD-L1 negative patients treated with nivolumab (26% versus 19% in PD-L1 positive and PD-L1 negative HCCs, respectively, by using a cut-off value of 1% of tumor cells) [42] These controversial results observed across different trials on ICIs are not surprising since all these studies were not adequately powered to differentiate responders and non-responders according to PD-L1 expression. The role of MSI-H in this setting remains to be fully elucidated
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