Immunotherapy in hepatocellular carcinoma: how will it reshape treatment sequencing?

by Selleckchem | Feb 02 2023

The treatment landscape of advanced hepatocellular carcinoma (HCC) has broadened with immune checkpoint inhibitors (ICIs) setting a novel standard of care. With the increased number of therapies either in first or in further line, disentangling the possible treatment sequences has become much more complex. Yet, all the second-line therapies have been evaluated after sorafenib. After ICIs, offering multikinase inhibitors is a widespread approach, either shifting forward sorafenib or lenvatinib, or choosing among regorafenib or cabozantinib, already approved in the refractory setting. Under specific circumstances, ICIs could be maintained beyond disease progression in patients with proven clinical benefit, as supported by some data emerging from phase III clinical trials with immunotherapy in HCC. Rechallenge with ICIs is an additional attractive alternative, although requiring careful and individual evaluation as efficacy and safety of such a strategy have not been yet clarified. Still, a considerable number of patients displays primary resistance to ICIs and might benefit from antiangiogenics either alone or in addition to ICIs instead. Hopefully, the ongoing clinical trials will enlighten regarding the most effective treatment pathways. The identification of predictive correlates of response to immunotherapy will help treatment allocation at each stage, thus representing an urgent matter to address in HCC research. With programmed death ligand 1 expression, tumor mutational burden, and microsatellite status being inadequate biomarkers in HCC, patient characteristics, drug safety profile, and regulatory approval remain key elements to acknowledge in routine practice. Despite the tissue remaining a preferred source, biomarkers discovery could take advantage of liquid biopsy to overcome the matter of tissue availability and track tumor changes. Lastly, tumor genetic phenotypes, tumor microenvironment features, gut microbiome, and markers of immune response and systemic inflammation are all potential emergent predictors of response to ICIs, pending validation in the clinical setting.

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The treatment of advanced hepatocellular carcinoma (HCC) has become more complex with the introduction of immune checkpoint inhibitors (ICIs), and treatment sequences are difficult to determine. Second-line therapies have been evaluated after sorafenib, with the option of shifting to multikinase inhibitors or maintaining ICIs with proven clinical benefit. Rechallenge with ICIs is also an option, but efficacy and safety have not been clarified. Antiangiogenics are an alternative for patients with primary resistance to ICIs. Ongoing clinical trials and biomarker discovery through liquid biopsy will provide more information on the most effective treatment pathways, but patient characteristics, drug safety, and regulatory approval remain key elements to consider in routine practice. Emerging predictors of response to ICIs include tumor genetic phenotypes, microenvironment, gut microbiome, and markers of immune response and inflammation, which need validation in the clinical setting.