Atezolizumab-bevacizumab plus Y-90 TARE for the treatment of hepatocellular carcinoma: preclinical rationale and ongoing clinical trials

ABSTRACT

Introduction

The treatment algorithm of advanced hepatocellular carcinoma (HCC) has evolved since the introduction of immunotherapy. The IMbrave150 trial set atezolizumab-bevacizumab as a new standard-of-care first-line treatment for unresectable HCC patients. However, for patients with intermediate or advanced stage with portal vein thrombosis but without distant metastases, ⁹⁰Yttrium transarterial radioembolization (⁹⁰Y-TARE) is considered the treatment of choice.

Areas Covered

We discuss the main evidence regarding the use of ⁹⁰Y-TARE in HCC, the recent progress of immunotherapy in this tumor, and the preclinical rationale of combining VEGF blockade with the other two treatment strategies.

Expert opinion

HCC has an extremely heterogeneous tumor immune microenvironment. This may explain the inconsistent outcomes obtained with immune-checkpoint inhibitors. The identification of patients who could benefit most from immunotherapy is crucial; however, reliable markers of response are lacking. Radiation therapy and VEGF inhibition have an established synergism with immunotherapy, mainly linked to enhanced antigen presentation and reduced immunosuppressive immune infiltrate. Combining an immune-checkpoint inhibitor with VEGF blockade and ⁹⁰Y-TARE might hence overcome primary resistances observed when each of these treatments is administerd alone.

KEYWORDS:

• Hepatocellular carcinoma
• immunotherapy
• VEGF
• atezolizumab
• bevacizumab
• radiation therapy
• TARE

Drug summary box

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Article highlights

• 90Y-TARE remains the pivotal treatment for BCLC B patients not suitable for other locoregional treatments or BCLC C with portal vein thrombosis and without metastasis.

• VEGF promotes tumor vascularization and has immunosuppressive effects. High levels of VEGF induce the expression of PD-1 and other inhibitory molecules, such as Tim-3, CTLA-4, and Lag-3, on tumor-infiltrating CD8+ T cells.

• Many preclinical studies documented enhanced tumor responses with the combination of RT and anti-VEGF agents.

• SIRT can enhance the number of released tumor antigens and has a proven synergism with immunotherapy.

• In the absence of predictive biomarkers to ICI for HCC patients and given the minority of patients who respond to single agent ICIs, combination strategies represent a promising approach to overcome primary resistance.

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

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.