Experimental drug treatments for hepatocellular carcinoma: clinical trial failures 2015 to 2021

ABSTRACT

Introduction

Hepatocellular carcinoma (HCC) is a major health problem worldwide with limited systemic therapy options. Since the approval of sorafenib in 2008, no systemic therapy has provided a sustained/robust/survival benefit for patients with advanced HCC until recently. Many initially promising therapies have been trialed, but survival outcomes remained stagnant. Knowledge concerning previous treatment failures may help inform future therapeutic approaches.

Area Covered

This article reviews recent advances in the treatment of HCC. Despite some recent success, many systemic and locoregional therapies have failed to produce significant improvements in outcome. These treatment failures are examined and insight into pathways for future success are discussed.

Expert Opinion

Combination atezolizumab and bevacizumab has changed the landscape of systemic treatment for patients with HCC when it became the first therapy after demonstrating improve outcomes over sorafenib. Clinical trials in patients with advanced HCC have inherent difficulty with challenges to determine if a patient’s declining liver function is secondary to disease progression, worsening cirrhosis, or drug toxicity, which may skew results. As we gain more knowledge of underlying genetic alterations behind the pathophysiology of the development of HCC, molecular markers may be identified to assist in predicting which patients would respond to a specific therapy.

KEYWORDS:

• Hepatocellular carcinoma
• treatment failure
• sorafenib
• atezolizumab-bevacizumab
• locoregional therapy

Article highlights

• Atezolizumab in combination with bevacizumab recently supplanted sorafenib, the standard systemic therapy in the treatment of hepatocellular carcinoma (HCC), since 2008, as the new first-line treatment for patients with advanced HCC.

• In addition to sorafenib, other tyrosine kinase inhibitors have been studied in advanced HCC with limited success.

• Although systemic cytotoxic chemotherapy has been the backbone of therapy for many malignancies, limited success with these agents has been noted in HCC.

• Immune therapies have demonstrated improved outcomes with immune checkpoint inhibitors and combination therapies may continue to improve outcomes.

• Liver dysfunction in trials evaluating HCC therapy may occur due to worsening underlying cirrhosis, progressing HCC, or drug toxicity, which can result in misclassification of an adverse event or failure of treatment due to drug inefficacy.

• Future studies identifying and evaluating molecular markers of tumorigenesis and biomarkers are expected to improve patient selection and treatment allocation relative to more targeted therapies.

This box summarizes key points contained in the article.

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

One reviewer has received honoraria from Roche, Eisai, Bayer, MSD, BMS, Beigene and Ipsen.

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

Additional information

Funding

This paper was not funded.