Durvalumab: an investigational agent for unresectable hepatocellular carcinoma

ABSTRACT

Introduction

Programmed death 1 (PD1), programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte associated protein 4 (CTLA-4) are proteins involved in the modulation of immune response, which are upregulated in hepatocellular carcinoma (HCC) tumor microenvironment (TME). Immune checkpoint inhibitors (ICIs) are a new class of drugs that counteract immunological tolerance to cancer cells. Despite the aggressiveness of HCC and its poor prognosis, only a few tyrosine kinase inhibitors (TKIs) and ICIs have been approved for patients with advanced disease.

Areas Covered

We analyze the current knowledge on Durvalumab, a human antibody against PD-L1 its pharmacodynamics, and pharmacokinetics. We provide a description of its application in HCC, illustrating clinical trials that have demonstrated the safety and efficacy in this setting, either as monotherapy or in combination with other ICIs or TKIs, or as adjuvant treatment.

Expert Opinion

Durvalumab is a promising drug that could extend the landscape of approved treatments for HCC. The clinical safety profile of Durvalumab was well manageable and comparable to other ICIs, with a low incidence of severe immune-related adverse events (irAEs). The importance of personalized therapy according to tumor characteristics is emerging, but very little is known about factors that could influence the efficacy of ICIs.

KEYWORDS:

• HCC
• Durvalumab
• immune checkpoint inhibitors
• tumor microenvironment
• PD-1
• PD-L1
• CTLA-4
• HIMALAYA
• Tremelimumab
• Atezolizumab
• Bevacizumab

Article highlights

• Durvalumab is a fully human IgG1 antibody that binds PD-L1 in order to inhibit its interaction with PD-1, reverting peripheral tolerance against tumor cells.

• Results of the PACIFIC trial permitted the approval of Durvalumab in NSCLC stage IIIb after chemotherapy and radiotherapy; its application was consequently tested in several solid tumors with promising results.

• Following the approval of Atezolizumab, Nivolumab, Pembrolizumab and Ipilimumab for the treatment of unresectable HCC, Durvalumab showed efficacy and safety in phase I/II studies with a good safety and efficacy profile as monotherapy, but especially in combination with an anti CTLA-4 or anti VEGF agents.

• The results of the phase III randomized clinical trial exploring the efficacy of Durvalumab in combination with the CTLA-4 inhibitor Tremelimumab (HIMALAYA) as first-line treatment in patients with advanced, unresectable HCC demonstrated a better efficacy than Sorafenib.

• Ongoing clinical trials are testing the application of Durvalumab in neo adjuvant and adjuvant settings.

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 an advisory role of Eisai Co., Ltd. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.