The dual checkpoint blockade in unresectable hepatocellular carcinoma: opportunities emerging in clinical trials

ABSTRACT

Introduction

To prevent damage from an immune response against autoantigens and toxins originating from the gut, the liver promotes an immune-tolerant milieu providing fertile ground for immune escape of cancer cells. Therefore, the use and evaluation of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) is a treatment rationale.

Area covered

In this article, we discuss the role of the dual ICIs blockade in advanced HCC, covering the biological basis for their combination, their mechanism of action, and the results of the early-phase studies testing nivolumab plus ipilimumab and durvalumab plus tremelimumab. Furthermore, we provide the results of the phase III HIMALAYA trial and an overview of the ongoing trials investigating the dual ICIs in different disease stages.

Expert Opinion

The potential approval of the dual ICIs blockade strategies for advanced HCC will set the entry of antiangiogenic-free options, expanding the proportion of patients eligible for a first-line treatment. However, it will pose a series of clinical challenges with a sizable proportion of patients, namely Child-Pugh B, elderly, and immunocompromised patients, still marginalized. Also, given the rate of disease progression, identifying reliable predictive biomarkers is crucial to inform treatment choice and sequences. Finally, the compelling response rate of such combinations is paving the way for their evaluation in earlier stages.

KEYWORDS:

• CTLA-4
• durvalumab
• HCC
• immune checkpoint inhibitors
• immunotherapy
• ipilimumab
• nivolumab
• PD-1
• PD-L1
• tremelimumab

Article highlights

• As a result of the peculiar immune-tolerant microenvironment of the liver, hepatocellular carcinoma (HCC) can elude the immune surveillance via various mechanisms, including impaired antigen presentation, dysregulation of T-cell response, and upregulation of immunosuppressive myeloid cells. Thus, a biological rationale supports the evaluation of immune checkpoint inhibitors (ICIs) in this setting.

• The combination of anti PD-(L)1 and anti-CTLA-4 resulted in a synergistic effect while reducing the rate of primary resistance.

• Nivolumab plus ipilimumab and durvalumab plus tremelimumab demonstrated promising clinical activity with a manageable safety in a mostly sorafenib-experienced population with unresectable HCC.

• A single priming dose of tremelimumab associated with durvalumab (STRIDE regimen) was proven as the most active strategy in the early-phase Study 22, with fascinating correlative results at the biological level.

• In the phase III HIMALAYA trial, the STRIDE regimen and durvalumab as single-agent were found to be effective first-line treatment options, proving to be superior and non-inferior compared to sorafenib, respectively.

• The potential approval of these compounds will expand the proportion of patients eligible for a first-line treatment, serving those with major contraindications to antiangiogenics, but treatment will remain challenging for certain subsets of patients.

• Reliable biomarkers of response and more appropriate radiological response criteria as well as high-quality evidence to guide treatment sequencing are urgently needed.

• Due to the compelling response rate in advanced HCC, numerous studies are investigating the dual immune checkpoint inhibition in earlier disease stages with preliminary promising data.

This box summarizes key points contained in the article.

Declaration of interest

A D’Alessio is supported by grant funding from the European Association for the Study of the Liver (Andrew Burroughs Fellowship). T Pressiani has received consulting fees from Bayer, Ipsen, IQVIA; and institutional research funding from Bayer, Lilly, Roche. N Personeni has received consulting fees from Amgen, Merck Serono, Servier; lectures fees from AbbVie, Gilead, Lilly, Sanofi; travel expenses from Amgen, ArQule; and institutional research funding from Basilea, Merck Serono, Servier. L Rimassa has received consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Servier, Taiho Oncology, Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. 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.