Anti-programmed cell death-1 and anti-programmed cell death ligand-1 immune-related liver diseases: from clinical pivotal studies to real-life experience

ABSTRACT

Introduction

Monoclonal antibodies directed against programmed cell death-1 (anti-PD-1) and its ligand (anti-PD-L1) showed a significant efficacy among different immunogenic metastatic tumors such as melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC). Between immune-related adverse events (irAEs) dependent on immune checkpoint inhibitors (ICPIs), immune-related liver diseases are uncommon and a definitive diagnosis is not always feasible.

Areas covered

We revised data from phase II/III clinical trials and real-world retrospective analyses on liver-related adverse events induced by anti-PD-1 (nivolumab/pembrolizumab) and anti-PD-L1 (atezolizumab) in advanced cancer populations (melanoma, NSCLC and RCC). Furthermore, we described clinical-pathological patterns of immune-related liver diseases in real-life.

Expert opinion

Use of anti-PD-1 and anti-PD-L1 led to a paradigm shift in the management of patients with melanoma, NSCLC and RCC. IrAEs can occur potentially in any tissue, leading to discontinuation of ICPIs, at least in a small proportion of these patients, and to a negative impact on their prognosis. Hepatobiliary immune-related adverse events are underestimated due to inappropriate monitoring. Development of novel diagnostic and therapeutic strategies for cancer patients receiving ICPIs as well as the identification of predictive biomarkers of liver injury could allow a better patients’ selection and improve clinical outcomes of immune-related liver diseases.

KEYWORDS:

• Anti-programmed cell death-1
• anti-programmed cell death-ligand 1
• immune checkpoint inhibitors
• immune-related liver disease
• hepatitis
• small-duct cholangitis
• large-duct cholangitis
• cholecystitis

Article highlights

• Available data from phase II/III clinical trials and real world retrospective analyses on hepato-biliary immune-related adverse events induced by anti-PD-1 and anti-PD-L1 in melanoma, NSCLC and RCC have been reported.

• We describe the different forms of hepatobiliary toxicity, their diagnosis and treatment, and the relevant clinical points on which pivotal studies were not focused, such as immune-mediated hepatitis, immune-mediated small-ducts cholangitis, immune-mediated large-ducts cholangitis, immune-mediated cholecystitis, rare immune-related liver diseases.

• Development of novel diagnostic strategies and predictive markers of drug-induced liver injury will be important to optimize both the correct selection of patients and clinical outcomes of immune-related liver diseases: GGT and ALP blood routine tests, as well as liver histology in the presence of early toxicity, should be improved;

• We suggest preemptive treatment with topical steroids or ursodeoxycholic acid if risk factors are present in order to reduce ICPI therapy drop-out;

• Multidisciplinary patient-oriented management of all immune-related hepatobiliary diseases, aiming to avoid the discontinuation of life-saving treatment, remains an unmet need.

Declarations of interests

Prof. A Ardizzoni has received research grant support from BMS and Celgene; personal fees for serving in a consultant and/or advisory role for BMS, MSD and Boehringer; honoraria from Eli-Lilly and Pfizer. The authors have no other 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 apart from those disclosed.

Reviewer Disclosures

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

Additional information

Funding

This manuscript has not been funded.