Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups

Abstract

Following the success of immune checkpoint blockers (ICBs) in different cancer types, a large number of studies are currently investigating ICBs in patients with hepatocellular carcinoma (HCC), alone or in combination with other treatments. Both nivolumab and pembrolizumab, as well as the combination of nivolumab plus ipilimumab have been granted accelerated approval by the United States Food and Drug Administration for sorafenib-pretreated patients. While nivolumab and pembrolizumab both failed to meet their primary endpoints in phase III trials, the combination of atezolizumab plus bevacizumab eventually improved overall and progression-free survival compared with sorafenib in a front-line phase III trial, and thus, will become the new standard of care in this setting. Despite this breakthrough, there are patient populations with certain underlying conditions that may not be ideal candidates for this new treatment either due to safety concerns or potential lack of efficacy. In this review, we discuss the safety of ICBs in patients with pre-existing autoimmune disease, IBD or a history of solid organ transplantation. Moreover, we summarise emerging preclinical and clinical data suggesting that ICBs may be less efficacious in patients with underlying non-alcoholic steatohepatitis or HCCs with activated Wnt/β-catenin signalling.

Keywords: hepatobiliary cancer; hepatocellular carcinoma; immunotherapy; molecular oncology.

Figure 1

Mechanisms of action of atezolizumab and bevacizumab. (A) Atezolizumab is a monoclonal antibody against PD-L1. It reverses T-cell suppression by preventing interaction between the inhibitory immune checkpoint molecules PD-1 and PD-L1. (B) Besides inducing tumour angiogenesis, VEGF also mediates immunosuppression within the tumour microenvironment by promoting immunosuppressive cells such as T_regs, MDSCs and TAMs, while suppressing antigen-presenting cells and CTLs. Bevacizumab is a monoclonal antibody against VEGF and reverses its angiogenic and immunosuppressive effects in the tumour microenvironment. APC, antigen-presenting cell; CTL, cytotoxic T lymphocyte; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; PD-1, programmed cell death protein 1; PD-L1, programmed cell death 1 ligand 1; TAM, tumour-associated macrophage; TCR, T-cell receptor; T_reg, regulatory T cell; VEGF, vascular endothelial growth factor.

Figure 2

Proposed treatment sequence for patients with advanced hepatocellular carcinoma. Atezolizumab plus bevacizumab, sorafenib, lenvatinib (all tested in first line), regorafenib, cabozantinib and ramucirumab (all tested in sorafenib-pretreated patients) have demonstrated efficacy in phase III trials. Boxes indicate main study inclusion criteria that separate them from the other studies and HRs for the primary survival endpoints. A blue background marks monoclonal antibodies, yellow background labels multi-tyrosine kinase inhibitors. In contrast to continuous lines, dotted lines represent treatment sequences that are not in accordance with drug labels but may also be considered in clinical practice. Nivolumab, pembrolizumab and nivolumab plus ipilimumab have been granted accelerated approval for sorafenib-experienced patients in the USA (but not in Europe) based on promising response rates from phase I/II trials. However, their role in patients previously treated with atezolizumab plus bevacizumab is unclear. AFP, alpha-fetoprotein; CR, complete response; mPVI, main portal vein invasion; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; U.S, United States.

Figure 3

Proposed treatment algorithms for special populations. Patients with prior solid organ transplantation, severe or poorly controlled autoimmune disease, or complicated IBD should not receive an immune checkpoint blocker (ICB)–based regimen due to considerable safety concerns. The potential use of ICBs as an ultima ratio in selected patients (eg, history of kidney transplantation) needs to be evaluated carefully on a case-by-case basis within a multidisciplinary team and the patient must be comprehensively informed about potential risks. Immunotherapy should not be withheld in patients with non-alcoholic fatty liver disease or Wnt/β-catenin activated hepatocellular carcinoma, as concerns regarding efficacy are based on preliminary evidence. Note that lenvatinib is approved for patients who have received no prior systemic therapy. Regorafenib, cabozantinib and ramucirumab are approved in sorafenib-experienced patients. HCC, hepatocellular carcinoma; IS, immunosuppression; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.

Figure 4

Considerations before initiation of immune checkpoint blockers in patients with a history of solid organ transplantation. The decision to use immune checkpoint blockers (ICBs) in patients with prior organ transplantation should only be made after careful evaluation within a multidisciplinary team. Some key points need to be addressed. This includes whether a potential organ rejection during ICB treatment will be life threatening due to lack of organ replacement therapy (ie, liver) or not (ie, kidney). History of prior organ rejection also needs to be incorporated into the risk–benefit analysis as it may be associated with an increased risk of rejection during ICB treatment. It is important to preferentially use alternative treatment option that have a better safety profile in transplant recipients. Tumour extent and growth rate and potentially associated imminent organ dysfunction should also be taken into account as a measure of urgency for using ICBs. ICB, immune checkpoint blocker.