Abstract and Introduction
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, with up to 90% of HCC cases occurring in the setting of underlying cirrhosis. Therapeutic landscape for advanced HCC has dramatically changed in recent years with the advent of immunotherapy, including several combinations. Data suggest that the surrounding liver milieu may influence tumour response. In addition, different aetiologies of HCC and their effects on the host liver may impact response to immunotherapy. However, to date, guidelines do not take into account this parameter to guide therapeutic selection, and phase III trials are likewise performed in patients irrespective of HCC aetiology. Moreover, most clinical trial data are collected in highly selected patients with preserved liver function (defined as Child-Pugh class A) and controlled portal hypertension, which does not accurately reflect routine clinical practice. In this review, we discuss the influence of liver disease aetiology on the response to immunotherapy in patients with advanced HCC. We also discuss the safety and efficacy of various immunotherapeutic agents in Child-Pugh B patients to determine if these treatments are beneficial in this vulnerable patient population.
Introduction
Liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide, with approximately 906 000 new cases and 830 000 deaths in 2020.[1] Hepatocellular carcinoma (HCC), the most common form of liver cancer, is frequently diagnosed at an advanced stage. In patients with advanced HCC, systemic therapies including targeted therapy, immunotherapy, or a combination of both are the mainstay of treatment.[2,3] In recent years, several systemic therapy options for advanced HCC have shown efficacy in the first- and second-line settings.[2]
Atezolizumab, an anti-programmed death-ligand 1 (PD-L1) monoclonal antibody, in combination with bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, is currently considered as the standard of care for the first-line treatment of advanced HCC.[2] First-line atezolizumab plus bevacizumab (AtezoBev) was shown to be superior to the multikinase inhibitor sorafenib in the IMbrave150 phase III trial, in which AtezoBev showed a median progression-free survival (PFS) of 6.9 months (95% confidence interval [CI], 5.7–8.6) and a median overall survival (OS) of 19.2 months (95% CI, 17.0–23.7) versus 4.3 months (95% CI, 4.0–5.6) and 13.4 months (95% CI, 11.4–16.9) with sorafenib respectively.[4,5] More recently, in the HIMALAYA phase III trial performed in patients with unresectable HCC and no previous systemic treatment, the Single Tremelimumab Regular Interval Durvalumab (STRIDE) regimen, which comprises a single high priming dose of tremelimumab (an anti-cytotoxic T lymphocyte–associated antigen 4 [CTLA4]) plus durvalumab (anti-PD-L1), significantly improved median OS compared to sorafenib (16.43 months [95% CI, 14.16–19.58] vs. 13.77 months [95% CI, 12.25–16.13]; p = .0035).[6] STRIDE regimen was approved by the Food and Drug Administration on 21 October 2022.
HCC is a unique neoplasm as 90% of cases develop in patients with cirrhosis, increasing the risk of complications such as liver dysfunction and portal hypertension.[3] On a global level, HCC is predominantly caused by viral infections, specifically that of hepatitis B virus (HBV) and hepatitis C virus (HCV), followed by other aetiologies such as chronic alcohol consumption, and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) caused by metabolic syndrome.[1,3] While the worldwide prevalence of HBV- and HCV-induced HCC is declining as a result of universal hepatitis B vaccination programmes and the advent of direct-acting antiviral agents against HCV, the prevalence of HCC due to NAFLD/NASH is steadily rising, particularly in the Western world, and worldwide alcohol consumption continues to increase.[1,3]
Despite the availability of several systemic therapeutic options for advanced HCC, they do not target the underlying liver disease. To date, there is a lack of solid prospective data supporting the selection of systemic treatment regimens for HCC based on liver disease aetiology. Aetiologies of the underlying chronic liver disease leading to HCC are heterogenous in randomized controlled trials (RCTs), with 70% of HCC cases attributed to viral hepatitis and 30% to non-viral aetiologies in IMbrave150, and 60% of patients in HIMALAYA having viral-related HCC versus 40% non-viral HCC.[5,6] In an exploratory study using updated IMbrave150 data, the benefit of AtezoBev versus Sorafenib on PFS and objective response rate (ORR) was confirmed in patients with non-viral HCC aetiology.[7] The safety profile was also better with the combination. Moreover, most patients included in RCTs such as IMbrave150 and HIMALAYA had a preserved liver function, defined as Child-Pugh class A (with but also without cirrhosis).[5,6] Patients with uncompensated cirrhosis (Child-Pugh class B or C) are usually excluded from HCC RCTs. Thus, several guidelines consider best supportive care as the only management option in patients with advanced HCC and Child-Pugh class B or C liver dysfunction.[8,9]
Understanding the impact of HCC aetiology and of impaired liver function on the efficacy and safety of systemic therapy could better guide healthcare professionals in the complex management of advanced HCC. Accordingly, this review discusses from an hepatologist's perspective the influence of underlying liver disease aetiology and liver function deterioration on immunotherapy in patients with advanced HCC.
Liver International. 2023;43(3):546-557. © 2023 Blackwell Publishing
