Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma

Abstract

Immune checkpoint inhibitor (ICI) therapy targeting anti-programmed cell death-1 (anti-PD-1) or its ligand (anti-PD-L1) is the backbone of numerous combination regimens aimed at improving the objective response and survival of patients with hepatocellular carcinoma (HCC). Clinical trials of immunooncology regimens in other cancer types have shed light on issues of study design, including how to choose candidate regimens based on early-phase trial results, statistical considerations in trials with multiple primary endpoints, and the importance of predictive biomarkers. In this review, the updated data from early-phase trials of combination immunotherapy for HCC are summarised. Since the most extensively tested combination regimens for advanced HCC comprise anti-PD-1/anti-PD-L1 agents plus antiangiogenic agents, the relative benefit and antitumor mechanism of antiangiogenic multikinase inhibitors versus specific VEGF/VEGFR inhibitors are discussed. Other critical issues in the development of combination immunotherapy, including optimal management of immune-related adverse events and the value of ICI therapy in combination with locoregional treatment for HCC, are also explored.

Cytotoxic immune cell-based immunotherapy for hepatocellular carcinoma

“…Nivolumab and pembrolizumab gained approval for treatment of advanced HCC based on encouraging results from phase I/II studies in advanced HCC patients with objective response rates of 17%-20% [70,71] . However, results from two phase III clinical studies did not reveal statistically significant improvement in survival benefit [72,73] . There are several ongoing trials with monoclonal antibodies against PD-1, such as nivolumab, pembrolizumab, tislelizumab, and camrelizumab, in HCC patients, either as monotherapy or in combination with other treatments.…”

“…As with other cancers, the combination regimens of nivolumab and ipilimumab led to grade 3-4 treatment-related adverse events occurring in 37.7% patients, which were more frequently observed with combination regimens than with single-agents, especially in patients who received higher dosages of ipilimumab. However, most of the adverse events were manageable with timely recognition, steroid treatment, and discontinuation of immunotherapy, with a very low rate of liver failure [73,85,86] .…”

Milestones in the pathogenesis and management of primary liver cancer

“…78,79 Faivre et al summarise the scientific rationale behind this combination strategy and the promising data from early-phase trials of combination therapy for HCC, 77 while Cheng et al further elaborate on recent advances in the development of predictive biomarkers, and explore the immune-related antitumour mechanisms of multikinase inhibitors (independent of their anti-VEGFR effects). 80 They also discuss the challenges of further development of different immunotherapy-based combination therapies, including selection and prioritisation of regimens based on limited preclinical and clinical data, and evaluation and management of adverse events. 80,81 Curative treatments of intrahepatic cholangiocarcinoma iCCA is a highly lethal hepatobiliary neoplasm whose incidence is increasing.…”

“…80 They also discuss the challenges of further development of different immunotherapy-based combination therapies, including selection and prioritisation of regimens based on limited preclinical and clinical data, and evaluation and management of adverse events. 80,81 Curative treatments of intrahepatic cholangiocarcinoma iCCA is a highly lethal hepatobiliary neoplasm whose incidence is increasing. This rare malignancy has recently received considerable clinical and investigative attention.…”

An apoptosis-related gene signature for the prognosis of hepatocellular carcinoma

“…And thus, the 5-year survival rate for HCC patients was found to be less than 12% (4). Although existing drugs such as sorafenib and immune checkpoint inhibitors could help improve patients' prognoses, the effect is still unsatisfactory (5). Therefore, more sensitive biomarkers are earnestly required for the early detection of HCC.…”