Immune-Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: A Synopsis of Response Rates

Abstract

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. A first-line standard of care, sorafenib results in median overall survival of 12 months in patients with Child-Pugh class A disease and 6 months in patients with Child-Pugh class B disease with objective response rates (ORRs) not exceeding 19%. These low efficacy rates have driven research on alternative therapeutic options, particularly immune-checkpoint inhibitors (ICIs). We reviewed the response rates (estimated by RECIST 1.1 criteria) across patients with advanced HCC treated with ICIs in phase I-IV clinical trials published between December 2012 to December 2020; 17 reports were identified as eligible and included in the quantitative analysis. Within the selected studies, pembrolizumab + lenvatinib reached the highest absolute ORR (36%), with first-line atezolizumab + bevacizumab showing the second highest ORR (27.3%). With regard to second-line therapy, nivolumab + ipilimumab reached an ORR of 32%, and pembrolizumab alone resulted in an ORR of 17% among sorafenib-experienced patients with advanced HCC. In summary, current studies show high response rates of ICIs in patients with advanced HCC. Nonetheless, further studies are required in the second-line setting to further evaluate ICI therapeutic superiority. Finally, it is of particular interest to examine the therapeutic potential of ICIs for patients with decompensated liver disease (Child-Pugh class C), currently not eligible for any systemic therapy. IMPLICATIONS FOR PRACTICE: Immune-checkpoint inhibitors (ICIs) can provide high objective response rates (ORR, estimated with RECIST 1.1. criteria) when used as first-line treatment in advanced hepatocellular carcinoma, particularly pembrolizumab + lenvatinib (ORR 36%) or atezolizumab + bevacizumab (ORR 27.3%). In sorafenib-experienced patients, nivolumab + ipilimumab (ORR 32%) provided the highest ORR among ICI-based regimens. These findings emphasize high therapeutic potential of ICI-based therapies in patients with advanced hepatocellular carcinoma, although further studies are required to further validate and define their role in this context.

Keywords: Atezolizumab; Hepatocellular carcinoma; Ipilimumab; Lenvatinib; Nivolumab; Pembrolizumab; Sorafenib.

Figure 1

Staging of hepatocellular carcinoma and therapeutic options: Overview. Abbreviations: AFP, alpha‐fetoprotein; BCLC, Barcelona Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; TACE, transarterial chemoembolization; UICC, Union for International Cancer Control.

Figure 2

Molecular mechanisms of immune‐checkpoint inhibitors. (A): Activation of immune checkpoints (PD‐1 and CTLA‐4) result in downregulation of the cytotoxic T‐cell response. Binding of PD‐1 with its ligand PD‐L1 expressed by cancer cells or antigen‐presenting cells limits the activation of T cells. CTLA‐4 modulates the same activity via binding to CD80/86 ligands on APCs/cancer cells. (B): In contrast, activation of CD8+ T cells occurs in the presence of immune‐checkpoint inhibitor therapy. Blocking CTLA‐4, PD‐1 with its ligands stimulates activation of PI3K/Akt and MAPK/ERK pathways, stimulating CD8+ T‐cell activation, proliferation, and increased T‐cell survival. Abbreviations: Akt, protein kinase B; APC, antigen‐presenting cell; CTLA‐4, cytotoxic T‐lymphocyte–associated antigen‐4; ERK, extracellular signal‐regulated kinase; LAT, linker for activation of T cells; mAb, monoclonal antibody; MAPK, mitogen‐activated protein kinase; MEK, mitogen‐activated protein kinase kinase; MHC, major histocompatibility complex; mTOR, mammalian target of rapamycin; PD‐1, programmed cell death‐1; PD‐L1, programmed cell death‐1 ligand 1; PI3K, phosphoinositide 3‐kinase; TCR, T‐cell receptor.

Figure 3

PRISMA (Preferred Reported Items for Systematic Reviews and Meta‐Analysis) flowchart of literature search.

Figure 4

Overall response rate among patients with advanced hepatocellular carcinoma treated with immune‐checkpoint inhibitors. Forest plot visualization of ORR among studies included in this review. Studies are separated by the therapeutic line. Abbreviations: 1L, first line; 2L, second line; 1L/2L, studies where immune‐checkpoint inhibitors were used in a mixed cohort of patients; NCT, National Clinical Trial number; ORR, objective response rate.