Recent advances in systemic therapy for hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors in the world. Therapeutic options for advanced HCC are limited. Systemic treatment, especially with conventional cytotoxic drugs, is usually ineffective. For more than a decade, sorafenib has been the only systemic drug that has been proven to be clinically effective for treating advanced HCC. However, over the past three years, the rapid progress of molecular targeted therapies has dramatically changed the treatment landscape for advanced HCC. Immune checkpoint therapies are now being incorporated into HCC therapies, and their combination with molecular targeted therapy is emerging as a tool to enhance the immune response. In this review, we summarize the development and progress of molecular targeted agents and immunotherapies in HCC.

Keywords: Combination; Hepatocellular carcinoma; Immunotherapies; Molecular targeted therapy.

Fig. 1

Worldwide Epidemiology of Liver Cancer in 2020. Data source: GLOBOCAN 2020 (http://gco.iarc.fr/). (A) The estimated age-standardized incidences of liver cancer worldwide in 2020. (B) Bar charts of the estimated number of incident cases worldwide. (C) Bar charts of the estimated number of deaths worldwide. (D) WHO estimated the number of deaths from liver cancer from 2020 to 2040

Fig. 2

Currently approved drugs for advanced HCC and timeline of pivotal clinical trials. The lines along the timeline indicate the time from the actual study start to FDA approval. The red boxes represent first-line therapies, and the green boxes represent second-line therapies

Fig. 3

Mechanism of combination therapies. (A) Complementary mechanisms of PD-1/PD-L1 and CTLA-4 inhibitors. Presentation of tumor-associated antigen by the major histocompatibility complex (MHC) expressed by APCs results in the release of an activation signal in combination with a co-stimulatory signal via the B7-CD28 pathway, leading to activation of T cells in the lymph node; B7 also binds to CTLA-4 with a higher affinity than that of CD28, in which case T cells cannot be activated. PD-1 on T cells inhibits antigen-specific T cell activation by interacting with its ligands PD-L1 and PD-L2. Immune escape is induced through the PD-1/PD-L1 axis, as well as the B7/CTLA-4 axis. This figure was adapted from Kudo, et al. [44]. (B) VEGF modulates the immunosuppressive TME, and TKIs restore this suppressive effect. Red arrows represent promotion effects. APCs, antigen presenting cells; CTL, cytotoxic T lymphocyte; CTLA-4, cytotoxic T-lymphocyte antigen 4; iDC, immature dendritic cell; matDC, mature dendritic cell; MDSCs, myeloid-derived stem cells; PD-1, programmed cell death protein 1; PD-L1, programmed cell death-ligand 1; TAMs, tumor-associated macrophages; TME, tumor microenvironment; Tregs, regulatory T cells. Note: This is an open access article distributed under the Creative Commons Attribution License that permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0)

Fig. 4

Signaling pathways and molecular targeted therapies for HCC. * represents monotherapies approved by the FDA, ** represents agents as a component of combination therapy approved by the FDA. This figure was modified from Mossenta, et al. [10]. Note: This is an open access article distributed under the Creative Commons Attribution License that permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0)

Fig. 5

Suggested systemic treatment strategies for advanced HCC. This algorithm is derived from recommendations of “Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline” [166]