Systemic treatment of liver cancer: Current status and future perspectives

Table 1 Comparison of core mechanisms of four targeted drugs

Drug	Target of action	Mechanism of action	Main indications	Key clinical data	Common adverse reactions
Sorafenib	VEGFR1-3, PDGFRβ, Raf kinase, KIT, FLT-3	Inhibit angiogenesis (VEGFR/PDGFR), block the Raf/MEK/ERK pathway, inhibit tumor proliferation, and enhance the immune response	Liver cancer, kidney cancer, thyroid cancer	The SHARP study: Median OS was 10.7 months vs 7.9 months (placebo). The Oriental study: In the Asia-Pacific population, the OS was 6.5 months vs 4.2 months	Diarrhea, fatigue, skin allergy, and hypertension
Lenvatinib	VEGFR1-3, FGFR1-4, PDGFRα, RET, KIT	Inhibit angiogenesis through multiple targets (VEGFR/FGFR/PDGFRα), block the proliferation of tumor cells (RET/KIT), and synergistically inhibit the Raf/Mek/Erk pathway	Liver cancer, thyroid cancer, kidney cancer	The REFLECT study: Median OS was 13.6 months vs 12.3 months (Sorafenib)	Hypertension, proteinuria, hand-foot syndrome, gastrointestinal reactions
Cabozantinib	MET, VEGFR1-3, RET, AXL, ROS1, NTRK, KIT	Inhibit the MET pathway (regulating tumor invasion and metastasis), block angiogenesis (VEGFR), inhibit drug resistance-related targets (AXL, ROS1), and regulate the immune microenvironment (reduce regulatory T cells, Treg cells)	Liver cancer, thyroid cancer, kidney cancer, non-small cell lung cancer	The CELESTIAL study: Median OS was 10.2 months vs 8.0 months (placebo)	Diarrhea, fatigue, loss of appetite, hypertension
Donafenib	VEGFR, PDGFR, Raf kinase (structural optimization of deuterated sorafenib)	Deuterium modification improves metabolic stability, inhibits the Raf/MEK/ERK pathway (more potent than sorafenib), suppresses angiogenesis (VEGFR/PDGFR), and improves the tumor immune microenvironment (enhances the efficacy of anti-PD-1)	Unresectable hepatocellular carcinoma (first-line treatment)	The ZGDH3 study: Median OS was 12.1 months vs 10.3 months (sorafenib)	Hand-foot skin reaction, diarrhea, thrombocytopenia

OS: Overall survival; VEGFR1-3: Vascular endothelial growth factor receptor 1-3; PDGFRβ: Platelet-derived growth factor receptor β; Raf kinase: Rapidly accelerated fibrosarcoma kinase; KIT: KIT proto-oncogene, receptor tyrosine kinase; FLT-3: FMS-like tyrosine kinase 3; MEK: Mitogen-activated protein kinase kinase; ERK: Extracellular signal-regulated kinase; FGFR1-4: Fibroblast growth factor receptor 1-4; PDGFRα: Platelet-derived growth factor receptor α; RET: RET proto-oncogene, receptor tyrosine kinase; MET: Mesenchymal-epithelial transition factor, receptor tyrosine kinase; AXL: AXL receptor tyrosine kinase; ROS1: ROS1 proto-oncogene, receptor tyrosine kinase; NTRK: Neurotrophin receptor tyrosine kinase; anti-PD-1: Anti-programmed cell death protein 1 antibody; ZGDH3: Zinc finger DHHC-type containing 3.

Table 2 Correlation between targets and pathogenesis of diseases

Target category	Related signaling pathways	Pathogenesis of the disease	Representative drugs
Angiogenesis targets	VEGF/VEGFR, PDGFR, FGFR	Excessive tumor angiogenesis promotes tumor growth and metastasis	Sorafenib, lenvatinib, donafenib
Proliferation-related targets	Raf/MEK/ERK, MET, RET	Abnormally activated proliferation signals (such as Raf mutations and MET amplifications) drive tumor progression	Sorafenib, cabozantinib, donafenib
Targets related to drug resistance/metastasis	AXL, ROS1, NTRK	Mediate tumor drug resistance (such as resistance to EGFR inhibitors) and metastatic spread	Cabozantinib
Regulation of immune microenvironment	STAT3, PD-1 cooperative pathway	The immunosuppressive state in the tumor microenvironment (for example, the activation of STAT3 inhibits the activity of immune cells)	Donafenib, sorafenib

PD-1: Programmed cell death protein 1; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; Raf kinase: Rapidly accelerated fibrosarcoma kinase; MEK: Mitogen-activated protein kinase kinase; ERK: Extracellular signal-regulated kinase; FGFR: Fibroblast growth factor receptor; RET: RET Proto-oncogene, receptor tyrosine kinase; MET: Mesenchymal-epithelial transition factor, receptor tyrosine kinase; AXL: AXL receptor tyrosine kinase; ROS1: ROS1 proto-oncogene, receptor tyrosine kinase; NTRK: Neurotrophin receptor tyrosine kinase; PDGFR: Platelet-derived growth factor receptor; EGFR: Epidermal growth factor receptor; STAT3: Signal transducer and activator of transcription 3.

Table 3 Comparison of core mechanisms of three immunotherapy drugs

Drug	Target of action	Mechanism of action	Main indications	Key clinical data	Common adverse reactions
Pembrolizumab	PD-1	Block the binding of PD-1 to its ligands PD-L1/PD-L2, relieve the immunosuppression of T cells, activate tumor-specific T cells, enhance the ability of the immune system to attack tumors, and restore the immune surveillance function through the inhibition of immune checkpoints	Melanoma, non-small cell lung cancer, head and neck cancer, gastric cancer, liver cancer, etc.	KEYNOTE-394: The median OS with pembrolizumab was 14.6 months, the 2-year OS rate reached 34.3%	Immune-related adverse reactions (pneumonia, colitis, thyroiditis), fatigue, skin rash
Nivolumab	PD-1	It binds to PD-1, blocks the PD-L1/PD-L2 signaling pathway, enhances the proliferation of T cells and the release of cytokines. When combined with CTLA-4 inhibitors, it can synergistically enhance the anti-tumor effect	Melanoma, non-small cell lung cancer, gastric cancer, renal cancer, etc.	CheckMate-040: The objective response rate (ORR) in the dose escalation cohort: 15%. ATTRACTION-4: The median OS for gastric cancer patients is 26.6 months	Immune-mediated pneumonia, hepatitis, endocrine diseases, infusion reactions
Ramucirumab	VEGFR2	It specifically binds to VEGFR2, inhibits VEGF-A-mediated angiogenesis, reduces the blood supply to tumors, and suppresses tumor growth and metastasis	Gastric cancer, liver cancer, non-small cell lung cancer, colorectal cancer	REACH-2 trial: The median overall survival for liver cancer patients with AFP ≥ 400 ng/mL is 8.5 months (compared with 7.3 months for the placebo group)	Hypertension, proteinuria, bleeding risk, gastrointestinal reactions

PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; PD-L2: Programmed death-ligand 2; OS: Overall survival; ORR: Objective response rate; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; VEGFR2: Vascular endothelial growth factor receptor 2; AFP: Alpha-fetoprotein.

Table 4 Correlation between targets and pathogenesis of the disease

Target category	Related signaling pathways	Pathogenesis of the disease	Representative drugs
Immune checkpoints	PD-1/PD-L1	Tumor cells evade immune surveillance and inhibit the activity of T cells through the overexpression of PD-L1	Pembrolizumab, nivolumab
Angiogenesis targets	VEGF/VEGFR2	Abnormal proliferation of tumor blood vessels promotes nutrient supply and metastasis	Ramucirumab
Synergistic treatment targets	CTLA-4 (combined with PD-1 inhibitors)	Dual inhibition of immune checkpoints enhances T cell activation and tumor infiltration	Nivolumab + ipilimumab

PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; VEGF: Vascular endothelial growth factor; VEGFR2: Vascular endothelial growth factor receptor 2; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4.

Table 5 Steps of systematic treatment for liver cancer and corresponding treatment procedures

Treatment stage	Type of recommendation	Recommended regimen	Applicable population	Evidence level
First-line treatment	Immune + anti-angiogenesis regimen (preferred)	Atezolizumab + bevacizumab	For unresectable patients with Child-Pugh class A who have not received previous systemic treatment	IA
		Sintilimab + bevacizumab biosimilar	For unresectable or metastatic liver cancer patients who have not received previous systemic anti-tumor treatment	IA
	Single-agent targeted therapy	Lenvatinib	For advanced liver cancer patients with unresectable liver function of Child-Pugh class A	IA
		Donafenib	For unresectable liver cancer patients who have not received previous systemic anti-tumor treatment	IA
		Sorafenib	For patients with liver function of Child-Pugh class A/B	IA
Second-line treatment	Targeted therapy	Cabozantinib	Hepatocellular carcinoma patients with Child-Pugh class A liver function who have previously received sorafenib treatment and failed	IA
		Ramucirumab	Treatment of hepatocellular carcinoma patients who have previously received sorafenib treatment and have an AFP level of ≥ 400 ng/mL	IA
	Single-agent immunotherapy	Pembrolizumab	Hepatocellular carcinoma patients who have previously received sorafenib or chemotherapy containing oxaliplatin	IA
		Nivolumab	Hepatocellular carcinoma patients who have progressed after previous sorafenib treatment or cannot tolerate sorafenib	IA
	Combination of dual immunotherapies	Nivolumab + ipilimumab	Hepatocellular carcinoma patients who have progressed after previous sorafenib treatment or cannot tolerate sorafenib	IA

AFP: Alpha-fetoprotein.