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.