Advancing human epidermal growth factor receptor 2-positive gastric cancer therapy: Toward targeted immunotherapy and antibody-drug conjugates

Table 1 Overview of traditional human epidermal growth factor receptor 2-positive gastric cancer treatment strategies

Therapeutic category	Regimen/agents	Mechanism of action	Limitations and challenges	Key clinical evidence
Traditional chemotherapy	Fluorouracil + platinum/taxanes	Interferes with DNA synthesis or cell division	Limited survival benefit; low response rates; short duration of response; lack of specificity; significant adverse effects	Multiple phase III trials
Trastuzumab + chemotherapy	Trastuzumab + chemotherapy (various combinations)	Blocks HER2 signaling; mediates ADCC; suppresses angiogenesis	Enhanced benefit in HER2-high; limited efficacy in HER2-low; primary/acquired resistance; HER2 heterogeneity affects efficacy; first-line: Median OS plateaued at 13-16 months; lack of breakthrough improvements; limited survival benefit PFS; second-line: Cross-line trastuzumab failed to improve PFS; lack of HER2 stratification; most patients eventually develop resistance	TOGA[11,14-16,32,33,37,38]
Other HER2-targeted agents	Pertuzumab	Forms dual blockade with trastuzumab	Failed primary endpoints in GC phase III; divergent responses between GC and breast cancer	JOSHUA, MARIANNE[40]
	Small-molecule TKIs	Inhibits HER2 intracellular tyrosine kinase activity	Lapatinib improved ORR but not OS; lapatinib + trastuzumab not superior to monotherapy; different HER2 expression patterns; more complex signaling pathways; unique tumor microenvironment	TYTAN, BO15970[32,38,40,41]

HER2: Human epidermal growth factor receptor 2; TKI: Tyrosine kinase inhibitor; ADCC: Antibody-dependent cellular cytotoxicity; OS: Overall survival; PFS: Progression-free survival; GC: Gastric cancer; ORR: Objective response rate.