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

Table 2 Overview of combination strategies for human epidermal growth factor receptor 2-positive gastric cancer

Therapeutic category	Regimen/agents	Mechanism of action	Key clinical trials/evidence	Ref.
Targeted + immunotherapy + chemotherapy triplet regimens	Pembrolizumab + trastuzumab + chemotherapy	Pembrolizumab: PD-1 inhibitor, reverses T-cell exhaustion; trastuzumab: Blocks HER2 signaling and induces ADCC; chemotherapy: Induces immunogenic cell death, enhancing tumor antigen presentation	KEYNOTE-811 (phase III): Became the new first-line standard for advanced HER2-positive GC/GEJA, demonstrating superior PFS and OS (median OS: 20.0 months vs 16.8 months)	Ding et al[17]; Wang et al[48]; Cheng et al[49]; Yamashita et al[51]; Li et al[55]; Zhu et al[56]; Yu et al[57]; Yi et al[58]
	Atezolizumab + trastuzumab + XELOX	Atezolizumab: PD-L1 inhibitor, enhances antitumor immunity; trastuzumab and chemotherapy: Provides direct HER2 blockade and tumor cell killing	A phase II randomized trial: In the perioperative setting for locally advanced resectable GC, significantly improved pathologic complete response rate (38% vs 14%)	Peng et al[1]
ADCs	Trastuzumab deruxtecan	HER2-targeted ADC with a topoisomerase I inhibitor payload and a cleavable linker, enabling a potent “bystander killing effect” against heterogeneous tumors	DESTINY-gastric series: DG-04 (phase III): Redefined 2nd-line standard (median OS: 14.7 months vs 11.4 months). DG-01 (phase II): Robust activity in later-line (ORR = 51.3%). DG-03/05: Evaluating 1st-line combinations	Shitara et al[46]; Oaknin et al[59]; Aoki et al[60]; Chen et al[61]; Janjigian et al[62]; Janjigian et al[63]; Shitara et al[64]; Shitara et al[65]; Yamaguchi et al[66]; Peng et al[67]
	Disitamab vedotin	HER2-targeted ADC with the microtubule inhibitor MMAE, enabling precise cytotoxicity and efficacy in HER2-low expressions	Phase I/II trials: Showed promising efficacy in heavily pretreated patients with HER2-overexpressing and HER2-low GC	Chen et al[61]; Xu et al[69]; Peng et al[70]
	Ado-trastuzumab emtansine	HER2-targeted ADC with the maytansinoid payload DM1, utilizing a stable, non-cleavable linker	Phase III trials (e.g., GATSBY): Failed to demonstrate superior survival benefit over standard chemotherapy in GC, limiting its clinical application	Pegram et al[45]; Barfield et al[71]
Investigational ADC agents	A166	A site-specifically conjugated ADC with a uniform drug-antibody ratio (approximately 4), delivering the potent microtubule inhibitor duostatin-5	Early-phase I trials: Showed preliminary antitumor activity in HER2-positive solid tumors (including GC), primarily in breast cancer models to date	Zhang et al[20]; Hu et al[73]; Liu et al[74]; Hu et al[75]
	LCB-ADC	A novel ADC with an optimized cleavable linker and MMAF payload, designed for enhanced tumor-specific payload release and a wider therapeutic window	Preclinical studies: Demonstrated superior potency and efficacy in HER2-high and ado-trastuzumab emtansine-resistant patient-derived xenograft models	Shin et al[21]; Díaz-Rodríguez et al[68]; You et al[72]

ADC: Antibody-drug conjugate; PD-1: Programmed cell death 1; HER2: Human epidermal growth factor receptor 2; PD-L1: Programmed cell death ligand 1; ADCC: Antibody-dependent cellular cytotoxicity; MMAF: Monomethyl auristatin F; MMAE: Monomethyl auristatin E; GEJA: Gastroesophageal junction adenocarcinoma; GC: Gastric cancer; OS: Overall survival; PFS: Progression-free survival; ORR: Objective response rate.