Molecularly guided therapy in gastrointestinal malignancies: From established targets to resistance and emerging precision strategies

Table 4 Molecularly targeted therapies in gastric and gastroesophageal junction adenocarcinoma

Molecular target/pathway	Biomarker/alteration	Representative therapy	Current clinical role	Evidence grade	Major resistance mechanisms/emerging strategies	Representative sources
HER2	HER2 overexpression and/or amplification, assessed using validated IHC and ISH-based methods	Trastuzumab + platinum/fluoropyrimidine chemotherapy ± pembrolizumab; T-DXd	Established first-line HER2-directed therapy based on ToGA and KEYNOTE-811. T-DXd is an established treatment option after trastuzumab-based therapy based on DESTINY-Gastric01	A	HER2 heterogeneity or loss, MET/EGFR/FGFR bypass signaling, PI3K pathway activation, and clonal evolution. HER2-low disease, next-generation ADCs, bispecific antibodies, CAR-T approaches, ctDNA-guided monitoring, and combination immunotherapy remain under investigation	Bang et al[72]; Shitara et al[74]; Nakamura et al[95]; Janjigian et al[73]
VEGFR-2	Not biomarker selected	Ramucirumab ± paclitaxel	Established second-line therapy based on REGARD and RAINBOW	A	Adaptive angiogenic resistance, alternative pro-angiogenic pathway activation, and vascular remodeling. Combinations with chemotherapy and immune checkpoint inhibitors are under investigation	Fuchs et al[77]; Wilke et al[78]; Nakamura et al[95]
VEGFR-2	Not biomarker selected	Apatinib	Later-line anti-angiogenic therapy, with regulatory approval in China	B	Alternative angiogenic pathway activation and adaptive vascular signaling	Wang et al[96]; Yuan et al[97]
VEGFR1–3	Not biomarker selected	Fruquintinib	Emerging anti-angiogenic therapy under clinical evaluation in gastric and GEJ cancer	C	Adaptive angiogenesis and pathway redundancy; combination approaches remain investigational	Wang et al[96]
CLDN18.2	CLDN18.2-positive, generally HER2-negative disease	Zolbetuximab + chemotherapy	Established first-line targeted therapy for appropriately selected CLDN18.2-positive, HER2-negative advanced gastric or GEJ adenocarcinoma based on SPOTLIGHT and GLOW	A	Heterogeneous antigen expression, variable assay thresholds, antigen loss, and treatment-related gastrointestinal toxicity. CLDN18.2 ADCs, bispecific antibodies, CAR-T therapy, and improved biomarker classification are under investigation	Shitara et al[74]; Nakamura et al[95]; Derks and van Laarhoven[88]
FGFR2b	FGFR2b overexpression	Bemarituzumab + chemotherapy	Clinical evidence from the phase II FIGHT study; further validation and treatment positioning remain necessary	B	FGFR2b expression heterogeneity, pathway bypass, and uncertainty regarding optimal biomarker thresholds. Earlier-line treatment and combination strategies are under investigation	Wainberg et al[100]; Yuan et al[97]
MET	MET amplification or other activating MET alterations	MET inhibitors	Early clinical or investigational development; no established routine role	C	Biomarker heterogeneity, pathway redundancy, and limited predictive consistency. Biomarker refinement and combination targeted therapy are under investigation	Wang et al[96]; Hsu et al[98]
HER2	HER2-positive refractory disease	Disitamab vedotin	Clinical activity reported in selected HER2-positive disease, with ongoing development	B	HER2 heterogeneity, antigen loss, payload resistance, and altered intracellular trafficking. ADC-based strategies are being developed to improve activity in heterogeneous or treatment-resistant disease	Shao et al[75]; Zhang et al[99]
HER2	HER2-positive disease	Zanidatamab; tucatinib-based therapy; pyrotinib	Emerging or region-specific clinical evidence; not uniformly established across gastric/GEJ cancer treatment settings	C	HER2 heterogeneity, downstream pathway reactivation, and acquired resistance. Dual or multi-agent HER2 blockade and treatment-sequencing strategies remain under investigation	Hu et al[68]; Shao et al[75]; Zhang et al[99]
KRAS/PI3K and related signaling pathways	KRAS or PI3K pathway alterations	Selective pathway inhibitors and molecularly matched combinations	Early clinical or investigational development	C	Pathway redundancy, feedback activation, and compensatory signaling. Combination pathway inhibition requires biomarker refinement and prospective validation	Yuan et al[97]; Kawakami[93]
VEGF/VEGFR and immune pathways	Not biomarker selected	VEGF/VEGFR inhibitor + immune checkpoint inhibitor	Investigational strategies with preliminary activity	C	Uncertain biomarker selection, adaptive angiogenesis, immune resistance, and overlapping toxicity. Optimal sequencing and combination partners remain under investigation	Yuan et al[97]; Kawakami[93]
VEGF + PD-1/PD-L1	Not biomarker selected	VEGF/PD-1 or PD-L1 bispecific antibodies	Early clinical investigation	C	Requires prospective validation of efficacy, safety, biomarker selection, and treatment sequencing	Yuan et al[97]; Kawakami[93]
MET/EGFR/FGFR/PI3K	Molecularly selected or pathway-driven disease	Combination targeted strategies	Investigational	C	Bypass signaling, clonal evolution, pathway redundancy, and intratumoral heterogeneity	Nakamura et al[95]

Evidence grading: Grade A, randomized phase III evidence and/or established standard-of-care treatment; Grade B, prospective phase II evidence or substantial clinical evidence; Grade C, early-phase, retrospective, or otherwise limited clinical evidence; Grade D, preclinical or experimental evidence. Evidence grades reflect the maturity and clinical validation of the available evidence and do not directly indicate the magnitude of treatment benefit. ADC: Antibody–drug conjugate; CAR-T: Chimeric antigen receptor T-cell therapy; CLDN18.2: Claudin 18.2; ctDNA: Circulating tumor DNA; EGFR: Epidermal growth factor receptor; FGFR: Fibroblast growth factor receptor; FGFR2b: Fibroblast growth factor receptor 2b; GC/GEJ: Gastric/gastroesophageal junction; HER2: Human epidermal growth factor receptor 2; MET: Mesenchymal–epithelial transition factor; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; PI3K: Phosphatidylinositol-3-kinase; T-DXd: Trastuzumab deruxtecan; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor.