Strategic integration of immunotherapy with chemotherapy, radiotherapy, and targeted therapy in gastric cancer management: A systematic review

Table 1 Summary of all combinational targeted therapy in gastric cancer[3,90-93]

Treatment combination	Mechanistic rationale	Key clinical trials	Main findings	Outcomes
Targeted therapy in GC	Targeted therapies aim to interfere with specific molecules involved in tumor growth and progression, such as HER2, VEGF, and EGFR, offering a more precise approach to cancer treatment	ToGA (trastuzumab for HER2-positive) NCT01041404. RAINBOW (ramucirumab for VEGFR2-positive) NCT02898077. REAL-3 (panitumumab for EGFR-positive NCT00824785	ToGA showed significant improvement in OS for HER2-positive GC patients treated with trastuzumab plus chemotherapy. RAINBOW demonstrated an increase in OS with Ramucirumab plus chemotherapy in VEGFR2-positive patients. REAL-3 did not show a survival benefit with the addition of panitumumab to chemotherapy	Improved survival in targeted patient populations. Potential for more personalized cancer treatment
Radiotherapy + targeted therapy	Targeted therapy can sensitize cancer cells to radiation by inhibiting DNA repair mechanisms, enhancing cell cycle control, or altering tumor oxygenation, thereby increasing the efficacy of radiotherapy	RTOG 1010 (for HER2-positive GC) NCT01196390. ARTIST-II (for adjuvant setting) NCT01761461	RTOG 1010 evaluated the addition of trastuzumab to chemoradiation for HER2-positive esophago GC, showing trends toward improved outcomes. ARTIST-II investigated adjuvant chemoradiotherapy plus targeted therapy in locally advanced GC, showing improved disease-free survival in certain subgroups	Potential improvement in locoregional control and disease-free survival, especially in genetically selected patient populations
Immunotherapy + chemotherapy	The combination exploits chemotherapy's ability to increase tumor antigenicity and reduce immunosuppressive elements in the tumor microenvironment, thereby enhancing the effectiveness of immunotherapy	CheckMate-649 NCT02872116. KEYNOTE-062 NCT02494583	CheckMate-649 showed a significant improvement in OS and PFS with the combination of nivolumab and chemotherapy in patients with advanced GC. KEYNOTE-062 evaluated the efficacy of pembrolizumab plus chemotherapy, demonstrating a durable response in a subset of patients with PD-L1-positive tumors	Increased OS and PFS in selected patient populations. Enhanced response rates, particularly in PD-L1-positive patients

EGFR: Epidermal growth factor receptor; GC: Gastric cancer; HER2: Human epidermal growth factor receptor 2; OS: Overall survival; PD-L1: Programmed death-ligand 1; PFS: Progression-free survival; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor.

Table 2 Predictive biomarkers in gastric cancer[119-122]

Biomarker	Clinical relevance	Alterations	Diagnosis	Targeted agents
HER2	Overexpressed in 15%-20% of GCs; associated with poor prognosis and aggressive disease	Gene amplification, protein overexpression	IHC, FISH	Trastuzumab, lapatinib
VEGF	Overexpression associated with angiogenesis and tumor progression	Protein overexpression	IHC, ELISA for serum VEGF levels	Bevacizumab, ramucirumab
MET	Amplification and overexpression linked to poor prognosis and aggressive behavior	Gene amplification, protein overexpression	IHC, FISH, NGS	MET inhibitors (e.g., crizotinib, onartuzumab)
PIK3CA	Mutations found in a subset of GCs; associated with activation of the PI3K/AKT pathway	Gene mutations	NGS, PCR-based mutation testing	PI3K inhibitors (e.g., buparlisib, alpelisib)
PD-L1	Linked to immune evasion by tumor cells; higher expression correlates with better response to immunotherapy	Protein overexpression	IHC	Pembrolizumab, nivolumab
CLDN18-ARHGAP26/ARHGAP	Fusions associated with a distinct subtype of GC; potential sensitivity to targeted therapy	Gene fusion	RNA sequencing, NGS	Ongoing research for specific targeted therapies
MSI-H/dMMR	Present in 15%-20% of GCs; associated with better prognosis and response to immunotherapy	Loss of mismatch repair protein function	PCR-based MSI testing, IHC for MMR proteins (MLH1, MSH2, MSH6, PMS2)	Pembrolizumab
FGFR2	Amplification seen in 5%-10% of GCs; linked to poor prognosis	Gene amplification	FISH, NGS	FGFR inhibitors (e.g., AZD4547, FPA144)
EBV	Found in approximately 10% of GCs; distinct molecular subtype with unique immune microenvironment	EBER positivity	ISH for EBER	Immunotherapy (ongoing research)
KRAS	Mutations present in a small percentage of GCs; linked to resistance to anti-EGFR therapies	Gene mutations	NGS, PCR-based mutation testing	Investigational KRAS inhibitors (e.g., AMG 510)

EBER: Epstein-Barr virus-encoded RNA; EBV: Epstein-Barr virus; EGFR: Epidermal growth factor receptor; FGFR2: Fibroblast growth factor receptor 2; FISH: Fluorescence in situ hybridization; GC: Gastric cancer; HER2: Human epidermal growth factor receptor 2; IHC: Immunohistochemistry; ISH: In situ hybridization; MET: Mesenchymal epidermal transition factor; MSI-H/dMMR: Microsatellite instability-high/mismatch repair deficient; NGS: Next-generation sequencing; PD-L1: Programmed death-ligand 1; VEGF: Vascular endothelial growth factor.