Perioperative immunotherapy in gastric cancer in the spotlight

Table 1 Adjuvant therapy: Summary of key randomized trials evaluating adjuvant therapy strategies in gastric and gastroesophageal junction adenocarcinoma

Trial name	Disease subtype	Strategy	DFS	OS
INT-0116 (SWOG 9008) (2001/2012)	G/GEJ adenocarcinoma	Adjuvant CRT vs observation	10-year median DFS: 27 months (CRT) vs 19 months	10-year median OS: 35 months (CRT) vs 27 months
			HR: 1.51 (1.25-1.83)	HR: 1.32 (1.10-1.60)
			P < 0.001	P = 0.0046
CLASSIC trial (2012/2014)	Gastric adenocarcinoma	Adjuvant CT (CAPOX) vs observation	5-year DFS: 68% (CAPOX) vs 53%	5-year OS: 78% (CAPOX) vs 69%
			HR: 0.58 (0.47-0.72)	HR: 0.66 (0.51-0.85)
			P < 0.0001	P = 0.0015
ARTIST trial (2012/2015)	Mostly gastric adenocarcinoma (few GEJ)	Adjuvant CT vs adjuvant CRT	3-year DFS: 78.2% (CRT) vs 74.2% (CT)	5-year OS: 75% (CRT) vs 73% (CT)
			P = 0.0862
			Subgrup with node metastasis 3-year DFS
			77.5% (CRT) vs 72.3% (CT)
			HR: 0.68 (0.47-0.99)	HR: 1.13 (0.77-1.64)
			P = 0.0471	P = 0.52
ARTIST 2 trial (2021)	Gastric adenocarcinoma only and node positive	Adjuvant	3-year DFS: 64.8% (S-1), 74.3% (SOX), 72.8% (SOXRT)	No OS data so far (secondary endpoint)
		S-1	HR S-1 vs SOX: 0.692, P = 0.042
			HR S-1 vs SOXRT: 0.724, P = 0.074
		SOX vs SOXRT	No difference was found between SOX and SOXRT (HR 0.971, P = 0.879)

DFS: Disease-free survival; OS: Overall survival; G/GEJ: Gastric and gastroesophageal junction; CRT: Chemoradiotherapy; HR: Hazard ratio; CT: Chemotherapy; CAPOX: Capecitabine, oxaliplatin, docetaxel; S-1: Oral 5-fluorouracil; SOX: S-1 and oxaliplatin; SOXRT: S-1 and oxaliplatin plus chemoradiotherapy.

Table 2 Neoadjuvant therapy: Overview of pivotal clinical trials investigating neoadjuvant therapy in gastroesophageal cancers

Trial name	Disease subtype	Strategy	R0 resection rate	OS
EORTC trial (2010)	G/GEJ adenocarcinoma	Neoadjuvant CT vs surgery	81.9% (CT) vs 66.7%; P = 0.036	Median OS not improved
			pCR: 7.1% (CT)	HR OS: 0.84 (0.52-1.35); P = 0.466
CROSS trial (2012)	Mostly distal esophagus (58%)	Neoadjuvant CRT vs surgery	92% (CRT) vs 69%	Median OS: 49.4 months (CRT) vs 24.0 months
	Mostly adenocarcinoma (75%)		pCR: 29% (CRT)	HR OS: 0.657 (0.495-0.871); P = 0.003

R0: Complete resection with no tumor within 1mm; OS: Overall survival; G/GEJ: Gastric and gastroesophageal junction; CRT: Chemoradiotherapy; HR: Hazard ratio; CT: Chemotherapy; pCR: Complete pathological response.

Table 3 Perioperative therapy: Landmark studies assessing perioperative therapy in gastric and gastroesophageal junction adenocarcinoma

Trial name	Disease subtype	Strategy	R0 resection rate	OS
MAGIC (2006)	G/GEJ adenocarcinoma	Perioperative ECF vs surgery	79.3% (ECF) vs 70.3%; P = 0.03	5-year OS: 36.3% (ECF) vs 23%
				HR: 0.75 (0.60-0.93); P = 0.009
FFCD 9703/ACCORD (2011)	G/GEJ adenocarcinoma	Perioperative 5-FU/cisplatin vs sugery	84% (5-FU/cisplatin) vs 74%; P = 0.04	5-year OS: 38% (5-FU/cisplatin) vs 24%
				HR OS: 0.69 (0.5-0.95); P = 0.02
CRITICS (2018)	G/GEJ adenocarcinoma	Perioperative CT vs perioperative CT + postoperative radiotherapy	80% (CT) vs 82% (CT + RDT)	Median OS: 43 months vs 37 months HR 1.01 (0.84-1.22), P = 0.9
FLOT4-AIO (2019)	G/GEJ adenocarcinoma	Perioperative FLOT vs ECF/ECX	85% (FLOT) vs 78% (ECF/ECX); P = 0.0162	Median OS: 50 months vs 35 months
				HR 0.77 (0.63-0.94), P = 0.012
ESOPEC (2024)	GEJ adenocarcinoma	Perioperative FLOT vs preoperative-CRT	94.3% (FLOT) vs 95% (CRT)	3-year OS: 57.4% (FLOT) vs 50.7% (CRT) HR: 0.7 (0.53-0.92), P = 0.01
				5-year OS: 50.6% (FLOT) vs 38.7% (CRT)
			pCR: 16.7% (FLOT) vs 10.1% (CRT)	Median OS: 66 months (FLOT) vs 37 months (CRT)
TOPGEAR	G/GEJ adenocarcinoma	Preoperative CRT + perioperative CT vs perioperative CT	No R0 difference (92%)	Median OS: 46 months (CRT) vs 49 months (CT)
			pCR: 17% (CRT) vs 8% (CT)	HR: 1.05 (0.83-1.31)
RESOLVE (2021)	G/GEJ adenocarcinoma	Perioperative SOX vs	93% (perioperative SOX) vs 88% (adjuvant SOX) vs 87% (adjuvant CAPOX) P = 0.075	No OS data
		Adjuvant SOX vs adjuvant CAPOX	pCR: 19% (perioperative SOX) vs 14% (adjuvant SOX)
RESONANCE (2024)	G/GEJ adenocarcinoma	Perioperative SOX vs adjuvante SOX	94.9% (perioperative SOX) vs 83.7% (adjuvant SOX), P < 0.0001	No OS data
			pCR: 22.3%
AIO/CAO STO 0801 (2018)	GEJ adenocarcinoma	Perioperative ECX ± Pa	No difference in R0 resection rate	No difference in OS: 49% (ECX + Pa) vs 62% (ECX)
			80% (ECX + Pa) vs 82% (ECX)	HR: 1.37 (0.84-2.25), P = 0.2
HERFLOT (2014/2023)	HER2 + G/GEJ adenocarcinoma	Perioperative FLOT ± T	Preliminary data	Preliminary data
			R0 ressection rate: 92.9%	3-year OS: 82.1%
			pCR: 21.4%
PETRARCA (2022)	HER2 + G/GEJ adenocarcinoma	Perioperative FLOT ± T ± Pe	The trial was closed prematurely	The trial was closed prematurely
			R0 ressection rate: 90% (FLOT) vs 93% (FLOT + T + Pe)	Median OS not reached
			pCR: 12% (FLOT) vs 35% (FLOT + T + Pe)	HR: 0.56, P = 0.24

R0: Complete resection with no tumor within 1mm; OS: Overall survival; G/GEJ: Gastric and gastroesophageal junction; ECF: Epirubicin, cisplatin, and fluorouracil; HR: Hazard ratio; CT: Chemotherapy; RT: Radiotherapy; FLOT: Fluorouracil, leucovorin, oxaliplatin, docetaxel; 5-FU: 5-fuorouracil; RDT: Radiotherapy ; ECX: Epirubicin, cisplatin, capecitabine; CRT: Chemoradiotherapy; pCR: Complete pathological response; Pa: Panitumumab; Pe: Pertuzumab; T: Trastuzumab; SOX: S-1 and oxaliplatin; CAPOX: Capecitabine, oxaliplatin, docetaxel.

Table 4 Perioperative immunotherapy: Emerging data on perioperative immunotherapy in gastric and gastroesophageal junction adenocarcinoma

Trial name	Disease subtype	Strategy	pCR rate	EFS
GASPAR (2022)	G/GEJ adenocarcinoma	Perioperative FLOT + spartalizumab	Early data: Major response rate of 50%	Not reported yet
DRAGON (2024)	G/GEJ adenocarcinoma	Perioperative SOX ± camrelizumab + rivoceranib	18.3% (SOX + RC) vs 5.0% (SOX)	Not reported yet
			OR: 4.5; P < 0.001
VESTIGE (2020/2025)	G/GEJ adenocarcinoma	Adjuvant Ipi/Nivo vs adjuvant CT after neoadjuvant CT	Not an endpoint	11.4 months (Ipi/Nivo) vs 20.8 months (CT)
				HR: 1.55 (1.07-2.25); P = 0.99
ATTRACTION-5 (2024)	G/GEJ adenocarcinoma	Adjuvant CT (CAPOX or S-1) ± nivolumab	Not an endpoint	3-year RFS: 68.4% (nivolumab) vs 65.3% (CT)
				HR: 0.9 (0.69-1.18); P = 0.44
KEYNOTE-585 (2023)	G/GEJ adenocarcinoma	Perioperative CT (cisplatin-based or FLOT) ± pembrolizumab	12.9% (CT + pembrolizumab) vs 2.0% (CT)	44.4 months (CT + pembrolizumab) vs 25.3 months (CT)
			P < 0.00001	HR: 0.81 (0.67-0.99); P = 0.0198
			For dMMR/MSI: 38.1%	Did not meet the threshold for statistical significance (P = 0.0178)
DANTE (2024)	G/GEJ adenocarcinoma	Perioperative FLOT ± atezolizumab	24% (FLOT + atezolizumab) vs 15% (FLOT); P = 0.032	No data
			For CPS ≥ 10: 33% vs 12%
			For dMMR/MSI: 63% vs 27%
MATTERHORN (2024/2025)	G/GEJ adenocarcinoma	Perioperative FLOT ± durvalumab	19.2% (FLOT + durvalumab) vs 7.2% (FLOT)	2-year EFS: 67.4% vs 58.2% HR: 0.71 (0.58-0.86)
			RR: 2.69, (1.86-3.9), P < 0.00001	The difference between the groups in OS has not reached statistical significance

pCR: Complete pathological response; EFS: Event-free survival; G/GEJ: Gastric and gastroesophageal junction; FLOT: Fluorouracil, leucovorin, oxaliplatin, docetaxel; SOX: S-1 and oxaliplatin; RC: Rivoceranib + camrelizumab; OR: Odds ratio; Ipi/Nivo: Ipilimumab + nivolumab; CT: Chemotherapy; CAPOX: Capecitabine, oxaliplatin, docetaxel; RFS: Relapse-free survival; HR: Hazard ratio; CPS: Combined positive score; dMMR: Deficient mismatch repair; MSI: Microsatellite instability; EFS: Event-free survival; OS: Overall survival.

Table 5 Biomarkers relevant to the management of gastric and gastroesophageal junction cancer

Biomarker	Description	Predictive/clinical implication	Current or potential application
PD-L1 (CPS)	Programmed death-ligand 1 expression in tumor and immune cells (CPS ≥ 1, ≥ 5, ≥ 10)	Higher response rates to ICIs	Used in metastatic setting; under evaluation perioperatively
MSI-H/dMMR	Microsatellite instability-high or mismatch repair deficiency	Strong predictor of response to ICIs; pCR > 50% in some trials	Approved in advanced setting; perioperative trials ongoing
EBV+ tumors	Epstein–Barr virus-associated gastric cancers (about 10% of cases)	Inflammatory microenvironment; often high PD-L1 expression and immune cell infiltration	Investigational use; potential future biomarker
TMB	High number of mutations per megabase of tumor DNA	Associated with increased neoantigen load and ICI responsiveness	Emerging biomarker; no standard use yet
ctDNA	Circulating tumor DNA detectable in plasma	May identify minimal residual disease. Early predictor of recurrence risk	Investigated to guide adjuvant therapy or intensification
Tumor immune microenvironment	Immune infiltrates, T-cell exhaustion markers, inflammatory gene signatures	May stratify tumors as “immune hot” or “cold” and guide combination strategies	Ongoing studies using transcriptomics and spatial profiling
TCGA molecular subtypes	TCGA classification: EBV, MSI, GS, CIN	May correlate with immunogenicity and therapy response; especially relevant for EBV and MSI subtypes	May guide therapy selection in precision oncology approaches
CLDN 18.2	Tight junction protein from the claudin family; detected by IHC	Emerging therapeutic target; clinical trials with zolbetuximab show benefit in CLDN18.2-positive gastric tumors	Approved in metastatic setting in some regions; under investigation in perioperative and earlier-stage disease
FGFR2b	Epithelial isoform of the FGFR2	Associated with poor prognosis and more aggressive tumor phenotype, predicts response to FGFR2b-targeted therapies	FGFR2b has been identified as a therapeutic target in G/GEJ cancers, particularly in subgroups with FGFR2 overexpression or amplification

PD-L1: Programmed death-ligand 1; CPS: Combined positive score; ICI: Immune checkpoint inhibitors; dMMR: Deficient mismatch repair; MSI: Microsatellite instability; MSI-H: Microsatellite instability-high; pCR: Complete pathological response; EBV: Epstein-Barr virus; TMB: Tumor mutational burden; ctDNA: Circulating tumor DNA; TCGA: The cancer genome atlas program; CLDN 18.2: Claudin 18.2; FRFR2b: Epithelial isoform of the fibroblast growth factor receptor; GS: Genomically stable; CIN: Chromosomal instability; IHC: Immunohistochemistry.