Table 1

Important clinical trials for key molecular biomarkers

Biomarker	Trial	n	Patients	Testing method	Biomarker cut-off value	Treatment	Efficacy outcomes
Biomarker	Trial	n	Patients	Testing method	Biomarker cut-off value	Treatment	Median OS	Median PFS	ORR
Established biomarkers
HER2	ToGA³¹ Phase III	594	Gastric or GEJ cancer	IHC & FISH	IHC3+ or HER2:CEP17 ratio ≥ 2	Trastuzumab + chemo vs. PL + chemo	13.8 m vs. 11.1 m (HR = 0.74, 95% CI: 0.60–0.91, P = 0.0046)	6.7 m vs. 5.5 m (HR = 0.71, 95% CI: 0.59–0.85, P = 0.0002)	47% vs. 35% (P = 0.0017)
	DESTINY-Gastric 01²⁹ Phase II	187	Gastric or GEJ cancer	IHC & ISH	IHC3+ or IHC2+/ISH+	Trastuzumab deruxtecan vs. chemo	12.5 m vs. 8.4 m (HR = 0.59, 95% CI: 0.39–0.88, P = 0.01)	5.6 m vs. 3.5 m (HR = 0.47, 95% CI: 0.31–0.71, P: NR)	51% vs. 14% (P < 0.001)
	DESTINY-Gastric 02³² Phase II	79	Gastric or GEJ cancer	IHC & ISH	IHC3+ or IHC2+/ISH+	Trastuzumab deruxtecan	12.1 m (95% CI: 9.4 m–15.4 m)	5.6 m (95% CI: 4.2 m–8.3 m)	42%
PD-L1	CheckMate 649³³ Phase III	1,581	Gastric or GEJ or oesophageal cancer	IHC	CPS ≥ 5	Nivolumab + chemo vs. chemo	14.4 m vs. 11.1 m (HR = 0.71, 98.4% CI: 0.59–0.86, P < 0.0001)	7.7 m vs. 6.05 m (HR = 0.68, 98% CI: 0.56–0.81, P < 0.0001)	60% vs. 45% (P: NR)
	KEYNOTE-859³⁴ Phase III	1,579	Gastric or GEJ cancer	IHC	CPS ≥ 1 and CPS ≥ 10	Pembrolizumab + chemo vs. PL + chemo	CPS ≥ 1: 13.0 m vs. 11.4 m (HR = 0.74, 95% CI: 0.65–0.84, P < 0.0001) CPS ≥ 10: 15.7 m vs. 11.8 m (HR = 0.65, 95% CI: 0.53–0.79, P < 0.0001)	CPS ≥ 1: 6.9 m vs. 5.6 m (HR = 0.72, 95% CI: 0.63–0.82, P < 0.0001) CPS ≥ 10: 8.1 m vs. 5.6 m (HR = 0.62, 95% CI: 0.51–0.76, P < 0.0001)	CPS ≥ 1: 52% vs. 43% (P = 0.0004) CPS ≥ 10: 61% vs. 43% (P < 0.0001)
CLDN18.2	SPOTLIGHT³⁵ Phase III	565	Gastric of GEJ cancer	IHC	≥ 75% of cells with moderate-to-strong membrane staining	Zolbetuximab + mFOLFOX6 vs. PL + mFOLFOX6	18.23 m vs. 15.54 m (HR = 0.75 m, 95% CI: 0.60–0.94, P = 0.0135)	10.61 m vs. 8.67 m (HR = 0.75, 95% CI: 0.60–0.94, P = 0.0066)	48% vs. 48% (P: NR)
	GLOW³⁶ Phase III	507	Gastric or GEJ cancer	IHC	Same as SPOTLIGHT	Zolbetuximab + CAPOX vs. PL + CAPOX	14.39 m vs. 12.16 m (HR = 0.771, 95% CI: 0.615–0.965, P = 0.0118)	8.21 m vs. 6.80 m (HR = 0.687, 95% CI: 0.544–0.866, P = 0.0007)	42.5% vs. 40.3% (P: NR)
Exploratory biomarkers
MET	VIKTORY³⁷ Phase II	20^†	Gastric cancer	NGS or FISH	MET amplification	Savolitinib	NR	NR	50%
FGFR2	FIGHT³⁸ Phase II	155	Gastric or GEJ cancer	IHC or NGS	IHC2+/3+ or amplification by ctDNA NGS	Bemarituzumab + mFOLFOX6 vs. PL + mFOLFOX6	Not reached vs. 12.9 m (HR = 0.58, 95% CI: 0.35–0.95, P = 0.027)	9.5 m vs. 7.4 m (HR = 0.68, 95% CI: 0.44–1.04, P = 0.073)	47% vs. 33% (P = 0.11)

↵^†The VIKTORY umbrella trial assigned a total of 105 patients to different biomarker-specific trials. We only described the 20 MET-amplified patients assigned to savolitinib treatment.
CAPOX, capecitabine and oxaliplatin; chemo, chemotherapy; CI, confidence interval; CLDN18.2, claudin 18.2; CPS, combined positive score; FGFR2, fibroblast growth factor receptor 2; FISH, fluorescence in situ hybridisation; GEJ, gastro-oesophageal junction; HR, hazard ratio; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridization; m, month; mFOLFOX6, modified 5-fluorouracil, leucovorin and oxaliplatin; NGS, next-generation sequencing; NR, not reported; ORR, objective response rate; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; PL, placebo.