New advances in targeted gastric cancer treatment

Table 1 Targeted agents that have been studied for the treatment of gastric neoplasia

Class (target)	Type	Agent	Current status in GC treatment	Indications	Treatment benefits
HER2 inhibitors	mAb	Trastuzumab	FDA approval 2010	HER2+ metastatic GC	↑ OS, ORR, PFS[30]
	mAb second generation	Pertuzumab	Phase III clinical trials ongoing	HER2+ metastatic/locally advanced unresectable GC	Under investigation[38]
	Antibody-drug conjugate	Trastuzumab etansine	Phase II/III clinical trials ongoing	HER2+ advanced GC	Under investigation[39]
	TKI	Lapatinib	Phase III clinical trials	First-line and second-line HER2+ advanced/metastatic GC	Benefits in some subgroups of patients; ↑ RR in second-line setting[42,43]
			Phase III clinical trials ongoing	Resectable GC	Under investigation[44]
EGFR inhibitors	mAb	Cetuximab	Phase II/III clinical trials	Advanced/metastatic GC	No benefits in first-line setting; modest benefit, reduced toxicity in second-line setting[52,57-59]
	Humanized mAb	Panitumumab	Phase III clinical trials	Advanced GC	No benefits[60]
		Nimotuzumab	Phase II clinical trials	Advanced GC	Promising results in EGFR2+/3+ subgroups of patients[69]
	TKI	Gefitinib	Phase I/II/III clinical trials ongoing	Resectable/advanced and metastatic GC	No benefits[72-74]
		Erlotinib	Phase II	Advanced/metastatic GC	No benefits so far; phase II trials pending results[75]
VEGF/VEGFR inhibitors	Anti-VEGF humanized mAb	Bevacizumab	Phase III clinical trials	Advanced GC, first-line treatment	↑ PFS, ORR, benefits in specific subgroups of patients[106-108]
			Phase III clinical trials	Perioperative chemotherapy in resectable GC	Under investigation[44,110]
	Anti-VEGF humanized mAb	Ramucirumab	FDA approval 2014	Advanced GC, second-line treatment	↑ OS, PFS[119-122]
	TKI	Apatinib	CFDA approval 2014	Metastatic GC, third-line treatment	↑ OS, PFS[127,129,131]
VEGFR, PDGFR, c-KIT, FMS, FLT inhibitor	TKI	Sunitinib	Phase I/II clinical trials	Advanced GC	↑ OS, ORR (second-line); promising results[133-136]
RAF, VEGFR, PDGFR inhibitor	TKI	Sorafenib	Phase I/II clinical trials	Advanced GC	↑ PFS, OS (second-line)[143]; conflicting data[144,145]
VEGFR, PDGFR, c-KIT inhibitor	TKI	Pazopanib	Phase I/II clinical trials	Advanced GC	Under investigation[150-152]
VEGFR, RAF inhibitor	TKI	Regorafenib	Phase I/II ongoing clinical trials	Refractory advanced GC	↑ PFS, OS, drawback: drug-related toxicity[156]; under investigation[157-159]
IGF-1 inhibitor	Humanized mAb	Figitumumab	Phase I ongoing clinical trials	Advanced GC	Under investigation[167,168]
FGF- inhibitors	TKI	AZD2171	Phase II clinical trials	Advanced GC, second-line treatment	Promising results[172]
		JNJ-42756493	Phase I ongoing clinical trials	Advanced GC	Promising results[173]
		Dovitinib	Phase I/II ongoing clinical trials	Advanced GC	Under investigation[183-185]
		Brivanib
		INCB054828
HGF/c-MET inhibitors	Humanized mAb	Rilotumumab	Phase II clinical trials	Advanced/metastatic GC	↑ OS in MET (+) subset of patients[188,189]
			Phase III clinical trials		Increased toxicity, ↓ OS, PFS
		Onartuzumab	Phase III clinical trials	MET(+), HER2(-) GC	Negative results
	TKI	Foretonib	Phase II clinical trials	Metastatic GC	Minimal efficacy[194]
PI3 kinase/mTOR inhibitors	Inhibitor	Everolimus	Phase III clinical trials	Advanced GC, second/third-line treatment	Negative results[207,208]
		Sirolimus	Phase I ongoing clinical trials	Advanced GC	Under investigation[209]
PARP inhibitors	Inhibitor	Olaparib	Phase II clinical trials	Metastatic/recurrent GC, second-line treatment	↑ OS in specific subgroup of patients; under investigation[211-213]
		Veliparib	Phase I ongoing clinical trials	Advanced GC	Under investigation[216]
Immuno-therapy/Immuno-checkpoint blockade	CTLA-4 inhibitor	Ipilimumab	Phase II clinical trials	Advanced/metastatic GC	Negative results[224]
	CTLA-4 inhibitor	Tremalimu-mab	Phase I/II ongoing clinical trials	Advanced GC	Synergistic effects for Tremelimumab and Durvalumab combination; under investigation[240,241]
	Binding of PD-1 with PD-L1 blockade	Nivolumab	Phase I/II ongoing clinical trials	Advanced/metastatic GC	Promising results[228]
		Pembrolizu-mab	Phase I-III ongoing clinical trials	Advanced/metastatic GC, naive patients and progression under treatment	Promising results[230]; under investigation[231-238,243,244]
	PD-L1 inhibitor	Durvalumab	Phase I clinical trials	Advanced GC	Promising results[239]
GCC inhibitor	Humanized mAb	MLN0264	Phase I/II ongoing clinical trials	Advanced/metastatic GC, GCC (+)	Promising results[247,248]
Tumour cell cycle inhibitor	CKI	Flavopiridol	Phase II clinical trials	Advanced GC	Negative results[251,252]
Tumour cell apoptosis	Proteasome inhibitor	Bortezomib	Phase II clinical trials	Advanced/metastatic GC	Negative results[262]
MMP inhibitors	Inhibitor	Marimastat	Randomized, double-blind, placebo-controlled study	Non-resectable GC, maintenance treatment	Survival benefit[265]

GC: Gastric cancer; mAb: Monoclonal antibody; OS: Overall survival; ORR: Overall response rate; PFS: Progression-free survival; TKI: Tyrosine kinase inhibitor; HER2: Human epidermal growth factor receptor type 2; EGFR: Epidermal growth factor receptor; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; PDGFR: Platelet-derived growth factor receptor; c-KIT: Stem cell factor receptor (CD117); FLT: Fms-related tyrosine kinase; RAF (protein): rapidly accelerated fibrosarcoma or rat fibrosarcoma; IGF-1: Insulin growth factor 1; FGF: Fibroblast growth factor; HGF: Hepatocyte growth factor; mTOR: Mammalian target of rapamycin; PARP: Poly (ADP-ribose) polymerase; CTLA-4: Cytotoxic T-lymphocyte-associated antigen 4; PD-1: Programmed cell death-1; PD-L1: Programmed cell death-ligand 1; GCC: Guanylyl cyclase C; CKI: Cyclin-dependent kinase inhibitor; MMP: Matrix metalloproteinase; FDA: Food and Drug Administration; CFDA: Chinese Food and Drug Administration.