MET Inhibitors for the Treatment of Gastric Cancer: What’s Their Potential?

Figures & data

Figure 1 c-MET/HGF pathway in gastric cancer pathogenesis. Hepatocyte growth factor (HGF) binds to c-MET, causing phosphorylation and activation of tyrosine kinase domain with consequent triggering of down-stream signaling via PI3K/AKT/mTOR pathway as well as RAS/RAF/ERK/MAPK pathway, eventually leading to tumor cell proliferation, tumor survival, angiogenesis and metastasis.

Table 1 MET Alteration in GC

Met Dysregulation In Gastric Cancer
MET Protein over-expression	Most common, detected by IHC, 50% of GC
MET gene amplification	Mutually exclusive with other amplifications, 4% of GC
Variable different MET gene mutations	Identified in multiple malignancies, 1–2% in GC
Enhanced paracrine ligand-mediated stimulation	Other factors at play including involvement and cross-talk with other pathways
Increased HGF ligand autocrine expression

Notes: This table displays the different mechanisms by which MET expression and MET pathway activation is enhanced in gastric cancer.

Abbreviations: MET, mesenchymal-epithelial transition; GC, gastric cancer; IHC, immunohistochemistry; HGF, hepatocyte growth factor.

Table 2 MET Inhibitors

Type	Target	Name	Mechanism of Action	Trial and Reference	Phase	Results
Tyrosine Kinase Inhibitors		Tinvatinib	Selective MET TKI inhibition	Kang Y. et al^Citation40	II	Modest activity 36% DCR, no ORR
				Pant S. et al^Citation83	II	ORR 41%, not much improvement over chemotherapy alone
		AMG 337		Van Cutsem et al^Citation41	II	ORR 18%
		Volitinib		Gavine et al^Citation43	preclinical	Favorable pre-clinical outcomes and acceptable safety in xenografts
		Savolitinib		VIKTORY Umbrella Trial^Citation44	II	ORR 50%
		Foretinib	Multi-kinase Inhibition	Shah M et al^Citation48	II	Minimal efficacy in unselected GC patients, best response SD 23%
		Crizotinib		Lee J et al^Citation50	Expanded Cohort	4 patients with MET+ GC, 2 had tumor shrinkage
Monoclonal Antibody	HGF	Rilotumumab	Blocks HGF	RILOMET-1^Citation52	III	Stopped early for non-response
				RILOMET-2^Citation53	III	Stopped early for non-response
	MET	Onartuzumab	Blocks MET	METGastric^Citation57	III	No difference in survival
	Bivalent MET inhibitor	Emibetuzumab	Blocks HGF binding and causes MET internalization	Sakai et al^Citation58	II	Well-tolerated, limited single agent activity, PFS only 47% at 8 weeks

Notes: The table above elaborates the different available MET/HGF inhibitors, whether targeting MET/HGF receptors or the RTK domain, including their mechanism of action, studies in which they were evaluated and the corresponding study results.

Abbreviations: MET, mesenchymal-epithelial transition; HGF, hepatocyte growth factor; ORR, overall response rate; DCR, disease control rate; PFS, progression-free survival; TKI, tyrosine-kinase inhibitor; SD, stable disease; GC, gastric cancer; RTK, receptor tyrosine kinase.

Figure 2 Mechanisms of Resistance to MET inhibitors.

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