New therapeutic options opened by the molecular classification of gastric cancer

Table 1 Selected active clinical trials involving molecular targeted therapies for specific gastric cancer subtypes

GC subtype	Molecular target	Therapeutic agents	Clinical trial name (ID)	Phase	Patients	Aditional treatments	ESCD	Clinical efficiency			Condition	Study (citation)
								ORR	mOS	mPFS
EBV	PD-1	Pembrolizumab	KEYNOTE-059 (NCT02335411)	II	316	Cis+5-FU	May-19	11.60%	5.6	2	Rec/Met GC	[37]
			KEYNOTE-061 (NCT02370498)	III	592	Paclitaxel	Jul-19		Failed		Adv GC	[38]
			KEYNOTE-062 (NCT02494583)	III	764	Cis+5-FU(X)	Jun-20				Adv GC
			KEYNOTE-585 (NCT03221426)	III	860	Cis+X(5-FU) or FLOT	Jul-23				GC
		Nivolumab +/-Ipilimumab (CTLA4 inhibitor)	ONO-4538-38 (NCT03006705)	III	700	S-1 or XOX	Jun-10				Stage III GC
			CheckMate649 (NCT02872116)	III	1266	XOX or FOLFOX	Oct-21				Adv/Met GC
			ONO-4538-37 (NCT02746796)	II/III	680	SOX or XOX	Aug-20				Adv/Rec GC
			ONO-4538-12 (NCT02267343)	III	480	Nivolumab vs Placebo	Aug-17	11.20%	5.32/4.14 P < 0.0001	1.61/1.45	Adv/Rec GC	[40]
	PD-L1	Avelumab	JAVELIN Gastric 300 (NCT02625623)	III	371	Avelumab + BSC vs Irinotecan + Paclitaxel	Sep-20				Rec/Met GC
			JAVELIN Gastric 100 (NCT02625610)	III	466	vs OX + 5-FU(X)(LV)	Mar 202 4				Adv/Met GC
		Durvalumab	NCT02572687	I	114	Ramucirumab	Sep-18	36%		2.6	Adv/Met GC	[43,45]
			NCT02340975	Ib/II	135	+/- Tremelimumab (CTLA4 inhibitor)	Aug-19				Rec/Met GC	[46]
			NCT02678182	II	770	Cis, X	Aug-10				Adv/Met HER2 neg. GC
		Atezolizumab	DANTE (NCT03421288)	II	295	FLOT	Feb-25				Adv GC
			ICONIC (NCT03399071)	II	40	FLOT-A	Aug-25				T1-T3 GC
	PIK3CA	BYL719	NCT01613950	I	18	AUY922	Mar-14	NA			Adv/Met GC
		AZD5363	NCT02451956	II	25	Paclitaxel	Dec-18				Adv GC with PIK3CA mutation
	ARID1A	PLX2853	NCT03297424	II	166		May-21				ARID1A mutations
		AZD2281 (Olaparib)	NCT02576444	II	64		Sep-18				PIK3CA, AKT, or ARID1A mutations
MSI	PD-1	Pembrolizumab	KEYNOTE-016 (NCT01876511)	II	171		Jun-21	40%	Not reached	5.4	MSI	[47]
GS	CDH1	NA	-			Prophylactic gastrectomy
	RHOA	NA				NA
	CLDN18-ARHGAP fusion	NA				NA
CIN	EGFR	Cetuximab	NCT00183898	II	75	XOX	Jun-18				Adv GC
		Panitumumab	NEOPECX (NCT01234324)	II	171	ECX, placebo	Aug-17				Adv GC incl. GEJ
			MEGA (NCT01443065)	II	162	FOLFOX/FOLFOX + panitumumab/FOLFOX + AMG102	Jan-19		13.1/8.3/11.5	5.8/5.2/7.6	Adv GC	[48]
		Nimotuzumab	NCT01813253	III	400	Irinotecan, placebo	Jan-18				EGFR overexpr. Adv GC or GEJ
			NIEGA (NCT03400592)	II	55	Irinotecan	Jun-18				Rec/Met GC with overexpr. EGFR
	HER2	Trastuzumab	NCT01260194	IV	4		Jan-15				GC
			HELOISE (NCT01450696)	IIIb	248	Cis + X + Herceptin (6 mg/kg or 10 mg/kg)	Aug-15		12.5/10.6 P = 0.2401		GC	[49]
			PETRARCA/FLOT6) (NCT02581462)	II/III	404	FLOT or FLOT + Herceptin/Pertuzumab	Mar-21				HER2+ GC or GEJ
			NCT02954536	II	37	Pembrolizumab or Pembrolizumab + X/Cis	Nov-19				HER2+ GC
			Her + XELOX (NCT01396707)	II	55	Herceptin + XELOX	Mar-18		21	9.8	Met/Rec HER2 + GC	[50]
			EVIDENCE (NCT01839500)		95		Feb-18		30	9.5	GC	[51]
		Trastuzumab emtansine	GATSBY (NCT01641939)	II/III	415	or Standard Taxane Therapy	Apr-16		7.9/8.6 P = 0.8589	2.66/2.89	Prev. treated for HER2+ Adv GC	[52]
		Pertuzumab	JACOB trial (NCT01774786)	III	780	Trastuzumab + 5-FU/X/Cis, placebo	Dec-21		17.5/14.2 P = 0.0565	8.5/7.0	HER2+ Met GC and GEJ	[53]
			NCT01461057	II	30	X + Cis + Trastuzumab	Sep-17				Met HER2 + GC or GEJ	[54]
			INNOVATION (NCT02205047)	II	220	Cis/X or Cis/5-FU +/- trastuzumab, placebo	Sep-24				GC, EGFR overexpress.	[55]
		Margetuximab	NCT02689284	Ib/II	72	Pembrolizumab	Mar-20				Adv/Met HER2 + GC or GEJ	[56]
			NCT01148849	I	67		Dec-17				HER2+ GC	[57]
	EGFR/ HER2	Lapatinib	LOGiC/TRIO-013 (NCT00680901)	III	545	XOX, Placebo	Dec-19		11.9/10.4; P = 0.3244	6.0/5.4; P = 0.0381	GC	[58,59]
			NCT02015169	II	32	XELOX	Nov-17				HER2 + GC with liver metastasis
	VEGF	Bevacizumab (Avastin)	NCT01471470	II	31	Docetaxel + X + Cis	Dec-19		38.6	13.1	Adv GC	[60]
			AGMT_GASTRIC-3 (NCT00952003)	II	40	1 OX + Irinotecan + Avastin; 2 Docetaxel + Avastin; 3 Avastin	Apr-18		11		GC	[61]
			NCT00911820	II	88	Cis+Irinotecan or Docetaxel + Cis + Irinotecan	Jun-18	0.57/0.51; P = 0.605	11.7/13.4; P = 0.714	7.9/8.4; P = 0.721	Met GC
			NCT01191697	II	35	XOX + trastuzumab	Apr-17		26.92	13.93	HER2 + Met GC	[62]
	VEGFR2	Ramucirumab (IMC-1211B)	Rainbow trial (NCT01170663)	III	665	Paclitaxel Placebo	Feb-17		9.6/7.4; P = 0.0169	4.4/2.9; P < 0.0001	GC	[63,64]
			ARMANI (NCT02934464)	III	280	Ramucirumab + Paclitaxel or FOLFOX4/mFOLFOX6/XELOX	Oct-19				Adv/ Met HER2- GC or GEJ
			RAINFALL (NCT02314117)	III	128	X + Cis, Placebo	May-18				Met GC	[65]
			NCT02898077	III	450	Paclitaxel, Placebo	Mar-21				GC
			RAMSES/FLOT7 (NCT02661971)	II/III	908	FLOT, Placebo	Oct-19				GC or GEJ
	VEGFR2/ TIE2	Regorafenib	INTEGRATE II (NCT02773524)	III	350	Placebo	Apr-19				GC	[66]
			NCT01913639	II	36	FOLFOX, Placebo	Jul-18				GC	[67]
	mTOR	Everolimus (RAD001)	AIO-STO-0111 (NCT01248403)	III	300	Paclitaxel, Placebo	Jul-17	8.0%/7.3%; P = 0.4	6.1/5.0; P = 0.54	2.2/2.07; P = 0.3	GC	[68]
		AZD2014	NCT03082833	II	25		Feb-19				TSC1/2 mut. or null GC
	MET	Onartuzumab	NCT01662869	III	562	mFOLFOX6, Placebo	Dec-15		11.0/11.3	6.7/6.8	Met HER2-/+ GC or GEJ	[69,70]

ESCD: Estimated study completion date; ORR: Overall response rate; mOS: Median overall survival (months); mPFS: Median progression free survival (months); Adv/Rec/Met: Advanced/recurrent/metastatic; GEJ: Gastroesophageal junction adenocarcinoma; Cis: Cisplatin; 5-FU: 5’Fluorouracil; S-1: Tegafur-gimeracil-oteracil potassium; X: Capecitabine; OX: Oxaliplatin; XOX: Capecitabine + oxaliplatin; FOLFOX: Leucovorin/fluorouracil/oxaliplatin; SOX: Tegafur/gimeracil/oteracil potassium + oxaliplatin; FLOT: Docetaxel + oxaliplatin + 5FU + leucovorin (calcium folinate); LV: Leucovorin; BSC: Best supportive care; AUY922: Hsp90 inhibitor; ECX: Epirubicin + cisplatin + capecitabine; NA: Not available.