Immune evasion mechanisms and therapeutic strategies in gastric cancer

Table 1 The summary of major clinical trials in gastric cancer involving immune checkpoint inhibitors

Therapeutic strategy	Trial identifier	Drug name	Stage	Number	Type of cancer	Immune criterion	ORR (%)	Median PFS (mo)	Median OS (mo)	6-mo PFS (%)	1-year PFS (%)	6-mo OS (%)	1-year OS (%)
Anti-CTLA-4	A Phase II trial of Tremelimumab[55]	Tremelimumab	II	18	Metastatic gastric and esophageal adenocarcinomas		5.5	2.83	4.83	-	-	-	33
	NCT01585987[56]	Ipilimumab	II	57	Advanced/metastatic gastric or gastroesophageal junction cancer		1.8 (irBORR)	2.72; 2.92 (irPFS)	12.7	18.3; 22.3 (irPFS)	8.4; 10.6 (irPFS)	-	-
Anti-PD-1 or Anti-PD-L1 alone	KEYNOTE-012 (NCT01848834)[57]	Pembrolizumab	Ib	39	PD-L1-positive adenocarcinoma of the stomach or gastroesophageal junction		22	1.9	11.4	26	-	66	42
	KEYNOTE-028 (NCT02054806)[58]	Pembrolizumab	Ib	23	Squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction in whom standard therapy failed and who had PD-L1–positive		30	1.8	7	30	22	60	40
	KEYNOTE-061 (NCT02370498)[59]	Pembrolizumab	III	296	Advanced gastric or gastroesophageal junction cancer	PD-L1 CPS ≥ 1	16	1.5	9.1	-	-	-	40
	JAVELIN solid tumor trial (NCT01772004) first-line switch-maintenance[62]	Avelumab	Ib	90	Advanced gastric or gastroesophageal cancer		6.7	2.8	11.1	23	13	-	46.2
	ATTRACTION-2 (NCT02267343)[2]	Nivolumab	III	330	Advanced gastric or gastroesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens		-	-	5.26	-	-	46.1	26.2
	JAVELIN Gastric 100 (NCT02625610)[61]	Avelumab	III	249	Locally advanced or metastatic gastric or gastroesophageal junction cancer		-	3.2	10.4	-	-	-	-
	JAVELIN Gastric 300 (NCT02625623)[60]	Avelumab	III	185	Advanced gastric or gastroesophageal junction cancer		2.2	1.4	4.6	-	-	41	-
Immune checkpoints combination (Anti-PD-L1 and anti-CTLA4)	CheckMate-032 (NCT01928394)[63]	Nivolumab	I/II	59	Locally advanced or metastatic chemotherapy-refractory gastric, esophageal, or gastroesophageal junction cancer		12	1.4	-	-	8	-	39
		Nivolumab 1 mg/kg + ipilimumab 3 mg/kg		49			24	1.4	-	-	17	-	35
		Nivolumab 3 mg/kg + ipilimumab 1 mg/kg		52			8	1.6	-	-	10	-	24
	NCT02340975[64]	Durvalumab + Tremelimumab (second-line)	Ib/II	44	Chemotherapy-refractory gastric cancer or gastroesophageal junction cancer		7.4	-	9.2	6.1	-	-	37
		Durvalumab (second-line)		44			0	-	3.4	0	-	-	4.6
		Tremelimumab (second-line)		22			8.3	-	7.7	20	-	-	22.9
		Durvalumab + Tremelimumab (third-line)		25			4	-	9.2	15	-	-	38.8
Immune checkpoint combined with chemotherapy	KEYNOTE-059 (NCT02335411)[3,65]	Pembrolizumab	II	259	Previously treated gastric and gastroesophageal junction cancer		11.6	2	5.6	14.1	-	46.5	23.4
						PD-L1 CPS ≥ 1	15.5	-	-	-	-	-	-
						PD-L1 CPS < 1	6.4	-	-	-	-	-	-
		Pembrolizumab + chemotherapy		25	Advanced gastric or gastroesophageal junction cancer		60	6.6	13.8	68	-	-	52
						PD-L1 CPS ≥ 1	68.8	-	11.1	-	-	-	-
						PD-L1 CPS < 1	37.5	-	19.8	-	-	-	-
		Pembrolizumab		31			25.8	3.3	20.7	34.9	-	-	63
Immune checkpoint combined with target angiogenesis	NCT02443324[67]	Ramucirumab + pembrolizumab	Ia/b	28	Advanced/metastatic gastric or gastroesophageal junction cancer		25	5.6	14.6	-	-	-	-
						PD-L1 CPS ≥ 1	32	8.6	17.3	-	-	-	66.7
						PD-L1 CPS < 1	17	4.3	11.3	-	-	-	41.7

OS: Overall survival; PFS: Progression-free survival; ORR: Objective response rate; irPFS: Immune-related progression free survival; irBORR: Immune-related best overall response rate; PD-L1: Programmed death-ligand 1: PD-L1 CPS: Programmed death-ligand 1 combined positive score; PD-1: Programed cell death protein 1.