Table 2.

Major clinical trials involving immune checkpoint inhibitors in non-colorectal gastrointestinal cancers.

Disease Category	Clinical Study (Phase)	References	Interventions	Inclusion Criteria	Major Findings Pertinent to MSI
Solid tumor	KEYNOTE-28 (1b)	[33]	Single-arm P	PD-L1 positive, previously treated	Higher RR in MSI-H tumors vs. non-MSI-H tumors
	KEYNOTE-158 (2)	[34,35]	Single-arm P	Previously treated	Higher RR in MSI-H or TMB-H tumors vs. non-MSI-H tumors
GC	KEYNOTE-12 GC cohort (1b)	[36]	Single-arm P	PD-L1 positive, previously treated	Higher RR in MSI-H tumors vs. non-MSI-H tumors
	KEYNOTE-59 (2)	[37]	Single-arm P	Progression after ≥2 prior lines of therapy including platinum and fluoropyrimidine	Improved RR and survival in MSI-H tumors vs. non-MSI-H tumors
	KEYNOTE-61 (3)	[38]	P vs. paclitaxel	Progression after first-line therapy with platinum and fluoropyrimidine	P improved RR and survival vs. paclitaxel in MSI-H tumors
	KEYNOTE-62 (3)	[39]	P vs. P + C vs. C	CPS ≥1, HER2 negative and treatment-naive	P improved RR and survival vs. C alone in MSI-H tumors
	CheckMate032 (1/2)	[40]	N vs. N + I	Previously treated	Higher RRs in MSI-H tumors vs. non-MSI-H tumors
	ATTRACTION-2 (3)	[41]	N vs. placebo	Previously treated with ≥2 prior lines of therapy	N/A
	ATTRACTION-4 (2/3)	[42]	N + C vs. placebo + C	HER2 negative, treatment-naive	N/A
	CheckMate649 (3)	[43]	N + C vs. N + I vs. C	HER2 negative, treatment-naive	N/A
EAC and ESCC	KEYNOTE-180 (2)	[44]	Single-arm P	Progression after ≥2 prior lines of therapy	Only one patient had an MSI-H tumor but did not respond to P
	KEYNOTE-181 (3)	[45]	P vs. C	Progression after first-line therapy	NA
	KEYNOTE-590 (3)	[46]	P + C vs. placebo + C	Treatment-naive	NA
ESCC	ATTRACTION-1 (2)	[47]	Single-arm N	Refractory or intolerant to fluoropyrimidine-, platinum- or taxane-based C	NA
	ATTRACTION-3 (3)	[48]	N vs. C	Refractory or intolerant to first-line therapy with platinum and fluoropyrimidine	NA
SBA	ZEBRA (2)	[49]	Single-arm P	Previously treated	Higher RR in MSI-H tumors vs. non-MSI-H tumors
AC	NCI9673 (2)	[50]	N vs. N + I	Previously treated	NA
HCC	KEYNOTE-224 (2)	[51]	Single-arm P	Refractory or intolerant to sorafenib	NA
	KEYNOTE-240 (3)	[52]	P vs. placebo	Refractory or intolerant to first-line therapy with sorafenib	NA
	CheckMate040 (1/2)	[53,54,55]	N vs. N + I	Previously treated with sorafenib	NA
	CheckMate459 (3)	[56]	N vs. sorafenib	Treatment-naive	NA
	IMbrave150 (3)	[57]	A + B vs. sorafenib	Treatment-naive	NA
BTC	NCT02829918 (2)	[58]	Single-arm N	Progression after 1–3 prior lines of therapy	All responders had pMMR tumors
	NCT02923934 (2)	[59]	Single-arm N + I	Prior therapy allowed	All responders had MSS/MSI-L tumors
PDAC	NCT02558894 (2)	[60]	D vs. D + T	Progression after first-line therapy with fluorouracil or gemcitabine	One out of three responders had MSI-H tumor with germline dMMR
GI NET	DART SWOG 1609 (2)	[61]	Single-arm N + I	Progression after ≥1 prior line of therapy	NA
	NCT03074513 (2)	[62]	Single-arm A + B	Prior therapy allowed	NA

Abbreviations: disease category—GC, gastric cancer; EAC, esophageal adenocarcinoma; ESCC, esophageal squamous cell carcinoma; SBA, small bowel adenocarcinoma; AC, anal cancer; HCC, hepatocellular carcinoma; BTC, biliary tract cancer; PDAC, pancreatic adenocarcinoma; GI NET, gastrointestinal neuroendocrine tumor; interventions—P, pembrolizumab; C, chemotherapy; N, nivolumab; I, ipilimumab; A, atezolizumab; B, bevacizumab; D, durvalumab; T, tremelimumab; results—RR, response rate; NA, not available.