Prognostic significance of tumor immune microenvironment and immunotherapy: Novel insights and future perspectives in gastric cancer

Table 1 Clinical trials using CTLA-4 and PD/PD-L1 checkpoint inhibitors

Checkpoint inhibitors	Study number	Phase	Status	Study design	Study population	Primary outcome measures	Secondary outcome measures	No. of patients (estimated enrollment)	Final results
Nivolumab, Ipilimumab	NCT03342417	II	Recruiting	NIVO + IPI	-Neoadjuvant breast cancer -Platinum-resistant advanced ovarian/GC	- % AE	- DOR, OS, QOL, recurrence rate	60	Pending
Nivolumab, Ipilimumab	NCT02872116 (CHECKMATE-649)	III	Recruiting	- NIVO + IPI/ -NIVO + chemo vs chemotherapy (XELOX/FOLFOX)	-Naive advanced/metastatic GC/GEJ	-OS NIVO + IPI vs chemo (PD-L1 + tumors) -OS NIVO + chemo vs chemo -ORR, PFS nivo + chemo vs chemo	-OS NIVO + IPI vs chemo -PFS NIVO + IPI/ NIVO + chemo vs chemo (PD-L1+) -ORR NIVO + chemo vs chemo	1349	Pending
Nivolumab, Ipilimumab	NCT02935634 (FRACTION-GC)	II	Recruiting	- NIVO + IPI -NIVO + RELATLIMAB -NIVO + BMS-986205	-Advanced GC	-ORR, DOR, PFS	-% AE, SAE, discontinuation/death due to treatment	300	Pending
Nivolumab, Ipilimumab	NCT03044613	Ib	Recruiting	- NIVO/NIVO + IPI prior to chemoradiation + NIVO	-Neoadjuvant treatment, resectable stage II/III EC/GEJ	-% AE	-Feasibility of induction treatment -Path CR -Quantity of NIVO bound to PD1 receptor -Changes in expression of immune markers -OS, RFS	32	Pending
Nivolumab, Ipilimumab	NCT03443856 (VESTIGE)	II	Not yet recruiting	- NIVO + IPI	-Adjuvant treatment GC/GEJ adenocarcinoma stage Ib-IVa, ↑risk of recurrence (ypN1-3 + /R1) after neoadjuvant treatment + resection	-DFS	-OS -Relapse rate -Loco-regional/distant failure rates -% AE, QOL, global health status	240	N/A
Nivolumab, Ipilimumab	NCT03409848 (INTEGA)	II	Recruiting	-IPI/FOLFOX + NIVO and TRAS	-Advanced/metastatic GC adenocarcinoma, previously untreated	-OS	-% AE -PFS, RR, QOL -Translational research -Central imaging review	97	Pending
Nivolumab, Ipilimumab	NCT02834013	II	Recruiting	-NIVO + IPI	-Rare tumors, including gastric NET, SqCC, GIST	-ORR-RECIST	-Toxicities -OS, PFS -Clinical benefit rate -ir-ORR/PFS	707	Pending
Nivolumab, Ipilimumab	NCT03126110	I/II	Recruiting	-NIVO + INCAGN01876 -IPI + INCAGN01876 -NIVO + IPI + INCAGN01876	-Advanced/metastatic malignancies, including GC	-Toxicities (%AE) -ORR-RECIST	-DR, DDC, PFS, OS- RECIST	450	Pending
Nivolumab, Ipilimumab	NCT03241173	I/II	recruiting	-NIVO + INCAGN0949 -IPI + INCAGN0949 -NIVO + IPI + INCAGN0949	-Advanced/ metastatic malignancies, including GC	-Toxicities (%AE) -ORR-RECIST	-DR, DDC, PFS, OS- RECIST	651	Pending
Ipilimumab	NCT01585987	II	Completed	-IPI vs BSC (5-FU)	-Unresectable/ metastatic GC/GEJ adenocarcinoma (following Ist line treatment)	-ir-PFS (ir RECIST) -% BOR	-PFS (mWHO) -OS	143	-ir-PFS ↓ (2.92 vs 4.89 mo); -mWHO-PFS↓ (2.72 vs 4.89) (P = 0.03); -OS at study completion 12.68 vs 12.06 mo
Tremelimumab, Durvalumab	NCT02658214	I	Recruiting	-TREME + DURVA + chemo (platinum-based SOC)	-Ist line locally advanced/ metastatic solid tumor, including GC/GEJ	-Laboratory findings -%AE, safety, tolerability -Tumor assessment (RECIST)	-	42	Pending
Nivolumab	NCT03453164 (CIRCUIT)	I/II	Recruiting	NIVO + radiotherapy	-Unresectable recurrent GC (3 rd line)	-DCR: -PD: on CT/ MRI/ PET-CT -CR/PR/SD	-Mean survival -% AE -Local control rate -% PL-L1+, MHCI- tumor cells -Cytokines serum concentration -% regT cells -% Ag-specific CTL	40	Pending
Nivolumab	NCT02267343	III	Active, not recruiting	NIVO vs placebo	-Refractory, unresectable, advanced/ recurrent GC/GEJ	-OS, PFS	-ORR, DOR, %AE, %SAE, safety	480	Pending
Nivolumab	NCT02746796	II/III	Recruiting	NIVO + chemo	-Ist line therapy, unresectable advanced/ recurrent GC/GEJ	-PFS -OS	-ORR, DOR, DCR -TTR, BOR -% AE, SAE, laboratory abnormalities	680	Pending
Nivolumab	NCT03006705	III	Recruiting	NIVO + chemo vs placebo + chemo	-Adjuvant treatment p stage III GC/GEJ (after D2 resection)	-RFS	-OS -Safety- % AE, SAE, laboratory abnormalities	700	Pending
Nivolumab	NCT02999295	I/II	Recruiting	-NIVO + RAMUCIRUMAB	-Advanced/ recurrent unresectable GC/GEJ	-No. of pts with DLT -6 mo PFS	-%AE -ORR -DCR -OS, PFS	44	Pending
Nivolumab	NCT02946671	I	Recruiting	-NIVO + MOGAMULIMUMAB (KW-0761 = anti-CCR4)	-Preoperator treatment against solid cancers, including GC	-% AE - FOXp3 + tumors by immunohistochemistry	-ORR-RECIST -% ↓Treg	18	Pending
Nivolumab	NCT02951091 (Biomarker – integrated Umbrella)	Observational	Recruiting	-NIVO/ AFATINIB/ GSK2636771 + PACLITAXEL	-Advanced GC -Different molecular cohorts: PD-L1+, MSI-H, EBV+ → NIVO	-PFS	-	400	Pending
Nivolumab	NCT02465060 (The MATCH screening trial)	II	Recruiting	-NIVO/ other agents (according to genetic testing)	-Advanced/ metastatic solid tumors (including GC), lymphomas, multiple myelomas → mismatch repair deficiency (loss of MLH1/ MLH2)	-ORR	-OS, PFS -TTP	6452	Pending
Nivolumab	NCT02862535	Ib	Active, non-recruiting	-ANDECALIXIMAB (GS-5745) ± NIVO/chemo	-Previously treated, advanced GC/GEJ adenocarcinoma (Japan)	-Safety (% AE)	- Serum concentration of Andecaliximab -% Ab-anti Andecaliximab	36	N/A
Pembrolizumab	NCT03382600 (MK-3475-659/ KEYNOTE 659)	II	Recruiting	-PEMBRO + OXALIPLATIN + TS-1 vs -PEMBRO + CISPLATIN + TS-1	-Advanced CG/GEJ adenocarcinoma, HER2(-), PD-L1+	-ORR-RECIST	-ORR (i-RECIST) -DCR, DOR, TTR, PFS (RECIST, iRECIST) -OS, % AE	90	Pending
Pembrolizumab	NCT02901301	I/II	Recruiting	-PEMBRO + TRASTUZUMAB + chemo	-Ist line advanced, GC HER2+	-Recommended dose -ORR-RECIST	-DOR -TTR	49	Pending
Pembrolizumab	NCT03342937	II	Recruiting	PEMBRO + XELOX	-Ist line metastatic GC adenocarcinoma	-PFS	-OS - % AE	50	Pending
Pembrolizumab	NCT02918161	II	Recruiting	PEMBRO + chemo (SOC)	-Perioperative setting GC/GEJ	-2 years DFS	- Pathol CR -OS, ORR (RECIST) -DFS	40	Pending
Pembrolizumab	NCT02689284	I/II	Recruiting	PEMBRO + MARGETUXIMAB	-HER2 + advanced, metastatic GC/GEJ	- Expansion phase dose of Margetuximab -Antitumor activity: RD, ORR (RECIST, ir-RECIST)	-OS -PFS	72	Pending
Pembrolizumab	NCT03257163	II	Recruiting	-PEMBRO + CAPECITABINE + radiotherapy (perioperative)	-Mismatch repair deficient, EBV+, operable GC	-RFS	-	40	Pending
Pembrolizumab	NCT03064490 (PROCEED)	II	Recruiting	-PEMBRO + chemoradiotherapy	-Neoadjuvant treatment, locally advanced EG cancers	-Pathol CR	-Toxicity (% AE)	38	Pending
Pembrolizumab	NCT02563548	Ib	Recruiting	-PEMBRO + PEGPH2O (Pegylated Recombinant Human Hyaluronidase)	-Hyaluronan-high (HA-H) patients with relapsed/ refractory cancers (adenocarcinoma)	-ORR	-DCR, DOR, PFS (RECIST, ir-RECIST)	81	Pending
Pembrolizumab	NCT02954536	II	Recruiting	-PEMBRO+TRASTUZUMAB+chemo	-Advanced, metastatic HER2+, EG (Ist line)	-PFS (RECIST)	-	37	Pending
Pembrolizumab	NCT03221426 (MK-3475-585) (KEYNOTE-585)	III	Recruiting	-PEMBRO + cemo vs placebo + chemo	-Neoadjuvant/adjuvant previously untreated GC/GEJ adenocarcinoma	-OS - EFS event-free survival) -Pathol CR -% AE + discontinuation of treatment	-DFS	860	Pending
Pembrolizumab	NCT03196232	II	Recruiting	-PEMBRO + EPACADOSTAT	-Metastatic/ unresectable GEJ	-6-mo PFS	-ORR (RECIST) -OS -RR	30	Pending
Pembrolizumab	NCT03019588 (MK-3475-063/ KEYNOTE-063)	III	Recruiting	-PEMBRO vs chemo (PACLITAXEL)	-Progression after Ist line platinum-fluoropyridine chemo, advanced GC/GEJ adenocarcinoma, PD-L1+ (Asia)	-OS, PFS (RECIST)	-ORR-RECIST -% AE, % discontinuation due to AE	360	Pending
Pembrolizumab	NCT03488667	II	Not yet recruiting	PEMBRO + mFOLFOX	-Neoadjuvant treatment GEJ adenocarcinoma -adjuvant treatment GC	-yp RR (pathologic response) -toxicity (% AE)	-ORR, DFS, OS -PET scan response rate - % PD-L1 + in tumor cells	40	N/A
Pembrolizumab	NCT03413397	II	Recruiting	PEMBRO + LENVATINIB MESYLATE	-Metastatic/ recurrent GC/GEJ	-ORR-RECIST	-PFS, OS -Characteristic immunologic changes	29	Pending
Pembrolizumab	NCT02730546	I/II	Recruiting	PEMBRO + chemoradiotherapy	-Locally advanced, operable, GEJ/gastric cardia adenocarcinoma (neoadjuvant setting)	-Path CR -PFS	-R0 resection, DSF -Dose-limiting AE, % surgical complications, OS, PFS, time to relapse	68	Pending
Pembrolizumab	NCT02318901	Ib/II	Active, not recruiting	PEMBRO-TRASTUZUMAB/ADO-TRASTUZUMAB-ETAMSINE/CETUXIMAB	-Unresectable HER2+, advanced GC/GEJ	-Dose of mAb combined with PEMBRO	-% grade 3-4 AE -RR (RECIST, ir-RECIST) -OS, PFS -Circulating tumor DNA -Imaging changes	90	N/A
Pembrolizumab	NCT03095781	I	Recruiting	PEMBRO + XL888 (= Hsp90 inhibitor)	-Advanced gastrointestinal cancer (including GC)	-Recommended dose for combined treatment	-ORR, PFS, RS (RECIST) -OS	50	Pending
Pembrolizumab	NCT02346955	I	Terminated	-CM-24[MK-6018 = mAb against CEACAM1] ± PEMBRO	-Advanced/recurrent malignancies (including GC)	-% AE, discontinuation due to AE, DLT	-Maximum drug concentration, half-life elimination, ORR, DOR	27	Pending
Pembrolizumab	NCT02178722 (KEYNOTE-037/ECHO-202)	I/II	Recruiting	-PEMBRO + EPACADOSTAT	-Selected carcinomas (including GC)	-% DTL -ORR	-PFS -% AE -OS	508	Pending
Pembrolizumab	NCT02903914	I/II	Recruiting	-PEMBRO + ARGINASE INHIBITOR INCB001158	- Advanced/metastatic solid tumors (including GC)	-% AE	- Rrecommended dose of arginase Inhibitor ± PEMBRO -Pharmacokinetic profile -Antitumor activity of drugs (RECIST, ir RECIST)	346	Pending
Pembrolizumab	NCT03122548	II	Active, not recruiting	PEMBRO + CRS-207	-Recurrent/metastatic GC/EG (1-2 prior lines of systemic treatment)	-% AE	-Tumor response (RECIST) -OS -Characterization of immune response -Analysis of biomarker expression	79	N/A
Pembrolizumab	NCT02393248	I/II	Recruiting	-INCB054828 + PEMBRO/ chemo/ TRASTUZUMAB	-Advanced malignancies (including GC), progression after prior treatment	-Maximum tolerated dose, pharmacodynamic of INCB054828	-ORR -Maximum/minimum plasma Concentration of NCB054828	280	Pending
Pembrolizumab	NCT02494583	III	Active, not recruiting	-PEMBRO vs -PEMBRO + chemo vs -Placebo + chemo	-Ist line treatment, advanced GC/GEJ	-PFS (RECIST) -OS	-ORR, DOR (RECIST) -QOL	764	N/A
Pembrolizumab	NCT02370498 (KEYNOTE-061)	III	Active, not recruiting	-PEMBRO vs chemo (PACLITAXEL)	-Advanced GC/GEJ adenocarcinoma, Progressed after Ist line (platinum + fluoropyrimidine), PD-L1+	-PFS, OS- in PD-L1+	-PFS, OS -TTP, ORR	592	Pending
Pembrolizumab	NCT02335411 (KEYNOTE-059)	II	Active, not recruiting	-PEMBRO or PEMBRO + chemo (CISPLATIN + 5-FU/CAPECITABINE)	-Recurrent/metastatic GC/GEJ adenocarcinoma	-% AE, discontinuation of treatment due to AE -ORR	-	316	Pending
Pembrolizumab	NCT03277352	I/II	Recruiting	-INCAGN01876 + PEMBRO + EPACADOSTAT	-Advanced/ metastatic malignancies	-% AE -ORR, CRR (RECIST)	-ORR, DCR, DOR, PFS, OS (rECIST, mRECIST)	166	Pending
Pembrolizumab	NCT02443324	I	Active, not recruiting	-PEMBRO + RAMUCIRUMAB	-GC/GEJ (NSCLC, transitional urothelial cancer, biliary tract cancer)	-DTL	-% BOR of CR/PR, ORR -% SD -DOR, time to response -PFS, OS -Pharmacokinetics	155	Pending
Avelumab	NCT02625623 (JAVELIN GASTRIC 300)	III	Active, not recruiting	-AVE + BSC vs -chemo+BSC/BSC	-Unresectable, recurrent, locally advanced/ metastatic GC/GEJ adenocarcinoma (3rd line)	-OS	-PFS, BOR -QOL	37	Pending
Avelumab	NCT03399071 (ICONIC)	II	Recruiting	-AVE + chemo (FLOT)	-Perioperative setting, operable EC/GC	-Pathol CR	-% grade 3-4 AE -Radiologic response (RECIST) -median PFS, OS	40	Pending
Avelumab	NCT02625610 (JAVELIN GASTRIC 100)	III	Active, not recruiting	-AVE maintenance vs Ist line continuation of chemo (OXALIPLATIN + FLUOROPYRIMIDINE)	-Unresectable, locally advanced/ metastatic GC/GEJ adenocarcinoma	-OS, PFS	-BOR (RECIST) -QOL -% AE	499	Pending
Avelumab	NCT01943461 (JAVELIN SOLID TUMOR JPN)	I	Active, not recruiting	-AVE	-Locally advanced/ metastatic solid tumors (Japan) → expansion part GC patients (Asia)	-DLT	-Concentration assessment, elimination half-life -% PD-L1 -BOR+ irBOR, PFS +irPFS -OS % Ab-anti AVE -% AE	57	Pending
Avelumab	NCT03475953 (REGOMUNE)	I/II	Not yet recruiting	-AVE + REGORAFENIB	-Advanced/metastatic digestive solid tumors (including GC)	-Recommended doses -Assessment of Regorafenib antitumor activity -Pharmacokinetics	-Maximum tolerated dose -DLT -% AE -BOR, ORR, PFS, OS -Blood/tumor growth biomarkers	212	Pending
Avelumab	NCT02554812 (JAVELINE Medley)	Ib/II	Recruiting	-AVE + other immunotherapies → AVE + PD 0360324 (M-CSF mAb) (gastric cancer)	-Locally advanced/ metastatic solid tumors (including GC)	-% DLT -ORR	-Serum concentration of drugs -Ab-anti drugs -TTR, DOR, PFS, OS -Tumor biomarkers (PD-L1, CD8+T cells)	560	Pending
Durvalumab	NCT02734004 (MEDIOLA)	I/II	Active, not recruiting	-DURVA + OLAPARIB (PARP inhibitor)	-Advanced solid tumors (including GC)	-DCR (at CT/MRI) -% AE -Safety- vital signs, blood samples	-% PD-L1 -DCR (mRECIST) -Time to treatment discontinuation) -OS -% change in tumor size (CT/MRI) -Serum concentration of Ab-anti drug -Pharmacokinetics -ORR, DOR, PFS (mRECIST)	148	Pending
Durvalumab	NCT02572687	I	Active, not recruiting	DURVA + RAMUCIRUMAB	-Locally advanced unresectable/ metastatic gastrointestinal (including GC/GEJ adenocarcinoma) and thoracic malignancies	-% DLT	-ORR, DCR -DOR, TTR -PFS -OS -Pharmacokinetics -% Ab-anti drug	114	Pending
Durvalumab	NCT02678182 (PLATFORM)	II	Recruiting	-DURVA vs. CAPECITABINE vs. TRASTUZUMAB vs. RUCAPARIB vs. surveillance	-Maintenance treatment, locally advanced/ metastatic HER2+/-EG, adenocarcinoma (after Ist line chemo)	-PFS (RECIST)	-PFR -OS, ORR (RECIST) -% AE -PFS, PFR, OS, ORR according to PD-L1 immunohistochemical status	770	Pending
Durvalumab	NCT02264678	I/II	Recruiting	-AZD6738 ± Chemo/OLAPARIB/DURVA	-Advanced malignancies (including GC)	-Safety, tolerability (AE, SAE)	-Pharmacodynamics, biomarker changes -Serum concentration of drug, half-life, etc. -BOR, ORR, % change in tumor size	250	Pending

NIVO: Nivolumab; IPI: Ipilimumab; TREME: Tremelimumab; DURVA: Durvalumab; PEMBRO: Pembrolizumab; AVE: Avelumab, TRAS: Trastuzumab; Chemo: Chemotherapy; AE: Adverse events; SAE: Serious adverse events; DLT: Dose limiting toxicities; DOR: Duration of response; OS: Overall survival; QOL: Quality of life; PFS: Progression free disease; ir-PFS: Immune-related progression free disease; PFR: Progression-free rate; ORR: Objective response rate; RR: Response rate; pathCR: Pathologic complete response, RFS: Relapse-free survival; DR: Disease response; DDC: Duration disease control; BOR: Best objective response; DCR: Disease control rate; PD: Progressive disease; CR: Complete response; PR: Partial response; SD: Stable disease; TTR: Time to response; NET: Neuroendocrine tumors; SqCC: Squamous cell carcinoma; GIST: Gastrointestinal stromal tumors; EBV: Epstein Barr virus; N/A: Not applicable.