Progress of immune checkpoint inhibitors in gastric cancer

Table 1 Immune checkpoint inhibitors approved by the Food and Drug Administration for gastric cancer

Drug	Brand name	Target	Medication regimen	Indication	Ref.
Nivolumab	Opdivo	PD-1	Alone	Stage II/III GC/GEJ with residual pathological tissue after neoadjuvant chemoradiotherapy	Kelly et al[10]
Nivolumab	Opdivo	PD-1	Nivolumab combined with chemotherapy (leucovorin, fluorouracil, and oxaliplatin or capecitabine and oxaliplatin)	Advanced metastatic HER-2-negative GC/GEJ	Janjigian et al[11]
Pembrolizumab	Keytruda	PD-1	Pembrolizumab combined with chemotherapy (cisplatin and 5-FU)	Locally advanced metastatic GC/GEJ	Sun et al[12]
Pembrolizumab	Keytruda	PD-1	Pembrolizumab combined with chemotherapy (platinum and fluoropyrimidine) and Trastuzumab	Locally advanced metastatic unresectable HER-2-positive GC/GEJ	Janjigian et al[13]
Pembrolizumab	Keytruda	PD-1	Pembrolizumab with chemotherapy (oxaliplatin with capecitabine or cisplatin and 5-FU)	Locally advanced metastatic HER-2-negative GC/GEJ	Rha et al[14]

GC/GEJ: Gastric cancer/gastroesophageal junction; HER-2: Human epidermal growth factor receptor 2; PD-1: Programmed death 1; 5-FU: 5-fluorouracil.

Table 2 Clinical trials of programmed death 1 for gastric cancer

Immune checkpoint inhibitor	Patient	Method	Phase	Ref.
Pembrolizumab	Recurrent or metastatic PD-L1-positive GC/GEJ	Intravenously once/2 weeks in 2 years or until progression or unbearable toxic reactions	Ib	Muro et al[37]
Pembrolizumab	Previously treated GC/GEJ	Intravenously once/3 weeks until progression, or unbearable toxic reactions	Ⅱ	Fuchs et al[38]
Pembrolizumab	Advanced GC/GEJ with poor outcomes after chemotherapy	Once/3 weeks for 24 months	III	Shitara et al[39]
Pembrolizumab	Untreated, advanced GC/GEJ with positive score (CPS) ≥ 1	Once/3 weeks	Ⅲ	Shitara et al[40]
Camrelizumab (SHR1210)	Recurrent, metastatic refractory or intolerant GC/GEJ after previous chemotherapy	Intravenously once and 4 weeks later once/2 weeks	I	Huang et al[41]
Pembrolizumab	Advanced PD-L1-positive GC/GEJ (CPS ≥ 1)	Intravenously once/3 weeks for 2 years	I	Chung et al[42]
Toripalimab	Advanced chemo-refractory GC patients	Monotherapy with Toripalimab (3 mg/kg, every 2 weeks)	Ib/II	Wang et al[43]
Nivolumab	Locally advanced or metastatic chemotherapy-refractory GC	Intravenously once/2 weeks	I/II	Janjigian et al[44]
Nivolumab	Advanced GC/GEJ, previously treated with chemotherapy	Intravenously once/2 weeks until progression or unbearable toxic reactions	Ⅲ	Kang et al[45]

CPS: Combined positive score; GC: Gastric cancer; GC/GEJ: Gastric cancer/gastroesophageal junction; PD-L1: Programmed death ligand 1.

Table 3 Clinical trials of immune checkpoint inhibitors combined with chemotherapy for gastric cancer

Immune checkpoint inhibitor	Medication regimen	Type of GC	Phase	Clinical trials
Camrelizumab	Combined with chemotherapy (oxaliplatin, paclitaxel)	HER-2 negative, unresectable GC with programmed death ligand 1 + combined positive score ≥ 1, MSI-H/dMMR, or EBV (+) GC	Completed	NCT04694183
Sintilimab	Combined with Apatinib and chemotherapy (S-1 fluoropyrimidine, nab-paclitaxel)	Unresectable patients with stage IV GC	II	NCT04267549
Nivolumab/Pembrolizumab/Atezolizumab	Combined with chemotherapy (cyclophosphamide and fludarabine)	Advanced relapse or progression of solid tumor	I	NCT03841110
Tislelizumab	Combined with Apatinib and chemotherapy (oxaliplatin and capecitabine)	Advanced HER-2-negative GC/GEJ with signet ring cell carcinoma or peritoneal metastasis and poor prognosis	Completed	NCT06238752
Pembrolizumab	HER-2 negative group: Combined with capecitabine/oxaliplatin. HER-2 positive group: Combined with Trastuzumab and capecitabine/cisplatin	EBV negative advanced GC/GEJ and microsatellite-stable (or mismatch repair-proficient) GC	II	NCT04249739
Margetuximab/Retifanlimab/Tebotelimab	Combined with chemotherapy, chemotherapy: Capecitabine and oxaliplatin or mFOLFOX6	HER-2-positive GC/GEJ	III	NCT04082364
Camrelizumab	Combined with FOLFOX	Advanced GC/GEJ	II	NCT03939962
Atezolizumab	Combined with docetaxel, oxaliplatin, and capecitabine	Resectable GC/GEJ	II	NCT03448835
Pembrolizumab	Combined with mFOLFOX6	Potentially resectable locally advanced GC/GEJ (T1N1-3M0 or T2-3NanyM0)	II	NCT03488667
Atezolizumab	Combined with chemotherapy (docetaxel, oxaliplatin, leucovorin calcium, fluorouracil, capecitabine)	Previously untreated localized GC/GEJ with MSI-H/dMMR	II	NCT05836584
Avelumab	Combined with peri-operative FLOT	Stage Ib (T1N1 only)-IIIC GC	III	NCT03979131
Avelumab	Combined with FLOT	Resectable GC/GEJ	II	NCT03399071
Atezolizumab	Combined with FLOT	Locally advanced, resectable GC/GEJ without distant metastases	II/III	NCT03421288

EBV: Epstein-Barr virus; FLOT: Docetaxel, oxaliplatin, fluorouracil/Leucovorin; FOLFOX: Folinic acid, fluorouracil, and oxaliplatin; GC: Gastric cancer; GC/GEJ: Gastric cancer/gastroesophageal junction; HER-2: Human epidermal growth factor receptor 2; MSI-H/dMMR: Microsatellite instability-high/DNA mismatch repair.

Table 4 Clinical trials of immune checkpoint inhibitors combined with targeted therapy for gastric cancer

Immune checkpoint inhibitor	Target drug	Targets	Type of GC	Phase	Ref.
Pembrolizumab	Trastuzumab	HER-2	Advanced unresectable metastatic HER-2-positive GC	III	Lee et al[79]
Pembrolizumab	Trastuzumab	HER-2	Metastatic HER-2-positive GC	II	Janjigian et al[80]
Pembrolizumab	Margetuximab	HER-2	Locally advanced unresectable HER-2-positive metastatic GC, programmed death ligand 1 unselected, which had progressed after treatment with Trastuzumab combined with chemotherapy	I/II	Catenacci et al[81]
SHR-1210	Apatinib	VEGFR-2	GC/GEJ	II	Xu et al[82]
Pembrolizumab	Lenvatinib	VEGFR	Metastatic or recurrent GC/GEJ	II	Kawazoe et al[83]
Pembrolizumab	Lenvatinib	VEGFR	Advanced metastatic and/or unresectable GC which failed systemic therapy	II	Taylor et al[84]
Nivolumab	Regorafenib	VEGFR	Refractory advanced GC	III	Lam et al[85]
Nivolumab	Regorafenib	VEGFR	Unresectable recurrent GC and refractory or intolerant to chemotherapy	I	Fukuoka et al[86]
Nivolumab	Anlotinib	VEGFR	Unresectable or metastatic GC patients who failed standard therapy	II	Wu et al[87]
Pembrolizumab	Cabozantinib	VEGFR	Refractory metastatic GC	II	Dayyani et al[88]
Pembrolizumab	Ramucirumab	VEGFR-2	Previously treated advanced GC	I	Herbst et al[89]
Nivolumab	Relatlimab	Lymphocyte activation gene-3	Unresectable stage II/stage III GC	II	Kelly et al[90]
Nivolumab	Mogamulizumab	C-C chemokine receptor 4	Unable to have standard operation, refused standard preoperative chemotherapy, electrocorticography performance status 0 or 1	I	Jinushi et al[91]
Nivolumab	Bemarituzumab	FGFR	Previously untreated advanced GC with FGFR2b overexpression	Ib/II	Wainberg et al[92]

FGFR: Fibroblast growth factor receptor; GC: Gastric cancer; GC/GEJ: Gastric cancer/gastroesophageal junction; HER-2: Human epidermal growth factor receptor 2; VEGFR: Vascular endothelial growth factor receptor.