Table 1 The clinical trial results of ICIs in GC.

NCT02370498

Pembrolizumab

/

No significant OS improvement but higher 24-month OS rate vs. paclitaxel. Enhanced OS benefit in PD-L1-positive gastric/GEJ cancer. Fewer TRAEs than paclitaxel.

[222]

NCT02589496

Pembrolizumab

/

~50% resistance to pembrolizumab. Nonsynonymous mutations correlate with antitumor activity and prolonged PFS. Diverse TCR repertoire and increased PD1 + CD8 + T cells linked to longer PFS and durable clinical benefit.

[223]

NCT02335411

Pembrolizumab

/

Promising activity and manageable safety in advanced gastric/GEJ cancer after ≥2 prior lines. Durable response observed in both PD-L1+ and PD-L1− tumors.

[224]

NCT02370498

Pembrolizumab

/

No significant OS improvement in PD-L1+ advanced G/GEJ cancer, but longer DOR and better safety profile.

[225]

NCT01848834

Pembrolizumab

/

Manageable toxicity and promising antitumor activity in PD-L1+ recurrent/metastatic GC; warrants further investigation in Phase II/III trials.

[226]

NCT02494583

Pembrolizumab

/

Maintains HRQOL; similar to chemotherapy in this population.

[227]

NCT02589496

Pembrolizumab

/

Pembrolizumab (MSI-H, EBV+ tumors): ORR 85.7% and 100%, respectively. In PD-L1+ (CPS ≥ 1%) vs. PD-L1− patients, ORR significantly higher (50.0% vs. 0.0%, P < 0.001). ctDNA levels at 6 weeks predict response and PFS; ctDNA decline correlates with better outcomes.

[228]

NCT02494583

Pembrolizumab

Chemotherapy

Pembrolizumab (PD-L1 CPS ≥ 1): OS non-inferior to chemotherapy, but not superior. For PD-L1 CPS ≥ 10, pembrolizumab extended OS, though not statistically significant. Pembrolizumab + chemotherapy showed no improvement in OS or PFS vs. chemotherapy alone. Fewer severe TRAEs with pembrolizumab.

[31]

NCT03675737

Pembrolizumab

Chemotherapy

Significantly extended OS, especially in PD-L1 CPS ≥ 1 and CPS ≥ 10 patients.

[33]

NCT02013154

Pembrolizumab

DKN-01

Good tolerability, no new safety signals. Enhanced antitumor activity in DKK1-high tumors in treatment-naive GEJ/GC patients.

[229]

NCT03609359

Pembrolizumab

Lenvatinib

Promising antitumor activity and acceptable safety in advanced GC. Confirmatory trials planned based on these results.

[230]

NCT03019588

Pembrolizumab

Paclitaxel

Inconclusive results due to small sample size, but show good tolerability and similar efficacy trend to KEYNOTE-061.

[231]

NCT02370498

Pembrolizumab

Paclitaxel

Similar HRQoL in advanced gastric and GEJ cancer patients.

[232]

NCT03615326

Pembrolizumab

Trastuzumab and chemotherapy

Trastuzumab + Chemotherapy vs. Pembrolizumab + Trastuzumab + Chemotherapy: Pembrolizumab significantly reduces tumor volume, achieves complete response in some patients, and markedly improves objective response rate.

[233]

NCT03382600

Pembrolizumab

SOX or S-1 and SP

Pembrolizumab + SOX or SP: Shows good efficacy and manageable safety.

[234]

NCT02267343

Nivolumab

/

Significantly improves long-term survival in advanced gastric/GEJ cancer patients.

[235]

NCT02951091

Nivolumab

/

Demonstrates durable survival benefit.

[236]

apicCTI-183895 (ClinicalTrials.jp)

Nivolumab

/

Neoadjuvant Nivolumab (monotherapy): Feasible in some resectable GC patients, with acceptable safety and potential for inducing major pathological responses.

[237]

NCT02872116

Nivolumab

Chemotherapy

Shows stable or improved HRQoL compared to chemotherapy alone in advanced/metastatic non-HER2 + GC /GEJC/EAC, with reduced risk of HRQoL deterioration.

[238]

NCT04078295

Nivolumab

E7389-LF

Shows promising antitumor activity in GC patients, with no new safety signals compared to monotherapy.

[239]

NCT03878472

Camrelizumab

Apatinib and S-1 ± oxaliplatin

Complete Pathological Response Rate: 15.8%

Major Pathological Response Rate: 26.3%

Pathological Response: Significantly associated with MSI, PD-L1 expression, and TMB.

[240]

NCT04195828

Camrelizumab

Apatinib and chemotherapy

Good tolerability and favorable response in locally advanced GC.

[241]

NCT04345783

Camrelizumab

Apatinib and S-1

Promising antitumor activity and manageable toxicity in advanced gastric/GEJ adenocarcinoma, regardless of PD-L1 expression.

[242]

NCT02734004

Durvalumab

Olaparib

Shows promising antitumor activity and safety.

[243]

NCT03941873

Tislelizumab

Sitravatinib

Generally well-tolerated, with preliminary antitumor activity in advanced HCC and GC /GEJC patients.

[244]

NCT05844371

Tislelizumab

XELOX therapy

Adding PD1 inhibitor improves 1-year DFS rate in locally lymph node-positive GC vs. chemotherapy alone. Treatment is safe and well-tolerated.

[245]

NCT02915432

Torpalima

XELOX

Shows manageable safety and promising antitumor activity in AGC patients, especially when combined with XELOX. High TMB may predict OS in AGC patients receiving monotherapy.

[246]

NCT03193190 and NCT03281369

Atezolizumab

PEGPH20

No clinical activity in GC patients. Safety profile consistent with known safety of each drug.

[247]

NCT03667170

Envafolimab

/

As the first subcutaneously administered single-domain anti-PD-L1 antibody, demonstrates good efficacy and acceptable safety in treating advanced dMMR/MSI-H solid tumors, with potential as a significant advancement in cancer therapy.

[248]

NCT01943461

Avelumab

/

Shows acceptable safety in advanced solid tumor patients in Japan, with some clinical activity in advanced gastric/GEJ cancer patients.

[249]

NCT04182724

PD1 inhibitor (selected according to the patient’s needs)

Albumin-bound paclitaxel and apatinib

Shows certain efficacy and safety in mGC patients.

[250]

NCT02699515

Bintrafusp (a first-in-class bifunctional fusion protein, composed of the extracellular domain of the TGFβ RII receptor fused to a human IgG1 antibody targeting PD-L1)

/

Shows controllable safety and clinical activity.

[251]

NCT03710265

SHR-1701 (a novel bifunctional fusion protein, composed of an anti-PD-L1 monoclonal antibody fused with the extracellular domain of TGF-β receptor II)

/

Demonstrates good safety and encouraging antitumor activity, providing a basis for further exploration.

[252]