*6.2.9. Immunotherapy/immuno-checkpoint blockade*

Because it was revealed that tumors evade host immune recognition [153], immunotherapy has emerged as a novel field of antitumor treatment, which acts by using the blockage mechanism of the inhibitory immune regulatory pathways. New agents targeting immune checkpoints, programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1), have been recently investigated.

Ipilimumab blocks the inhibitory receptor called cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Unfortunately, a phase II trial assessing the efficacy of ipilimumab after first-line chemotherapy in unresectable locally advanced or metastatic gastric cancer patients revealed no statistically significant improvement in OS [154].

Nivolumab blocks the interactions between PD-1 and PD-L1 stimulated immune function in vitro, showing antitumor activity in preclinical models. A phase I/II study of nivolumab monotherapy versus nivolumab combined with ipilimumab in patients with advanced or metastatic solid tumors, including gastric cancer, is still ongoing [155]. Interim results revealed that nivolumab monotherapy demonstrated encouraging antitumor activity in heavily pretreated gastric cancer patients [156]. Furthermore, a phase III trial is currently assessing the tolerability and efficacy of nivolumab in patients with unresectable advanced or recurrent gastric cancer refractory to standard chemotherapy [157].

Pembrolizumab is an agent that blocks the binding of PD-1 to PDL-1, demonstrated to have good tolerability, as well as anti-tumor activity in a phase 1 study including recurrent and metastatic gastric adenocarcinoma patients with PD-L1 (+) tumors [158]. Other phase I-III trials are investigating this agent in advanced gastric cancer [159, 160], with the aim of investigating the molecular subtypes of gastric tumors through integrative genomic analysis [161]. Some phase I/II studies are assessing its efficacy in combination with other classes of agents (anti-HER2 or anti-VEGFR monoclonal antibodies, multitargeted TKIs) [162–165].

Durvalumab, an anti-PDL-1 drug, has shown some activity in gastric cancer treatment [166]. The combination of durvalumab and tremelimumab (anti-CTLA-4) plus first-line chemotherapy is currently being investigated in advanced solid tumors (including gastric cancers) [167, 168].
