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Toihata et al. J Cancer Metastasis Treat 2018;4:24  I  http://dx.doi.org/10.20517/2394-4722.2017.82                          Page 7 of 10

               Table 2. The phase III clinical trials of immunotherapy for esophagogastric junction and gastric adenocarcinoma
                                                       Patients                                   Primary
                Trial               Drug       Target                      Treatment
                                                        (EGJ)                                    endpoint
                CheckMate 649   Nivolumab      PD1      594     Nivolumab and ipilimumab vs. 5-FU and   OS
                (NCT02872116)                  CTLA-4   (106)   oxaliplatin
                KEYNOTE-062     Pembrolizumab  PD1      545     Pembrolizumab vs. pembrolizumab, 5-FU and   PFS and OS
                (NCT02494583)                           (49)    cisplatin
                                                                or capecitabine vs. 5-FU and cisplatin
                KEYNOTE-061     Pembrolizumab  PD1      665     Pembrolizumab vs. paclitaxel     PFS and OS
                (NCT02370498)                           (137)
                ONO-4538-12     Nivolumab      PD1      261     Nivolumab vs. placebo            OS
                (NCT02267343)                           (0)

               CTLA-4: cytotoxic T-lymphocyte-associated protein 4; OS: overall survival; PD1: programmed death protein 1; 5-FU: 5-fluorouracil; PFS:
               progression-free survival

               abundance of specific bacterial species in the oral and fecal microbiome enhanced systemic and antitumor
               immunity [43,44] . For example, in the patients with advanced tumor who received immunotherapy, the use of
                                                                                                       [45]
               antibiotics caused poor prognosis. In addition, oral administration of bacteria improved anti-tumor effect .
                                                                                   [46]
               Some immune checkpoints, such as lymphocyte activation gene 3 protein (LAG3) , T-cell immunoglobulin
                                        [47]
                                                                                               [48]
               and mucin domain 3 (TIM3) , T-cell immune-receptor with Ig and ITIM domains (TIGIT)  are being
               currently investigated in clinical trials, in order to develop new drugs in the near future.
               CONCLUSION
               Global standard treatment for metastatic EGJ and gastric adenocarcinoma is the combination of platinum-
               agents and fluoropyrimidine. The availability of targeted agents such as trastuzumab or ramucirumab,
               have become a new hope to the patients with this aggressive tumor. Immune checkpoint inhibitors have
               emerged as a novel therapeutic option. Discovering the best combination of these drugs may lead a dramatic
               improvement of the prognosis of these aggressive tumors.


               DECLARATIONS
               Authors’ contributions
               Concept, design, literature search and manuscript preparation: Toihata T
               Concept, design, and manuscript editing: Imamura Y
               Manuscript review: Watanabe M, Baba H

               Financial support and sponsorship
               None.


               Conflicts of interest
               There are no conflicts of interest.


               Patient consent
               Not applicable.


               Ethics approval
               Not applicable.


               Copyright
               © The Author(s) 2018.
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