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Page 6 of 10                           Toihata et al. J Cancer Metastasis Treat 2018;4:24  I  http://dx.doi.org/10.20517/2394-4722.2017.82

               ABT-806, TBD2, ramucirumab, and nivolmab) are assigned according to the biomarkers, along with
                                    [32]
               standard chemotherapy . VIKTORY is a screening trial without drug intervention for metastatic GC
               patients who failed or progressed on first-line chemotherapy, using cancer panel/nanostring CNV and
                                   [33]
               immunohistochemistry . These efforts may create new algorithms in upper gastrointestinal cancers.

               IMMUNOTHERAPY
               The most advanced of the emerging development in EGJ and gastric adenocarcinoma is immunotherapy.
               Programmed death protein 1 (PD1), programmed cell death 1 ligand 1 (PD-L1) and cytotoxic T lymphocyte
               protein 4 (CTLA4) are the key drugs to regulate cellular immune functions. Pembrolizumab and nivolumab,
               which are being developed as anti-PD1 antibodies, have been examined in clinical trials.

               Pembrolizumab
               Pembrolizumab is a selective, humanized, high-affinity IgG4-κ monoclonal antibody. By binding to PD1,
               pembrolizumab block the interaction between PD-1 and its ligands. In the USA, pembrolizumab was
               approved by the FDA for the treatment of melanoma, non-small-cell lung cancer and head and neck cancer.
               In a phase Ib trial (KEYNOTE-012), the safety and activity of pembrolizumab was assessed in patients
               with PD-L1 positive advanced EGJ and gastric adenocarcinoma. The median PFS and the median OS were
                                                                          [34]
               1.9 months (95% CI 1.8-3.5) and 11.4 months (95% CI 5.7) respectively . The KEYNOTE-061 is a phase III
               trial as a second-line therapy for PD-L1-positive patients, comparing pembrolizumab with paclitaxel. The
               KEYNOTE-062 is phase III trial of pembrolizumab alone or combination with FP or capecitabine vs. FP or
               capecitabine alone as a first-line therapy for PD-L1-positive patients. Both of these trials are still in progress.

               Nivolumab
               Nivolumab is a fully human IgG4 monoclonal antibody inhibitor of PD-1. In the ATTRACTION-2 study,
               which was a randomized phase III trial, investigating the efficacy and safety of nivolumab as a third-line
               for unresectable advanced and recurrent EGJ and gastric adenocarcinoma regardless of PD-L1 expression.
               Median OS was 5.26 months (95% CI 4.60-6.37) in the nivolumab group and 4.14 months (95% CI 3.42-4.86)
               in the placebo group (HR 0.63, 95% CI 0.51-0.78; P < 0.0001), resulting in a new treatment option for these
                      [35]
               cancers . The other anti PD-L1 antibody, such as avelumab, durvalumab and atezolizumab have been
               expected to advanced EGJ and gastric adenocarcinoma. Two randomized phase III trials of avelumab in EGJ
               and gastric adenocarcinoma are undergoing [Table 2].


               CheckMate-032 is an ongoing trial, evaluating nivolumab alone, and nivolumab in combination with
               ipilimumab, for various solid tumors including previously treated advanced EGJ and gastric adenocarcinoma,
               regardless of PD-L1 expression status. Patients were randomly assigned in to the following three groups,
               NIVO3 group (nivolumab: 3 mg/kg, once every 2 weeks), NIVO1 plus IPI3 group (nivolumab: 1 mg/kg
               plus ipilimumab: 3 mg/kg, once every 3 weeks) and NIVO3 plus IPI1 group (nivolumab: 3 mg/kg plus
               ipilimumab: 1 mg/kg, once every 3 weeks). The median OS were 6.2 months (95% CI 3.4-12.4) in NIVO3
               group, 6.9 months (95% CI 3.7-11.5) in NIVO1 plus IPI3 group and 4.8 months (95% CI 3.0-8.4) in NIVO3
               plus IPI1 group [36,37] . In addition, CheckMate 649 examining nivolumab plus ipilimumab or nivolumab
                                                                                               [38]
               plus chemotherapy compared with patients receiving chemotherapy alone are also in progress . Utilizing
               nivolumab in combination with the other agents may be a major option for EGJ and gastric adenocarcinoma.

               Future prospect of immunotherapy
               Many study reported that PD-L1 expression has been related with poor prognosis and associated with
               response to immunotherapy [39-42] . On the other hands, only a few studies reported that PD-L1 blockade
                                                 [35]
               was effective without PD-L1 expression . These results indicated that PD-L1 is not yet established as a
               biomarker for PD-L1 inhibitors. Recent reports suggested that host microbiome and tumor and stromal
               genomic profiles may be related with response to immune checkpoint blockade [9,10] . The diversity and
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