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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