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Kiyozumi et al. J Cancer Metastasis Treat 2018;4:31 I http://dx.doi.org/10.20517/2394-4722.2017.77 Page 7 of 15

Onartuzumab is a monovalent antibody that acts against c-MET and binds to the extracellular domain of
c-MET preventing the ligand HGF. A phase III trial compared mFOLFOX6 with or without onartuzumab in
MET-positive and HER2-negative gastroesophageal adenocarcinoma (GEC) (METGastric trial) . However,
[30]
addition of onartuzumab to first-line mFOLFOX6 did not significantly improve clinical benefits in OS, PFS,
or ORR. Predictive biomarkers that identify patient groups who will most likely gain clinical benefit from
onartuzumab require further investigation.

mTOR targeted therapies
The mTOR is known to be the mammalian target of rapamycin and is encoded by the mTOR gene in
humans. Phosphatidylinositol 3-kinase (PI3K)/Akt and mTOR activated in 30%-60% of gastric cancer PI3K/
Akt/mTOR pathway dysregulations are associated with chemotherapy resistance .
[31]
Everolimus is an oral mTOR inhibitor and was established as standard therapy in several types of cancer.
Although everolimus in a phase II trial was demonstrated to be significantly beneficial clinically , in a
[32]
phase III trial, everolimus did not significantly improve OS for AGC after first- or second-line chemotherapy
compared with BSC (GRANITE-1) . The reason for these results was discussed to be partially attributable
[33]
to the slightly higher percentage of placebo groups who initiated antineoplastic therapy after a study on
drug discontinuation. In everolimus treatment, the predictive biomarker also needs to be investigated to
determine its more effective use.

Anti-Claudin 18.2 monoclonal antibody
The Claudin-18 splice variant 2 (CLDN18.2) belongs to a family of tight junction proteins. Claudin 18.2 is
expressed in several types of cancer including GC. Claudiximab (IMAB362) is the chimeric monoclonal
anti-CLDN18.2 antibody which activates antibody and component dependent cytotoxicity. In the FAST
study, combinations of claudiximab with first line chemotherapy was evaluated in patients with advanced
or recurrent GC or GEJA (NCT01630083). Claudiximab in combination with EOX (epirubicin + oxaliplatin
+ capecitabine) as first line have been showed clinically benefit in PFS and OS in this study . Therefore, it
[34]
will be expected to establish the evidence from a phase III trial in future.

Anti-matrix metalloproteinase-9 antibody
Matrix metalloproteinase (MMPs) is a matrixin, a class of enzymes that belong to the zinc metalloproteinases
family. MMP-9 is an extracellular enzyme which progress angiogenesis, tumor proliferation, and metastasis.
GS-5745 is a monoclonal antibody that inhibits MMP-9 and has been combined with other chemotherapies .
[35]
Andecaliximab (GS-5745) is now being examined in a phase III trial in GC with mFOLFOX as 1st line
(NCT02545504).

IMMUNOTHERAPY FOR GASTRIC CANCER
Cancer immunotherapy is the use of the immune system in humans themselves to treat cancer.
Conventionally, active immunotherapy, adoptive immunotherapy or antibody therapy have been developed
as anticancer treatment. Active immunotherapy, which has been used in an attempt to stimulate the host’s
immune response to disease, such as a cancer vaccine, dendritic cell (DC) therapy, or cytokine therapy,
was approved for some cancer types. Antibodies play a key role in adaptive immune response. Adoptive
immunotherapy and antibody therapy use anti-tumor responses, monoclonal antibodies, lymphocytes and
cytokines. However, the clinical effect of these therapies is limited and disparity exists for each evidence
level for cancer treatment.

Most recently, immunotherapy has been acknowledged to be one of the most advanced therapies available
in the treatment of cancer. We can experience the paradigmatic shift in the treatment of cancer including
melanoma, NSCLC, renal cell carcinoma, and gastrointestinal cancer. Many clinical trials have been