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advanced or metastatic urothelial carcinoma. Durvalumab has also been shown to be efficient in GC.
Therefore, evaluating the safety, tolerability, antitumor activity, PK, pharmacodynamics and immunogenicity
of durvalumab in combination with tremelimumab, which is a human IgG2 fully monoclonal antibody that
acts against CTLA-4, and examining tremelimumab monotherapy in subjects with metastatic or recurrent
GC or GEJA are ongoing in a phase Ib/II trial. Durvalumab has also been evaluated for efficiency with
another medicine, epacadostat (INCB024360) (ECHO-203, NCT02318277) . Epacadostat is a potent and
[45]
novel indolemine-2, 3 dioxygenase (IDO1) inhibitor. IDO1 is an enzyme responsible for oxidizing tryptophan
into kynurenine and is implicated in immune modulation through its ability to limit T cell function and
engage mechanisms of immune tolerance. IDO1 is focused upon as an immune subversion strategy and
therapies targeting IDO1 are being evaluated in many types of cancer including GC.

DISCUSSION AND CONCLUSION
Although several clinical trials have attempted to improve prognosis in GC patients and their survival
[46]
rate has been improving in recent years, unresectable or metastatic AGC has been untreatable, and median
survival at this stage remains poor . Therefore, research into more effective therapeutic targets, biological
[47]
mechanisms, and treatments for AGC is essential.

Research that targeted therapy, including target genes, signaling pathways and drugs, is being developed
day by day. Over the past few years, trastuzumab, as a first-line treatment for AGC and ramucirumab, as
[4]
a second-line treatment has been recommended worldwide. Although many clinical trials have failed and
[5]
have been unable to contribute new clinical benefits, further research has been conducted into establishing
the next standard treatment for GC. In the present article, we summarized recent clinical trials. At this
time, many useful basic research and preclinical trials are being performed and their progress is expected to
provide us with better treatment for patients with GC in the near future.

In the field of immunotherapy, especially, more innovative treatments and combinations with other therapies
are expected to be established. In addition to the clinical trials listed in this article, various other clinical
trials and preclinical research are conducted in several types of cancer. Immunotherapeutic approaches with
other agents, chemotherapies, targeting therapies, radiations, or different kinds of immunotherapies are
currently being investigated to determine whether each clinical outcome is improved or not. In combined
immunotherapy and cytotoxic chemotherapy, the synergism of these combinations is expected to lead to
immunogenic cell death (ICD) . ICD is a form of cell death induced by cytotoxic agents such as oxaliplatin.
[48]
As another mechanism, gemcitabine or docetaxel reportedly inhibits the increasing myeloid-derived
suppressor cells and B cell. Based on those mechanisms, a trial combination comparing nivolumab and
conventional chemotherapy and other clinical trials is ongoing. In phase I or I/II trials, combinations of
targeting therapies and immunotherapies, such as atezolizumab, which is a PD-L1 inhibitor, and bevacizumab,
are examined in participants with solid tumors including GC (NCT02715531). In other types of cancer, the
safety and tolerability of these therapies have been confirmed. If such trials demonstrate clinical benefit in
GC, we can expect an increase of various combination patterns of therapies that have different anticancer
mechanisms. Simultaneously, a start on evaluating adverse events and long-time clinical benefits should be
made as soon as possible. This is particularly necessary considering that a diverse range of adverse events in
immunotherapy have already been reported in many trials including GC themes; furthermore, whether or
not exacerbation factors exist in some combination therapies must be confirmed. In preclinical research, the
combination of multiple immune checkpoint therapy has been verified in mice. In light of this knowledge,
more innovative treatment for GC is expected to be developed.

In another respect, combinations of multiple drug regimens that have been approved for other types of cancer
are expected for adaptation expansion to GC. For example, in melanoma, the FDA has already approved many
drugs and combinations, such as ipilimumab alone, combined nivolumab and ipilimumab, pembrolizumab