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is the most recommended curative choice. For unresectable or metastatic advanced gastric cancer (AGC),
chemotherapy treatment is first selected.

Conventionally, cytotoxic agents, such as 5-fluorouracil (5-FU), platinum agent, irinotecan, taxanes, and
anthracyclines, are used for AGC. Among these, recommended as the first-linetreatment, is a combination
of 5-FU and platinum-based chemotherapy with or without docetaxel. This treatment results in a median
overall survival (OS) of 10-15 months and a median progression-free survival (PFS) of 5-6 months . For
[2]
second-line treatment or after treatment, docetaxel, irinotecan, and paclitaxel are known to improve
prognosis compared with best supportive care (BSC) . Although chemotherapy has improved survival in
[3]
patients with AGC, the prognosis of these patients remains poor.

However, some therapies targeting biological molecules have been reported to prolong the OS of patients with
AGC. Trastuzumab, a monoclonal antibody for human epidermal growth factor receptor2 (HER2), has already
been established with chemotherapy as first-line treatment for HER2-positive AGC patients . In addition,
[4]
ramucirumab, an anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody has also proven to be
efficient for second-line treatment . Therefore, this targeted therapy field is indeed currently evolving.
[5,6]
Recently, immunotherapy has also been expected to be an innovative therapy for several types of cancer.
Cancer immunotherapy can reverse tumor immune escape associated with suppression of the immune
checkpoint pathway. Immunotherapies targeting programmed death 1 (PD-1)/programmed death-ligand 1
(PD-L1) checkpoints have been identified to be an important scientific breakthrough and have already been
approved in treatment of many types of cancer including melanoma, non-small cell lung cancer (NSCLC)
and renal cell carcinoma. In addition, immunotherapy has begun to be approved for last-line treatment in
GC patients based on the latest clinical trial data . Immunotherapy has important clinical application with
[7]
favorable outcomes, limitations, and acceptable adverse events, with it having been applied in many past and
undergoing clinical trials.

In this article, the latest knowledge of focused on common cancer targets, signaling pathways, targeting
therapies, and immunotherapies for AGC are reviewed and future prospects for AGC treatment are described.

TARGETED CHEMOTHERAPY
Since trastuzumab, a monoclonal antibody that targets HER2, was established as standard therapy for
unresectable GC in a HER2-positive patient , many other targets have been reported as new therapytargets.
[4]
Furthermore, phase III trials that target HER2, epidermal growth factor receptor (EGFR), vascular
endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR), MET, or the
mechanistic target of rapamycin (mTOR) have been examined with new findings [Figure 1 and Table 1]. We
introduce the current knowledge of targeting therapies for GC.

Anti-HER2 monoclonal antibodies
HER2 is a proto-oncogene encoded by ErbB2 on chromosome 17. Trastuzumab was the first HER2-targeted
drug to be developed and introduced for the treatment of HER2-positive metastatic breast cancer. Trastuzumab
induces antibody-dependent cytotoxicity which causes the downregulation of cell cycle disorders. The ToGA
trial, comprising randomized controlled trials recruiting patients with histology confirmed, inoperable,
locally advanced, recurrent, or metastatic adenocarcinoma, was the first randomized phase III trial to show
trastuzumab plus chemotherapy . The result of this trial with trastuzumab plus chemotherapy is superior
[4]
to chemotherapy alone for HER2-positive advanced or metastatic gastric cancer with regard to OS and DFS.
Furthermore, up to 22.1% of patients were HER2-positive [Immunohistochemistry (IHC)2+/ fluorescence in situ
hybridization (FISH)+ or IHC3+] in this trial and especially, the OS of the HER2 high-expression group was
16.0 months. This result precisely demonstrated the efficiency of trastuzumab for AGC.