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Page 6 of 15 Kiyozumi et al. J Cancer Metastasis Treat 2018;4:31 I http://dx.doi.org/10.20517/2394-4722.2017.77

most. The necessity to search a biomarker to detect patient groups who have responded to bevacizumab
treatment in this trial has been discussed.

Anti-VEGFR monoclonal antibody
Ramucirumab is directed against the VEGFR2 that mediated the majority of downstream effects of VEGF in
angiogenesis by binding to VEGFR2 as a receptor antagonist blocking VEGF/VEGFR2. In a phase III study of
AGC, ramucirumab monotherapy increased median survival time (MST) compared with placebo (REGARD
study) . Furthermore, in another phase III study of AGC, the combination of ramucirumab with paclitaxel
[5]
significantly increased both OS and PFS compared with placebo with paclitaxel (RAINBOW study) .
[6]
Therefore, ramucirumab was established as one standard therapy for unresectable GC. The REGARD trial
and RAINBOW trial both demonstrated the role of VEGFR-2 as an important therapeutic target in AGC. In
the AVAGAST study, the efficiency of bevacizumab for Asian patients tended to be insufficient. In addition,
second and further lines of therapy are more commonly received in Asia. In the REGARD trial, the control
arm was designed in BSC. Therefore, other factors might experience difficulty in influencing the results.
In the latest ongoing phase III study, the combination of ramucirumab with capecitabine and cisplatin is
compared in PFS to capecitabine and cisplatin as first-line therapy in metastatic GC or GEJA (RAINFALL
trial, NCT02314117).

TKIs
Apatinib (also known as YN968D1) is a small-molecule tyrosine kinase inhibitor (TKI) that highly selectively
binds to and strongly inhibits VEGFR2 and decreases the VEGF-mediated endothelial cell migration,
proliferation, and tumor microvascular density. This agent also inhibit c-kit and c-SRC tyrosine kinases
mildly. In a phase III trial, apatinib treatment significantly improved OS and PFS in patients who had at least
two lines of prior chemotherapy fail compared with BSC . Therefore, apatinib is focused on as a novel type
[25]
of targeted treatment for AGC in several lines of therapy.

Regorafenib is an oral multikinase inhibitor, targeted angiogenic (VEGFR1, VEGFR2, and TIE2), stromal
and oncogenic receptor tyrosine kinases. In a phase II trial, regorafenib significantly increased PFS compared
with placebo as second-line or later-line therapy in AGC (INTEGRATE trial) . Preliminary biomarker
[26]
analysis from this trial suggested that the benefit of regorafenib was comparable in patients with VEGFA
levels above and below the median. Especially, multitargeted tyrosine kinase inhibitors and similar have
been required to define the subset of patients who could influence the clinical benefits. At the present time,
a phase III trial is planned.

c-MET signaling pathway inhibitors
c-MET is a transmembrane tyrosine kinase receptor for hepatocyte growth factor (HGF). c-MET activation
promotes cell growth, invasion, and HGF/c-MET activation that occurs in several types of cancer including
GC . Furthermore, HGF/c-MET pathway has been related to tumor formation and metastasis.
[27]
Rilotumumab is a fully human IgG2 monoclonal antibody that acts against HGF that blocks the binding
of HGF to its receptor and inhibits HGF/c-MET-mediated response. A phase III study (RILOMET-1)
compared epirubicin + cisplatin + capecitabine (ECX) with or without rilotumumab in untreated patients
with unresectable/advanced GC or GEJA who were c-MET positive and HER2 negative according to stained
immunohistochemistry. The study was prematurely ended because of an imbalance of deaths and OS, PFS,
ORR were worse in the rilotumumab arm . Simultaneously, another phase III study (RILOMET-2) that
[28]
compared capecitabine and cisplatin (XP) with or without rilotumumab was ceased for the same reason .
[29]
Considering these results, the influence of the aggression of cancer was mentioned. To clarify the cause of
these results, clinical and biological analysis of the association between c-MET and GC is required.