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including transforming growth factor α (TGFα) and ErbB. EGFR has been identified as an anticancer
therapeutic target and many drugs that inhibit these bindings have been developed, including cetuximab,
panitumumab, and nimotuzumab.

Cetuximab is an IgG1 monoclonal antibody that inhibits ligand binding to the EGFR and stimulates cell-
[12]
mediated cytotoxicity . Addition of cetuximab to conventional chemotherapy has already been established
[13]
as one of the first-line chemotherapy regimens in many types of cancer including patients with KRAS wild-
type metastatic colorectal cancer (CRC) [14,15] . In a phase III trial of GC, addition of cetuximab to capecitabine
+ cisplatin did not improve OS and PFS (EXPAND study) . These results were generally consistent between
[16]
subgroups. Therefore, the critical factor of a negative result was unclear. In CRC, KRAS mutations are
negative predictive biomarkers of cetuximab efficiency. However, KRAS mutations appear at low frequency
in GC. Thus, this study could not have detected KRAS mutations as a predictive biomarker in GC patients.
Other trials in advanced NSCLC have reported EGFR expression levels as a predictive biomarker of OS in
patients treated with cetuximab. Searching the characteristics of molecular or patient groups is required for
effective treatment with cetuximab.

Panitumumab is a recombinant, fully human, IgG2-monoclonal antibody that is highly selective for
EGFR. Panitumumab in combination with chemotherapy has been established as the first-line and second-
line treatment of KRAS wild-type metastatic colorectal cancer . In a phase III trial of esophagogastric
[17]
adenocarcinoma, addition of panitumumab to epirubicin + oxaliplatin + capecitabine (EOC), in interim
analysis, median OS in patients allocated modified-dose EOC + panitumumab was inferior to that of patients
allocated EOC and could not be recommended for use in populations with advanced esophagogastric
adenocarcinoma (REAL3 study) . Some factors associated with poor outcomes have been discussed. For
[18]
one, combinations of EOC with full-dose panitumumab during the initial stages of the trial were associated
with unacceptably high rates of grade 3 diarrhea. Therefore, oxaliplatin and capecitabine doses had to be
reduced in this study. Another factor is that negative interaction might have occurred between panitumumab
and EOC components or it may have been necessary to select patients by molecular characteristics.
Therefore, identifying a subpopulation of patients benefiting from panitumumab or more details verifying
the mechanism of molecular signaling is required.

Nimotuzumab is a recombinant humanized monoclonal immunoglobulin G1 antibody that acts against
human EGFR and blocks the binding of EGF and transforming growth factor-α to EGFR [19,20] . This mechanism
inhibits cancer-cell proliferation, angiogenesis, and induces apoptosis. Although a phase II trial, as second-
line therapy, nimotuzumab plus irinotecan vs. irinotecan alone to AGC was performed, with no superiority of
nimotuzumab plus irinotecan over irinotecan was alone observed . However, nimotuzumab plus irinotecan
[21]
showed that potential improvement in a subgroup of patients with EGFR high expression subgroup was based
on improved PFS, OS, and response rate. Therefore, in second-line treatment, a phase III study aimed at
comparing the efficacy of nimotuzumab and irinotecan combination therapy on irinotecan alone in patients
with EGFR overexpressed advanced GC or gastro-esophageal junction adenocarcinoma (GEJA) is ongoing
(ENRICH study, NCT01813253). The results will be reported in 2017, with some efficiency expected.

Anti-VEGF monoclonal antibody
VEGF is a signal protein produced by cells that stimulate the formation of blood vessels and mediate tumor
angiogenesis . Bevacizumab is a humanized monoclonal antibody that blocks angiogenesis by inhibiting
[22]
VEGF-A, which stimulates angiogenesis in many types of cancer and was the first available angiogenesis
inhibitor . In a phase III trial, adding bevacizumab to capecitabine-cisplatin in first-line treatment of
[23]
AGC did not increase OS compared with capecitabine-cisplatin (AVAGAST trial) . However, adding
[24]
bevacizumab to chemotherapy significantly increased PFS and overall response rate (ORR). Especially, in
the European and Pan-American regions, the clinical benefit of the addition of bevacizumab increased the