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evaluate the effi cacy of molecular targeted drugs in GC addition of ramucirumab resulted in a signifi cant survival
are summarized in Table 2. benefi t; the median OS increased from 7.4 to 9.6 months
(HR: 0.807; 95% CI: 0.678-0.962), and the median PFS
Trastuzumab
increased from 2.9 to 4.4 months (HR: 0.635; 95% CI:
Trastuzumab is a recombinant humanized mAb directed 0.536-0.752). Currently, a randomized Phase II trial
[53]
against the extra-cellular domain of HER-2. Amplifi cation investigating the effi cacy of ramucirumab as a fi rst-line
or overexpression of HER-2 has been observed in treatment in GC is ongoing. [58]
7-34% of GC. [16,17,56] A recent large-scale Phase III study Colorectal cancer
(the ToGA trial) demonstrated that trastuzumab combined
with cisplatin and capecitabine provided a signifi cant Estimated new cases of CRC exceed 1.2 million/year
survival advantage over chemotherapy alone in patients worldwide, with more than 600,000 deaths/year. Liver
[59]
with HER-2-positive GC and confi rming that HER-2 metastases are observed in 25% of CRC patients at the
is a crucial therapeutic GC target. The median OS time of diagnosis and recurrence after surgery is often
[51]
was 13.8 months in the trastuzumab plus chemotherapy encountered. The 5-year survival rate of patients with
group (n = 294) and 11.1 months in the chemotherapy distant metastases diseases is only 10-20%, although that
alone group (n = 290; hazard ratio [HR]: 0.74; 95% of patients without lymph node metastasis is more than
confi dence interval [CI]: 0.60-0.91; P = 0.0046). In 80%. The majority of CRC occurrences are sporadic,
[60]
the subgroup with high HER-2 expression (defi ned without the existence of family history or genetic
as immunohistochemistry 2+ and fl uorescence in situ pre-disposition, and the etiological factors for CRC
hybridization positive, immunohistochemistry 3+), the tumorigenesis appear to be complex and heterogeneous.
median OS was 16.0 months in the trastuzumab plus There has been signifi cant progress in identifying
chemotherapy group and 11.8 months in the chemotherapy distinct molecular pathways leading to CRC that include
alone group (HR: 0.65; 95% CI: 0.51-0.83). Trastuzumab either increased function of oncogenes or loss of tumor
is the fi rst molecularly targeted drug that has been proven suppressor genes. Currently, the recent introduction
[61]
effi cacious against GC. of molecular targeted drugs has improved the treatment
of advanced CRC. Cetuximab and panitumumab
Ramucirumab
(EGFR mAbs) and bevacizumab (VEGF, mAb) have
Ramucirumab is a human mAb that binds to VEGFR-2 ushered in a new era of targeted therapy for CRC. [62-65]
and works as a receptor antagonist blocking the Table 3 summarizes molecular targeted drugs used to
binding of VEGF to the receptor. A Phase I trial treat CRC.
demonstrated its anti-tumor activity and anti-angiogenic Bevacizumab
effect over a wide range of doses, suggesting clinical
[57]
effi cacy. In the REGARD Phase III randomized trial, Bevacizumab, developed in the early 1990s, is a
355 patients were treated with best supportive care recombinant, humanized immunoglobulin G1 (IgG1)
plus ramucirumab or placebo in a second-line setting. mAb that effectively disrupts the interactions of all
[66]
Both the median OS (5.2 vs. 3.8 months; HR: 0.776; isoforms of VEGF-A with VEGFRs. Pre-clinical studies
95% CI: 0.603-0.998) and the median progression-free have demonstrated that bevacizumab exhibits a broad
[67]
survival (PFS) (2.1 vs. 1.3 months; HR: 0.483; 95% range of anti-tumor activity. The AVF2107 study, a
CI: 0.376-0.620) were signifi cantly longer in the trial to investigate the effi cacy of bevacizumab combined
ramucirumab than the placebo group, and the safety with irinotecan, bolus 5-FU and leucovorin (LV) (IFL)
[52]
profi le of the drug was acceptable. In the RAINBOW for patients with previously untreated mCRC,
[63]
Phase III trial, ramucirumab was used as a second-line demonstrated that the addition of bevacizumab to
[53]
treatment in addition to paclitaxel (665 patients). The IFL improved the RR and prolonged OS. In another
Table 2: Results of completed Phase III trials with molecular targeted therapy in advanced GC
Target Trial Regimen Patients (n) OS (month) P
HER2 ToGA Cisplatine, capecitabine or FU ± trastuzumab 584 13.8 versus 11.1 (fi rst-line) 0.0046
HER2 LOGIC Capecitabine, oxaliplatin ± trastuzumab 545 12.2 versus 10.5 (fi rst-line) 0.35
HER2 TyTAN Paclitaxel ± lapatinib 261 11.0 versus 8.9 (fi rst-line) 0.21
EGFR EXPAND Cisplatine, capecitabine ± cetuximb 679 9.4 versus 10.7 (fi rst-line) 0.95
EGFR REAL3 Oxaliplatin, capecitabine, epirubicin ± panitumumab 553 8.8 versus 11.3 (fi rst-line) 0.013
VEGFR-2 REGARD BSC ± ramucirumab 355 5.2 versus 3.8 (second-line) 0.047
VEGFR-2 RAINBOW Paclitaxel ± ramucirumab 665 9.6 versus 7.4 (second-line) 0.017
VEGFR-A AVAGAST Cisplatine, capecitabine or FU ± bevacizumab 774 12.1 versus 10.1 (fi rst-line) 0.10
mTOR GRANITE-1 BSC ± everolimus 633 5.4 versus 4.3 (second- or third-line) 0.12
HER2: Human epidermal growth factor receptor 2; EGFR: Epidermal growth factor receptor; VEGFR-2: Vascular endothelial growth
factor receptor-2; VEGFR-A: Vascular endothelial growth factor receptor-A; mTOR: Mammalian target of rapamycin; OS: Overall
survival; FU: Fluorouracil; BSC: Best supportive care; GC: Gastric cancer

166 Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦