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Eto et al. J Cancer Metastasis Treat 2018;4:23 I http://dx.doi.org/10.20517/2394-4722.2017.73 Page 5 of 9

Accordingly, the recommended first-line treatment of HER2-positive metastatic GC in Japan is a combination
of trastuzumab and Cape/CDDP or a combination of trastuzumab and SP.

Second-line treatment
Second-line chemotherapy is known to prolong the survival of metastatic GC patients, and is recommended
for patients with acceptable performance status. Among cytotoxic agents, monotherapy with DTX, CPT-11 or
paclitaxel (weekly administration, wPTX) are available options. Randomized trials conducted in Germany
[42]
and Korea have indicated survival benefits of DTX or CPT-11 over BSC. The German study compared
[42]
[43]
CPT-11 as a second-line chemotherapy with BSC but was ended prematurely due to poor accrual. The
median OS was 4.0 vs. 2.4 months in the CPT-11 and placebo arms, respectively (P = 0.012). The Korean
study compared either CPT-11 or DTX as salvage chemotherapy (SLC) with BSC. The median OS of the
[43]
SLC and the BSC arms were 5.1 and 3.8 months (P = 0.004), respectively. The WJOG4007 compared wPTX
[44]
with CPT-11 in Japanese patients with advanced GC, after failure of primary combination chemotherapy
using fluoropyrimidine plus cisplatin. The median OS of wPTX and CPT-11 groups was 9.5 and 8.4 months,
respectively (P = 0.38). In addition, third-line chemotherapy was administered in 89.8% of the wPTX group
and in 72.1% of the CPT-11 group. Based on these findings, both wPTX and CPT-11 are considered reasonable
second-line treatment options for advanced GC.

More recently, two large international phase III trials (REGARD and RAINBOW) have revealed the
survival benefits of ramucirumab, a fully human monoclonal antibody against the vascular endothelial
growth factor receptor (VEGFR)-2 [30,31] for previously treated advanced gastric or gastroesophageal junction
(GEJ) adenocarcinoma. In the REGARD trial , patients were randomly assigned (2:1) to receive BSC plus
[31]
either intravenous ramucirumab 8 mg/kg or placebo once every 2 weeks. The median OS was 5.2 months
in the ramucirumab group and 3.8 months in the placebo group (HR: 0.77, 95% CI: 0.60-0.99; P = 0.047),
while the median PFS was 2.1 and 1.3 months, respectively. Ramucirumab appeared to be well tolerated,
although rates of hypertension were higher in the ramucirumab group than in the placebo group. The
RAINBOW trial compared ramucirumab plus PTX vs. placebo plus PTX in patients with previously
[30]
treated advanced GC. Patients were randomly assigned in a 1:1 ratio to receive either intravenous
2
ramucirumab 8 mg/kg or placebo on days 1 and 15, plus intravenous PTX 80 mg/m on days 1, 8, and 15
of a 28-day cycle. OS was significantly longer in ramucirumab plus PTX group than in the placebo plus
PTX group (the median OS of 9.6 and 7.4 months, P = 0.017). The toxicity of ramucirumab plus PTX was
tolerable.

Nab-paclitaxel (nab-PTX) is a nanoparticle-albumin-bound paclitaxel and it does not contain the solvent
cremophor EL and ethanol. Therefore, nab-paclitaxel can reduce the risk of a hypersensitivity reaction and
can be administered to patients who are intolerant of alcohol. The ABSOLUTE trial is a phase III study to
[45]
evaluate the efficacy and safety of nab-PTX vs. wPTX in Japanese patients with advanced GC refractory to
first-line chemotherapy. The median OS was 10.3 months in the nab-PTX every 3 weeks group, 11.1 months
in the weekly nab-PTX group and 10.9 months in the wPTX group. Weekly nab-PTX was non-inferior to
wPTX in terms of OS.

In summary, the recommended second-line treatment for metastatic GC in Japan is ramucirumab plus
wPTX, and the alternative choice is monotherapy of either DTX, CPT-11, nab-PTX or ramucirumab.

Immune checkpoint inhibitors in GC treatment
The ATTRACTION-2 (ONO-4358-12) trial evaluated the efficacy and safety of nivolumab, a fully human
IgG4 monoclonal antibody inhibitor of programmed death-1, in patients with advanced GC or GEJ cancer
who had been treated with two or more chemotherapy regimens . The median OS was 5.26 months in
[46]
the nivolumab group and 4.14 months in the placebo group (HR 0.63, 95% CI: 0.51-0.78; P < 0.0001). The