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5-FU-based and cisplatin-based combinations were considered as an acceptable standard therapy according
to trial in Asia . Then, capecitabine, which is an oral fluoropyrimidine, and oxaliplatin, which is third-
[32]
generation diaminocyclohexane platinum compound, were developed. A phase III in Germany showed
that the combination of fluorouracil, leucovorin, and oxaliplatin improved median PFS compared with
fluorouracil, leucovorin, and cisplatin (5.8 months vs. 3.9 months), but not siginificant . The REAL-2 trial
[33]
demonstrated possible replacement of 5-FU into capecitabine or cisplatin into oxaliplatin . These results
[34]
have led to trend toward preference of capecitabine plus cisplatin or capecitabine plus oxaliplatin in the USA.

S-1, which is oral fluoropyrimidine preferred in Japan, was reported to be similarly effective for survival with
a better toxicity compared with infusional fluorouracil in West [35,36] . However, dose of S-1 administered each
2
time in West (25 mg/m ) is lower than that in Asia (40-60 mg/body) . Thus, more evidence is needed to get
[37]
acceptance for S-1 in the USA.
DCF was evaluated in a randomized study, V-325 in 2006 [38,39] . It showed that median OS of DCF was
significantly longer than CF (9.2 months vs. 8.6 months; P = 0.02), but DCF produced more toxicity [38,39] .
Several modified DCF regimens demonstrated the efficacy and the safety [40-42] . Thus, the original DCF is not
recommended, and modified DCF is still one of the option in specific cases.

Second/third line therapy
For second line therapy, ramucirumab (an anti-VEGFR2 monoclonal antibody) is the only molecular-targeted
drug with a confirmed minimal survival benefit in a global phase 3 trial. The REGARD trial compared
ramucirumab and placebo, and showed that median OS in ramucirumab group was better than that in
placebo group (5.2 months vs. 3.8 months) . The RAINBOW trial compared paclitaxel with and without
[43]
ramucirumab, and showed that OS in ramucirumab plus paclitaxel was significantly longer than in placebo
plus paclitaxel (median 9.6 months vs. 7.4 months) . Ramucirumab plus paclitaxel is the preferred regimen
[44]
in the second line setting. Docetaxel, irinotecan and paclitaxel have significantly prolong OS compared to
best supportive care, but all these trials were flawed [45-47] .

Immune checkpoint blockade has received global attention in recent years [48-50] . Keynote-059 assessed efficacy
and safety of pembrolizumab, programmed death-1 (PD-1) inhibitor, monotherapy showed that overall response
rate (ORR) was 11.2% and median duration of response (DOR) was 8.1 months in all cohort . ORR was
[51]
higher in PD-1 ligand (PD-L1) positive patients than PD-L1 negative patients (15.5% vs. 5.5%). Checkmate 032
assessed the combination of two checkpoint inhibitors, nivolumab (PD-1 inhibitor) and ipilimumab (cytotoxic
T-lymphocyte-associated protein 4 inhibitor), and showed that ORR for combination therapy in PD-L1 positive
patients was 40%, which was higher than nivolumab monotherapy . Interestingly, among 7 patients with high
[52]
microsatellite instability (MSI-H) tumors in Keynote-059, ORR was 57% and the CR rate was 14.3%. Given this
result, the FDA has approved pembrolizumab for the treatment of patients with PD-L1 positive GAC who have
received 2 or more lines of chemotherapy. Pembro is also approved for MSI-H tumor patients. Therefore, now
we have to consider all 3 biomarkers for gastroesophageal adenocarcinoma patients (Her2, PD-L1, and MSI).

PERSPECTIVE FOR TARGETED THERAPY AND IMMUNOTHERAPY
Targeted therapies against stem cells
Cancer stem cells possess the capacity to self-renew and to cause the heterogeneous lineages of cancer cells.
Several makers and pathways related to gastric cancer stemness have been identified . Cancer stem cells
[53]
are resistant to several chemotherapy, and thus targeting cancer stem cells is a potential therapy to overcome
treatment resistance. Two stemness related pathways, Hedgehog and signal transducer and activator of
transcription 3 (STAT3) pathway, were assessed in clinical trials so far. Vismodegib, which inhibit Hedgehog
signals by binding smoothened (SMO), in combination with FOLFOX was assessed in phase 2, but did not
benefit PFS (11.5 months vs. 9.3 months; P = 0.34) . Moreover, BRIGHTER study assessed napabucasin,
[54]