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Page 4 of 10 Toihata et al. J Cancer Metastasis Treat 2018;4:24 I http://dx.doi.org/10.20517/2394-4722.2017.82

RAINBOW trial showed a significant benefit of ramucirumab for advanced EGJ and gastric adenocarcinoma,
as the second-line chemotherapy.

The REGARD trial [phase III, including advanced EGJ (n = 90) and gastric adenocarcinoma (n = 265)]
exhibited a significant benefit of ramucirumab (OS 5.2 months for ramucirumab vs. OS 3.8 months for
placebo; HR 0.776, 95% CI 0.603-0.998; P = 0.047). However, in a subgroup analysis of EGJ adenocarcinoma,
the trial did not exhibit any significant benefit of ramucirumab (ramucirumab groups vs. placebo groups,
HR 0.76; 95% CI 0.47-1.21). The incidence of hypertension was higher in the ramucirumab group than in
[14]
the placebo group (16% vs. 8%) . In the RAINBOW trial [phase III, including advanced EGJ (n = 137) and
gastric adenocarcinoma (n = 528)], the ramucirumab plus paclitaxel conferred a significantly prolonged OS,
compared to the placebo plus paclitaxel group (9.6 vs. 7.4 months, HR 0.807; 95% CI 0.678-0.962; P = 0.017).
In a subgroup analysis of EGJ adenocarcinoma, the trial revealed survival benefit of adding ramucirumab,
either (ramucirumab plus paclitaxel groups vs. placebo plus paclitaxel groups, HR 0.39; 95% CI 0.26-0.59).
Grade 3 or 4 adverse events that occurred in more than 5% of patients in the ramucirumab and paclitaxel
group vs. placebo and paclitaxel group were as follow; neutropenia (41% vs. 19%), leucopenia (17% vs. 7%),
[7]
hypertension (14% vs. 2%), fatigue (12% vs. 5%), anemia (9% vs. 10%), and abdominal pain (6% vs. 3%) .
Bevacizumab (anti-VEGF antibody)
Bevacizumab, which is a monoclonal antibody that targets vascular endothelial growth factor A (VEGF-A),
inhibiting tumor growth in preclinical studies [15,16] . In AVAGAST trial [phase III, including advanced EGJ
(n = 103) and gastric adenocarcinoma (n = 671)], bevacizumab did not confer any survival benefit (median
OS 12.1 months in bevacizumab plus XP; vs. median OS 10.1 months in XP alone). In a subgroup analysis of
[17]
EGJ adenocarcinoma, there was no survival benefit (data not available) .
Lapatinib
Lapatinib is the dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth
factor receptor 2 (HER2) tyrosine kinases. In the TRIO-013/LOGiC trial [phase III, including advanced EGJ
(n = 46), esophageal (n = 20) and gastric adenocarcinoma (n = 424)], lapatinib plus capecitabine and oxaliplatin
(CapeOX) showed no additional efficacy as the first-line treatment for HER2 positive patients [median OS
12.2 months in CapeOX + lapatinib groups (95% CI 10.6-14.2) vs. median OS 10.5 months in CapeOX groups
(95% CI 9.0-11.3), HR 0.91; 95% CI 0.73-1.12; P = 0.35]. In a subgroup analysis of EGJ adenocarcinoma, there
[18]
was no survival benefit (CapeOX + lapatinib groups vs. CapeOX groups, HR 0.90; 95% CI 0.44-1.85; P = 0.77) .
TyTan study [phase III, including advanced EGJ (n = 2) and gastric adenocarcinoma (n = 259)] demonstrated
that lapatinib plus paclitaxel did not improve OS in HER2-positive patients compared to paclitaxel alone
[median OS 11.0 months in lapatinib plus paclitaxel group (95% CI 9.5-14.5) vs. median OS 8.9 months in
[19]
paclitaxel alone group (95% CI 7.4-11.1), HR 0.84; 95% CI 0.64-1.11; P = 0.1044] .

Cetuximab, or panitumumab (anti-EGFR antibody)
Cetuximab is an EGFR antibody, widely used for patients with KRAS wild-type metastatic colorectal
[22]
cancer [20,21] , recurrence or metastatic squamous-cell carcinoma of the head and neck , and advanced non-
[23]
small-cell lung cancer . In the EXPAND trial [phase III, including advanced EGJ (n = 144) and gastric
adenocarcinoma (n = 747)], the efficacy of adding cetuximab to capecitabine plus cisplatin was examined.
However, there was no benefit to adding of cetuximab to chemotherapy compared to chemotherapy alone
in the first-line treatment [median PFS 4.4 months in cetuximab plus capecitabine and cisplatin groups
(95% CI 4.2-5.5); vs. median PFS 5.6 months in capecitabine and cisplatin alone groups (95% CI 5.1-5.7); HR
1.09; 95% CI 0.92-1.29; P = 0.32]. In a subgroup analysis of EGJ adenocarcinoma, there was no benefit to add
cetuximab, either [median PFS 5.6 months in cetuximab plus capecitabine and cisplatin groups vs. median
[24]
PFS 5.6 months in capecitabine and cisplatin alone groups; HR 1.12; 95% CI 0.73-1.71] .