Page 99 - Read Online

Toihata et al. J Cancer Metastasis Treat 2018;4:24 I http://dx.doi.org/10.20517/2394-4722.2017.82 Page 5 of 10

Panitumumab is a fully human immunoglobulin G2 monoclonal antibody targeting EGFR. In advanced
[25]
colorectal adenocarcinoma, panitumumab significantly improved PFS . The REAL3 trial [phase III,
including advanced EGJ (n = 169), esophageal (n = 220) and gastric adenocarcinoma (n = 167)] revealed no
survival benefit of adding panitumumab to epirubicin, oxaliplatin and capecitabine (EOC) chemotherapy
[median OS 11.3 months in EOC alone groups (95% CI 9.6-13.0) vs. median OS 8.8 months in panitumumab
plus EOC groups (95% CI 7.7-9.8), HR 1.37; 95% CI 1.07-1.76; P = 0.013]. In a subgroup analysis of EGJ
adenocarcinoma, the trial revealed no survival benefit of adding panitumumab, either (EOC alone groups vs.
[26]
panitumumab plus EOC groups, HR 1.27; 95% CI 0.78-2.07) .

Rilotumumab, and onartuzumab (MET/HGF inhibitor)
Rilotumumab is a fully human monoclonal antibody that selectively targets the ligand of the MET receptor,
hepatocyte growth factor (HGF). In the RILOMET-1 trial [phase III, including advanced EGJ (n = 124), distal
esophageal (n = 67) and gastric adenocarcinoma (n = 63)], median OS was 8.8 months (95% CI 7.7-10.2) in the
rilotumumab group, compared with 10.7 months (95% CI 9.6-12.4) in the placebo group (HR 1.34, 95% CI 1.10-1.63;
P = 0.003), demonstrating that rilotumumab conferred no survival benefit. In a subgroup analysis of EGJ
adenocarcinoma, rilotumumab conferred no survival benefit (the rilotumumab group vs. the placebo group,
[27]
HR 1.28; 95% CI 0.83-1.98) .
Onartuzumab is a recombinant, fully humanized, monovalent monoclonal antibody that binds the
[28]
extracellular domain of MET, blocking interaction with HGF . In METGastric trial [phase III, HER2-
negative and MET-positive tumors, including advanced EGJ (n = 130) and gastric adenocarcinoma
(n = 432)], no survival benefit was observed in onartuzumab plus mFOLFOX group, compared to placebo
plus mFOLFOX (median OS 11.3 months in placebo plus mFOLFOX group vs. median OS 11.0 months in
onartuzumab plus mFOLFOX group, HR 0.82; 95% CI 0.59-1.15; P = 0.24). In a subgroup analysis of EGJ
adenocarcinoma, no survival benefit was observed in onartuzumab plus mFOLFOX group (median OS not
estimable in placebo plus mFOLFOX group vs. median OS 11.0 months in onartuzumab plus mFOLFOX
[29]
group, HR 1.12; 95% CI 0.58-2.19) .

Everolimus (mTOR inhibitor)
Everolimus is an oral mTOR inhibitor. In GRANITE-1 [phase III, including advanced EGJ (n = 187) and
gastric adenocarcinoma (n = 656)], everolimus did not significantly improve OS, compared to placebo alone
(median OS, 5.4 months in everolimus vs. median OS, 4.3 months in placebo, HR 0.90; 95% CI 0.75-1.08; P =
0.124). In a subgroup analysis of EGJ adenocarcinoma, everolimus did not significantly improve OS, either
[30]
(everolimus vs. placebo, HR 0.84; 95% CI 0.61-1.16) .

Trastuzumab emtansine (anti-HER2 antibody)
Trastuzumab emtansine (T-DM1) is anti-HER2 monoclonal antibody consisting of trastuzumab linked
to emtansine (DM1), which is a microtubule inhibitor. In GATSBY [phase II/III, including HER2-positive
advanced EGJ (n = 110) and gastric adenocarcinoma (n = 235)], there was no superiority of T-DM1 to taxane
[median OS 7.9 months with T-DM1 (95% CI 6.7-9.5) vs. median OS 8.6 months with taxane (95% CI 7.1-11.2),
HR 1.15; 95% CI 0.87-1.51; P = 0.86]. In a subgroup analysis of EGJ adenocarcinoma, similarly to the above,
there was no superiority of T-DM1 to taxane (median OS 7.1 months with T-DM1 vs. median OS 8.5 months
[31]
with taxane, HR 1.18; 95% CI 0.70-2.01) .

Future prospect of molecularly targeted drugs
Although precision medicine still remains developing for the upper gastrointestinal malignancies, there
are some new approaches such as VIKTORY, and PANGEA trials. PANGEA is a phase II trial that
gastroesophageal tumors are classified into the following six categories (HER2+, MET+, FGFR2+, VEGFR2+,
MSI-H, and EGFR+), and then paired specific targeted therapies (trastuzumab, TBD, anti-EGFR antibody