57capecitabine) showed improved progression-free survival
(median = 4.8 months versus 7.9 months; hazard ratio = 0.47,
95% CI = 0.31–0.70; p = 0.0001), overall survival (OS)
(8.4 months versus 13.2 months; HR = 0.51, 95% CI =0.36–0.73;
p = 0.0001), and ORR (objective response rate) (28% versus 43%)
when compared to EOX in claudin-positive patients (in phase II
multicenter and randomized FAST study). IMAB362-related
adverse events including vomiting, neutropenia, and anemia are
mostly mild. Claudin 18.2 was evaluated in tumor samples by
immunohistochemistry and the benefit of IMAB362 was more
pronounced in those with very high Claudin 18.2 (PFS—
HR = 0.36; p < 0.0005; OS—HR 0.45; p < 0.0005) [ 37 ]. Of
note, claudin 18 translocation is more commonly seen in genomi-
cally stable tumors and thus the results may not be readily applied
to esophageal or gastresophageal junction adenocarcinomas,
which are predominantly chromosomally instable.Hepatocyte growth factor (HGF) activates multiple signal path-
ways to promote cancer proliferation, survival, and migration. The
mesenchymal-epithelial transition (MET) signaling pathway is one
of the most critical among them [ 38 ]. Expression of c-MET is
positive in over 60% of gastric tumors and positivity is associated
with poorer prognosis [ 39 ]. Rilotumumab is a fully human, mono-
clonal antibody that neutralizes HGF. Promising activity with a
40% reduction in risk of progression was demonstrated in an early
phase study when it was combined with ECX (epirubicin, cisplatin,
and capecitabine) [ 40 ]. Toxicity profile was a concern and there
were significantly higher incidence of grade 3 or 4 neutropenia,
anemia, and thromboembolic events. The subsequent phase III
RILOMET-1 study in MET-positive and HER2-negative patients
was terminated early due to an imbalance in deaths between the
study arms [ 41 ]. Indeed, overall survival, progression- free survival
and response rate were all inferior in the rilotumumab arm. No
subgroup effect was identified and toxicity profile was again a con-
cern. It has been criticized that ECX may not be the ideal back-
bone to combine with new target therapy in clinical trials due to
the safety profile and potential drug interaction. However, another
phase III MetGastric study also reported negative result of onartu-
zumab, a monovalent anti-MET antibody, in similar group of
MET-positive, HER2-negative patients [ 42 ]. Overall survival was
similar in both study arms (11.0 months vs 11.3 months, HR 0.82;
p = 0.244) using mFOLFOX6 with or without onartuzumab.
Exploratory subgroup analyses showed improved overall survival
for the onartuzumab arm in non-Asian patients and patients with
no prior gastrectomy regardless of MET status. In contrast with
the RILOMET-1 study, neither detrimental effect on survival nor
significant increase in major adverse events was observed. Taking
into account the result of RILOMET-1 and MetGastric study,1.6 Hepatocyte
Growth Factor
and Mesenchymal-
Epithelial Transition
(MET) Receptor
Target Therapy of Esophageal Adenocarcinoma