55America and Latin America appeared to have a survival benefit
with the addition of bevacizumab (11.5 months v 6.8 months, HR
0.63), whereas patients enrolled in Asia (90% from Japan and
Korea) appeared to have no benefit (HR 0.97). Subsequent serum
biomarker analysis of the AVAGAST study identifies regional varia-
tion of serum angiopoietin-2 that may explain partly the regional
difference in efficacy [ 23 ]. The AVATAR study was a smaller repli-
cate of AVAGAST study in Chinese patients, and it did not meet
the primary study end point [ 24 ]. Nevertheless, the signal is prom-
ising for anti-angiogenesis therapy in gastric and esophagogastric
junction adenocarcinoma.
Ramucirumab is a fully human IgG1 monoclonal antibody
against VEGFR-2. The efficacy of ramucirumab was proven first as
a monotherapy in the REGARD study and then in combination
with paclitaxel in the RAINBOW study in second-line treatment of
advanced or metastatic disease [ 25 , 26 ]. In the REGARD study,
patients who received ramucirumab monotherapy has a 22% reduc-
tion in risk of death (5.2 months vs 3.8 months, HR 0.78;
p = 0.047) and 52% reduction in risk of disease progression
(2.1 months vs 1.3 months, HR 0.48, p < 0.0001). Treatment
response was seen in 4% of the patient and in total 49% of patients
achieved disease control [ 25 ]. Ramucirumab in combination with
paclitaxel in the RAINBOW also showed a significant improve-
ment of median overall survival (9.6 months vs 7.4 months,
HR0.81; p = 0.017) and progression-free survival (4.4 months vs
2.9 months, HR 0.64; p < 0.0001) [ 26 ]. The response rate was
28% and 90% of patients achieved disease control. Ramucirumab
has a favorable side effect profile. To fully explore the role of ramu-
cirumab in gastric and esophagogastric adenocarcinoma, bio-
marker studies and combination regimen in first-line setting are
ongoing.
Apatinib is a small molecule tyrosine kinase inhibitor that binds
to VEGFR-2 in a highly selective manner. It demonstrated signifi-
cant activity in patients who have failed at least two prior lines of
systemic therapy in a phase III randomized controlled study [ 27 ].
Compared to best supportive care, apatinib led to a 29% reduction
in the risk of death (6.5 months vs 4.7 months, HR 0.71;
p = 0.0156) and 56% reduction in the risk of progression
(2.6 months vs 1.8 months, HR 0.44; p < 0.001). Hand-foot syn-
drome, proteinuria, and hypertension were the most common
grade 3 or 4 adverse events with apatinib..
Evidences proved the use of anti-angiogenic agents in advanced
or metastatic gastric and esophagogastric adenocarcinoma. Efficacy
is more pronounced in later-line setting. More effort is still needed
to identify predictive markers to better select patients for such
treatment.
Target Therapy of Esophageal Adenocarcinoma