Despite improvements in systemic chemotherapy (CT), the prognosis of metastatic 
adenocarcinoma of the gastroesophageal junction remains poor. Over the years, 
new targeting agents have become available and were tested, with or without CT, 
in first or subsequent lines of therapy. The epidermal growth factor receptor 
family was targeted with monoclonal antibodies (MoAbs) (trastuzumab, cetuximab, 
panitumumab) and tyrosin kinase inhibitors (TKIs) (lapatinib, erlotinib, 
gefitinib). Only trastuzumab, in combination with cisplatin and 
fluoropyrimidines, significantly improved overall survival (OS) in first-line 
therapy (13.8 vs. 11.1 months). Angiogenesis also was targeted with MoAbs 
(bevacizumab and ramucirumab); ramucirumab, a vascular endothelial growth 
factor-receptor 2 antagonist, enhanced OS in two phase III studies in the first 
(9.6 vs. 7.4 months) and subsequent lines of treatment (5.2 vs. 3.8 months), 
while the bevacizumab study was negative. TKIs (sunitinib, sorafenib, 
regorafenib, apatinib) were tested in this setting in phase II studies in the 
second/third line, only showing modest antitumor activity. The hepatocyte growth 
factor receptor (MET) was targeted in untreated patients in a phase III trial 
with MoAb rilotumumab, with or without CT, but the study was stopped because of 
mortality excess in the rilotumumab arm. Mammalian target of rapamycin (MTOR) 
pathway inhibition with everolimus was tested in pretreated patients in a 
placebo-controlled phase III trial who failed to improve OS (5.4 vs. 
4.3 months). In conclusion, considering the modest survival gain obtained 
overall, the high cost of these therapies and the quality of life issue must be 
primarily considered in treating these patients.