*6.2.3.1. Anti-VEGF monoclonal antibodies*

Bevacizumab (Avastin) efficacy as a first-line treatment in combination with cisplatin-based chemotherapy for advanced gastric cancer was evaluated in the phase III AVAGAST trial (Avastin in gastric cancer) [115], which demonstrated a median PFS and overall response rate significantly improved in the bevacizumab group, but without a significant benefit in OS. Another phase III study, AVATAR, also found that bevacizumab combined with capecitabine/ cisplatin chemotherapy did not significantly improve OS in patients with advanced gastric cancer [116]. Possibly, the negative results of these studies might have resulted from not having selected the most molecularly suitable gastric cancer patients.

The MAGIC-B study is currently assessing the role of bevacizumab for perioperative chemotherapy in resectable adenocarcinoma of the stomach, [117]. Hopefully, this trial will allow for the detection of predictive biomarkers that could identify the subset of patients with the greatest potential benefit from the use of perioperative VEGF-A inhibitory monoclonal antibody [118].

Currently, the safety and efficacy of adding bevacizumab to taxane-based chemotherapeutic regimens irinotecan [119] or anti-Her2-targeted treatment in advanced/metastatic gastric cancer is being evaluated in several clinical trials with pending results [120].

### *6.2.3.2. Anti-VEGF receptor monoclonal antibodies*

Ramucirumab is a human monoclonal antibody that inhibits VEGFR-2. It was approved by the FDA as a single agent in gastric cancer after progression on a platinum- or fluoropyrimidine-containing regimen, based on the phase III REGARD study (second-line ramucirumab monotherapy for advanced gastric adenocarcinoma), which found significantly longer OS for ramucirumab versus best supportive care (BSC) [42]. Furthermore, the results of a phase III clinical trial of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the secondline treatment of metastatic gastric adenocarcinoma (RAINBOW trial) revealed significantly longer PFS and OS for the ramucirumab group [121], also leading to approval by the FDA of ramucirumab in combination with paclitaxel as a second-line therapy. Therefore, ramucirumab is for the moment, the only antiangiogenic agent that has been approved for the treatment of gastric carcinoma [122].

Endostar is a novel recombinant human endostatin, which was investigated [123] combined with SOX (S-1/oxaliplatin) for the first-line treatment of patients with advanced gastric cancer; the results showed significantly better PFS for the group including Endostar. More studies for the efficacy of Endostatin in stomach cancer settings are needed.
