*6.2.3. VEGF/VEGF receptor inhibition*

The second generation of anti-HER2 agents includes Pertuzumab, which binds to a distinct site on the HER2 receptor. This drug is currently being investigated in the phase III JACOB study in patients with HER2-positive metastatic or locally advanced gastric cancer. [101]. Trastuzumab emtansine (TDM-1) is another second-generation agent currently assessed in a

Lapatinib is an oral TKI of EGFR and HER2, which was studied in combination with standard chemotherapy in patients with HER2-positive advanced gastric adenocarcinomas in the phase III LOGIC study [45] and in the phase III Asian TyTAN trial without demonstrating an improvement in OS. Currently, the MAGIC-B study is evaluating the addition of lapatinib to perioperative epirubicin, cisplatin, and capecitabine (ECX) chemotherapy in patients with

EGFR overexpression is found in 30-50% of gastroesophageal tumors, associated with a more

Cetuximab (Erbitux) is a chimeric monoclonal anti-EGFR antibody. Unfortunately, clinical trials, including the phase III EXPAND trial did not demonstrate a PFS or OS benefit for cetux-

Panitumumab is a fully human monoclonal anti-EGFR antibody without a demonstrated efficacy in naive patients with advanced esophagogastric cancer according to the results of clini-

Nimotuzumab is a recombinant humanized monoclonal antibody that was evaluated in a double-blind phase II trial [109] including patients with advanced gastric cancer who received nimotuzumab plus irinotecan versus irinotecan alone, showing no difference in PFS or OS between these two groups. Nevertheless, the EGFR2+/3+ subgroups presented a significant

Gefitinib is an oral EGFR TKI currently assessed in a phase I/II study, in combination with chemoradiation, in subjects with resectable gastric cancer [110], in a phase II study in patients with unresectable and/or metastatic gastric carcinomas, and also in a phase III trial in patients with advanced gastro-esophageal junction cancers after progression on chemotherapy [111]. The results of these studies could define the role of this agent in gastric cancer treatment.

Erlotinib (Tarceva) is an oral EGFR TKI, shown to be active in a phase II trial only in patients

with gastro-esophageal cancer, but not in those with gastric cancer [112].

imab as first-line chemotherapy in the treatment of gastric cancer [105, 106].

second-line phase II/III trial in advanced gastric cancer [102].

*6.2.1.2. Tyrosine kinase inhibitors (TKIs) of HER2*

HER2 (+) gastric cancers [103].

*6.2.2. EGFR inhibition*

118 Gastric Cancer

aggressive behavior [104].

*6.2.2.1. Anti-EGFR monoclonal antibodies*

cal trials including the REAL-3 study [107, 108].

benefit when treated with nimotuzumab.

*6.2.2.2. TKIs of EGFR*

Angiogenesis is an essential event in tumor growth and spread. VEGF has demonstrated a major role in tumor angiogenesis, growth, and metastasis in numerous tumors, including gastric cancer [113], therefore, being considered an essential therapeutic target. Data revealed that VEGF expression correlates with the clinical stage and prognosis of gastric cancer [114].
