**2.2. Pertuzumab**

Pertuzumab is a humanized monoclonal antibody that binds to the HER2 domain II—the interface of the dimer formation of HER. As discussed earlier, since trastuzumab binds to the HER2 domain IV—a region not involved in receptor dimerization [26, 27], trastuzumab inhibits ligand-independent dimerization of HER2 while it is not effective for the inhibition of ligand-dependent heterodimerization. These biological properties could imply one mechanism of trastuzumab resistance. For example, HER ligands are able to induce the formation of HER2-containing heterodimers such as the ligand-dependent HER2/HER3 heterodimer even in the presence of trastuzumab; thus HER3 plays some roles in trastuzumab resistance. Notably, HER3 is overexpressed in 14–62% of GC [28–30], and HER3 *per se* is associated with poor survival rates. Considering that pertuzumab binds to the HER2 domain II and subsequently blocks the heterodimerization of HER2 with other members of the HER family, pertuzumab is expected to overcome trastuzumab resistance.

In *in vitro* studies and animal models, pertuzumab and trastuzumab showed synergistic antitumor effects [31–33]. Subsequent RCT in HER2-positive metastatic breast cancer demonstrated that pertuzumab, trastuzumab, and docetaxel significantly improved overall survival rates for HER2-positive metastatic breast cancer when compared with placebos, trastuzumab, and docetaxel [34]. Such positive results were maintained when the follow-up period was extended [35]. Motivated by the promising results, a phase III study is ongoing which randomizes HER2-positive advanced GC patients to first-line trastuzumab, cisplatin, and fluoropyrimidine with or without pertuzumab [36].
