**2.5. Cetuximab, panitumumab, and nimotuzumab**

**2.2. Pertuzumab**

226 Gastric Cancer

**2.3. T-DM1**

two arms [37].

**2.4. Lapatinib**

lapatinib.

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, per-

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 fluoro-

T-DM1 is an antibody drug conjugate of trastuzumab and emtansine (DM1), a microtubule inhibitor. TDM-1 is expected to deliver a cytotoxic agent directly to cancer cells. Unfortunately, however, the efficacy of T-DM1 as compared to taxane as a second-line setting failed to meet its primary endpoint (GATSBY trial). The mOS, mPFS, and RR were not different between the

Lapatinib is a small molecule inhibitor of the intracellular domain of tyrosine kinase of EGFR and HER2, thus interrupting EGFR- and HER2-associated downstream signaling cascades. Theoretically, lapatinib and trastuzumab synergistically act even on the status of trastuzumab resistance. Indeed, a meta-analysis has revealed [38] the efficacy of lapatinib on HER2-positive breast cancer patients. Accordingly in GC, lapatinib in combination with chemotherapy has been evaluated by two randomized trials as first-line [39] and secondline [40] settings. Unfortunately, the addition of lapatinib to capecitabine plus oxaliplatin (LoGiC trial) [39] or the addition of lapatinib to paclitaxel (TyTAN trial) [40] failed to demonstrate any significant improvement of mOS when compared with chemotherapy without

However, some confusion may exist when considering clinicopathological subsets that receive benefit from agents against HER2. A LoGiC study revealed that Asian or younger

tuzumab is expected to overcome trastuzumab resistance.

pyrimidine with or without pertuzumab [36].

Cetuximab is a recombinant human-mouse chimeric anti-EGFR antibody. A randomized EXPAND study as a first-line setting revealed that the addition of cetuximab to capecitabine plus cisplatin provided no additional benefit to chemotherapy [41]. Panitumumab is a fully humanized anti-HER1 antibody. A REAL-3 study randomized advanced GC patients to firstline epirubicin, oxaliplatin, and capecitabine with or without panitumumab [42]. Again, pertuzumab provided no additional survival benefit to chemotherapy or seemed to be even harmful.

Following by the negative results of the two RCTs (EXPAND and REAL-3), another anti-EGFR antibody, nimotuzumab, a recombinant humanized monoclonal antibody against EGFR [43, 44] has been developed. Regrettably, however, a randomized phase II study adding firstline nimotuzumab to S-1 plus cisplatin failed to improve mOS when compared to S-1 plus cisplatin. In this study, even among the EGFR2+/3+ subgroup, adding nimotuzumab did not provide any additional benefit to the S-1 plus cisplatin combination [43]. However, nimotuzumab and irinotecan could improve survival rates in the EGFR2+/3+ subgroup [44]. The exact reasons underlying these different results according to the chemotherapy agents combined with nimotuzumab are unclear, but putative mechanisms responsible for the confusing results may be negative synergistic effects between the anti-EGFR antibody and capecitabine.

Unlike in colorectal cancer, KRAS mutations have not been a negative predictive marker for EGFR-targeting therapy in GC [45], and prespecified KRAS mutations have limited clinical value. Therefore, the significance of KRAS gene mutations, which is a predictive factor for a lack of efficacy in colorectal cancer, may not be extrapolated to GC, and KRAS mutations are not validated at this time. It is possible that alternative mechanisms other than KRAS mutations to escape from cetuximab action may exist. In this regard, attempts to find predictors of the efficacy of EGFR-targeting therapies have been reported in Refs. [46–48]; however, a small number of patients investigated in such biomarker analyses and a retrospective study design may preclude drawing a meaningful conclusion. Furthermore, the very low rate of KRAS mutation in GC (3–9%) [46–48] also hinders further application in clinical practice. The identification of reliable predictive markers is of paramount importance for selecting the most appropriate agents to the patients benefiting most.
