**2.4. Lapatinib**

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 lapatinib.

However, some confusion may exist when considering clinicopathological subsets that receive benefit from agents against HER2. A LoGiC study revealed that Asian or younger (age <60 years old) patients may benefit from lapatinib [39], while a ToGA trial proved trastuzumab efficacy to be more effective in patients from Central/South America or from Europe, or in older patients [13]. In addition, the TyTAN study, which was conducted only in Asia, failed to identify any clear subgroup benefit from lapatinib except for patients from mainland China. Therefore, it is important to clarify biomarkers that may predict which patients may benefit from dual EGFR/HER2 inhibition.
