88 Background: Advanced gastric cancer (GC) is an incurable disease. HER2 overexpression has been reportedin 6%–35% of gastric and gastroesophageal tumors, whereas the EGFR is upregulated in about 18%–28%. Clinical studies confirm that targeting HER2 in combination with chemotherapy is an effective strategy, achieving a median survival of ∼13.5 mos. Lapatinib, a dual tyrosine kinase inhibitor of HER2 and the EGFR, inhibits tumor growth and modulates expression of fluoropyrimidine-targeting genes. LPT109747 is an international, multicenter phase II study investigating the combination of lapatinib + capecitabine in patients with advanced gastric or gastroesophageal junction adenocarcinoma. Methods: Primary endpoints of the study included clinical response rate, 5 mo PFS and mRNA and protein expression levels of genes involved in the 5-FU and HER2 pathway. HER2 overexpression was not required at study entry. Oral lapatinib was administered (1,250 mg/d, continuously) during a monotherapy run-in period (day -7 to 0) and in combination with oral capecitabine (1,000 mg/m2 BID, 14 of 21 days). Patients were treated until disease progression (PD) or study withdrawal. Biopsies were performed on days -7 and 0. Safety was assessed every 3 weeks and response every 6 weeks by RECIST. Results: Sixty-seven patients were included in the current analysis: 25% female, 75% male; 51% Caucasian, 45% Asian; median age 60 y (range: 22-89 y); 75% GC, 25% GEJ. All 67 patients were evaluable for response. The overall response rate was 22.4% (16.4% confirmed). 45% of patients had stable disease, and 24% had PD. No complete responses were observed. PD or death at < 5 mo was 63%. At the time of data cut off, PFS at 5 mo was 28.4% (17.3%–40.5%); median follow up was 26.4 weeks (CI: 22.1; 55.9); 39% of patients remain in follow up. Most frequent grade 3/4 events were anemia (13%), hand-foot syndrome (12%), decreased appetite (10%), and nausea (9%). Conclusions: The combination of lapatinib + capecitabine shows promising efficacy and is well tolerated as 1st line treatment for advanced GC. An analysis of biomarker data may help identify who may benefit most from this regimen. [Table: see text]