Background: ECF/X (epirubicin (E) + cisplatin (C) + 5-fluoruracil (F) or capecitabine (X)) is a reference chemotherapy (CT) regimen in metastatic GC. Trastuzumab with CF/X prolonged survival (OS) of metastatic HER2+ gastric or esophagogastric junction cancer (GC) patients (pts). Lapatinib (LAP) inhibits both, EGFR1 and HER2, and showed activity in phase II GC trials. This double-blind Phase II study prospectively addressed efficacy and safety of LAP with ECF/X in GC pts with discordant FISH or IHC HER2 status or EGFR1+. Methods: Pts without prior palliative CT, screened centrally for HER2/EGFR1 (by FISH and IHC) were enrolled into 3 strata: 1) HER2 FISH+ and IHC 2/3+, 2) HER2 FISH- and IHC 2/3+, or 3) HER2 IHC 0/+ and EGFR1 FISH+ or IHC 2/3+. Pts without HER2 + or EGFR1+, by FISH or IHC, were excluded. Pts were randomized to LAP 1250mg (arm 1) or placebo (arm 2), with ECF or ECX (investigator-selected) for 6 cycles. Primary endpoint was progression free survival (PFS). Secondary endpoints were toxicity, response rates, OS, HER2 concordance and correlation of HER2/EGFR. Results: The trial was prematurely closed to patient accrual given the LOGIC trial results at ASCO 2013. A total of 69 pts were tested in central lab of whom 9 (13%), 5 (7.2%) and 25 (36.2%) were in stratum 1, 2 and 3. Of these, 28 patients (6/4/18) were randomized (14 in arm 1, 14 in arm 2) and followed up. Due to the low number of pts accrued, no formal statistical tests were carried out. No safety concerns were found in arm 1. No complete responses were seen. 6 pts had partial responses in arm 1 vs. 3 pts in arm 2. Median PFS was 7.1 months in arm 1 vs. 5.9 months in arm 2 (HR=0.94, 95% CI: 0.41-2.14) for all pts, and 6.2 months in arm 1 vs. 6.3 months in arm 2 (HR=0.99, 95% CI: 0.36-2.75) for stratum 3 pts, respectively. Median overall survival was 13.8 months in arm 1 vs. 10.1 months in arm 2 (HR=0.90, 95% CI: 0.35-2.27) for all pts. Conclusions: Lapatinib with ECF/X did not show appealing activity in EGFR+ metastatic GC patients in this small phase 2 trial. The combination was well tolerated. Clinical trial information: NCT01123473