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Background: HER2 amplification is common in upper GI tract(UGIT)adenocarcinomas and inhibition improves clinical outcomes.Lapatinib ditosylate(L),a dual anti EGFR and anti HER2 tyrosine kinase inhibitor with preclinical activity against these cancers,was investigated in a phase Ⅲ,randomized,double blind trial evaluating efficacy and safety in combination with CapeOx as first-line treatment of advanced or metastatic HER2+ UGIT ACs.Methods: Subjects had measurable and/or non-measurable disease with overexpression or amplification of HER2(IHC2+ and FISH amplified,or IHC 3+,or FISH,CISH,or SISH amplified).HER2 status was reviewed by the central lab.Subjects were randomized 1:1 to CapeOx q3w(oxaliplatin 130mg/m2 day 1; capecitabine 850mg/m2/BID days 1 – 14),and daily L(1250mg)(CapeOx+L)or placebo(CapeOx+P).The primary efficacy population(PEP)comprised all subjects whose tumors were centrally confirmed to be FISH amplified.The primary endpoint was overall survival(OS)of the PEP.Secondary endpoints included progression free survival(PFS),overall response rate(ORR)and safety.Results: 545 pts were randomized and 487 had HER2+ centrally confirmed.The primary endpoint was not reached with a hazard ratio(HR)for OS of CapeOx+L compared to CapeOx+P of 0.91(95%CI 0.73,1.12,p=0.35); median 12.2 vs.10.5 months,respectively.HR for uncensored PFS was 0.86(95%CI 0.71-1.04,p=0.10); median 6.0 vs.5.4 months.The analysis of PFS censored by the time of subsequent anticancer therapy as per protocol showed a HR of 0.82(95%CI 0.68,1.00,p=0.04).ORR was 53%in the CapeOx+L arm and 40%in the CapeOx+P arm.Pre-specified subgroup analyses showed significant improvements in OS in Asian pts(HR= 0.68)and those under 60 years(HR=0.69).There was no association between IHC and OS.Toxicity profiles were similar except for increased overall diarrhea,and skin toxicity and grade 3+ diarrhea(12 vs 3%)with CapeOx+L.Conclusions: The addition of L to CapeOx did not reach its primary endpoint,though certain subgroups showed improvement.Further clinical and molecular analyses will be presented.