Background: Targeted therapies (tx) in GEA have had limited efficacy despite recognition of numerous ‘targetable’ molecular events. This may be due to the molecular heterogeneity (MH) that exists between patients (pts), within the primary tumor (PT), between PT and synchronous metastatic lesions (MLs), and in lesions over time. Current biomarker profiling (BP) is performed on one site, usually the PT, yet this fails to capture the MH of GEA, with likely major clinical implications. Classic trial designs are challenged by MH, low frequency oncogenic drivers, and scarcity of tissue. There is need for novel trial designs and BP technologies that address these concerns, provide tx algorithms for pts with multiple aberrations, and have access to several txs. Methods: This phase IIa, open-label, non-randomized ‘platform trial’ enrolls pts with newly diagnosed metastatic GEA or recurrent disease after curative-intent surgery. Baseline tumor BP is performed on PT/ML along with circulating free (cf)DNA. Pts receive first line (1L) mFOLFOX6 + biologic tx based on BP of the ML using a prioritized tx algorithm (HER2+: trastuzumab; MET+: none; FGFR2+: none; EGFR+: ABT806; MSI-H: nivolumab; ‘RAS-like’: ramucirumab). MET/FGFR2 arms (~10% of all pts) are tx’d with cytotoxics only and followed for natural outcome until/if tx becomes available on study. At first progression (PD1), pts undergo biopsy of growing ML and change to 2L FOLFIRI + biologic agent as assigned in 1L tx. Upon results of PD1 biopsy, pts change to a new biologic tx if the molecular category evolves. At PD2, pts change to 3L FOLTAX + biologic as determined after PD1, and switch biologic tx from PD2 biopsy result. All PD1/PD2 tumor/cfDNA samples undergo BP to assess evolution and resistance mechanisms. Co-primary endpoints: safety, feasibility, and overall survival (OS) of this personalized treatment strategy (excluding MET/FGFR2) compared to historical controls (HR 0.66). Secondary endpoints include rate of baseline MH between PT and ML leading to new treatment assignment; utility of cfDNA; overall progression-free survival (PFS)/response rate (RR); OS/PFS/RR in each targetable group. Since 8/2015, 38 of 68 planned pts have been accrued. Clinical trial information: NCT02213289