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Background: Met is associated with a poor outcome in many cancers, including NSCLC. Met activation is a mechanism of resistance to EGFR inhibition, supporting dual inhibition of Met/EGFR. MetMAb is a monovalent monoclonal antibody that specifically binds the Met receptor. Methods: OAM4558g is a global randomized, double-blind phase II study comparing MetMAb plus erlotinib (ME) to placebo plus erlotinib (PE) in 2nd/3rd line NSCLC. Tissue collection was mandatory to assess c-Met IHC expression levels (Met Dx). Co-primary endpoints were PFS in the Met Dx and ITT populations. Safety and OS were additional endpoints. Following the initial unblinding, Met Dx- patients (pts) were removed from ME. Results: 128 NSCLC pts were equally randomized to receive ME or PE. 95% of tissue was evaluable for c-Met IHC, 88% for EGFR and KRAS mutations (mut), and 75% for MET FISH. Baseline characteristics were well balanced. 54% of pts had Met Dx NSCLC, which was associated with a worse outcome (OS HR 2.52, PE cohort). A total of 99 PFS and 70 OS events have occurred, median follow up is 9.9mos. In the Met Dx group, ME resulted in a statistically and clinically significant improvement in both PFS and OS. An OS benefit from ME was observed in MET FISH NSCLC as well as in FISH-/IHC; removing pts with EGFR mut did not alter results. Selective benefit of ME was not observed in other subgroups. E-related toxicities were comparable between treatment arms. Conclusions: Met Dx NSCLC represented more than half the population and was associated with a worse outcome. The addition of M to E in these pts significantly improved PFS and OS, resulting in a near 3-fold reduction in the risk of death. This benefit was not exclusive to EGFR mut or MET FISH and was observed in FISH-/IHC pts suggesting IHC is a more sensitive predictor of benefit from MetMAb.