Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC.

Abstract

7505 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. Median (mo) Population N PFS HR OS HR PE ME 95% CI P c-Met IHC+ 65 0.47 1.5 3.0 0.26–0.85 0.01 0.37 4.6 12.6 0.20–0.71 0.002 MET FISH+ (≥5 copies) 19 0.47 2.4 12.6 0.15–1.49 0.19 FISH-/IHC+ 37 0.44 3.6 7.1 0.17–1.15 0.09 FISH-/IHC+/EGFR wt 32 0.59 3.6 7.1 0.22–1.59 0.29 c-Met IHC-* 56 3.02 9.2 5.5 1.13–8.11 0.021 ITT* 128 1.09 8.2 7.1 0.62–1.91 0.76 * Initial data cut.