Background: Lenvatinib is an oral receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFRβ. A phase 2 study in patients with advanced endometrial cancer following 1 or 2 prior platinum-based treatments was performed and is presented in a separate abstract. Here we report potential predictive markers of clinical benefit. Methods: Pre- and post-treatment plasma samples collected from 122 of 133 treated subjects were analyzed for 50 circulating cytokine and angiogenic factors (CAFs) using ELISA and multiplex assay platforms; 107 archival tumor tissues obtained from 133 enrolled subjects were analyzed for gene mutation (mut) (81 samples) and gene expression profiling (GEP) (64 samples). For GEP analysis, the NanoString nCounter platform was used to measure the expression level of approximately 300 genes identified preclinically as relevant. Correlation with clinical outcome measures including maximal tumor shrinkage (MTS), objective response rate (ORR), PFS, and OS was performed. Results: Clinical correlation identified baseline levels of 7 CAFs related to angiogenesis (Ang-2, IL-8, HGF, VEGFA, PlGF, Tie-2, and TNFa) that associated with survival. Only baseline levels of Ang-2 associated with greater MTS (R=0.36 [Spearman], P<0.001), ORR (61% vs 18%), mPFS (9.5 vs 3.7 mos), and mOS (23 vs 8.9 mos) as determined using a defined cut-off value for baseline Ang-2. In gene mut analysis, no significant correlations were observed among the genes tested. Mut in PIK3CA showed a trend toward shorter OS (p = 0.085). In GEP analysis, expression levels of approximately 90 genes correlated with clinical outcome. Combination of GEP and CAF signatures identified signaling pathways, including Ang-2, that associated with OS. Clinical and preclinical GEP analysis identified overlapping gene signatures involving MAPK and PI3K signaling pathways that contributed to lenvatinib resistance. Conclusions: Baseline circulating Ang-2 levels may potentially predict outcomes in patients with advanced endometrial cancer and require further examination. This may provide a basis for stratification of patients in future clinical trials. Clinical trial information: NCT01111461.