Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFRα. Two phase 3 trials in differentiated thyroid cancer [DTC] and hepatocellular cancer [HCC] are ongoing. Baseline levels (BL) of circulating cytokines and angiogenic factors (CAFs) were evaluated across multiple phase 2 trials in 6 different types of solid tumors. Methods: BL serum or plasma samples from a total of approximately 500 patients were analyzed for about 50 CAFs using ELISA and multiplex assay platforms* in 5 phase 2 trials of lenvatinib for thyroid cancer (DTC and medullary thyroid cancer [MTC]), HCC, glioblastoma, endometrial cancer (EC), and melanoma (with or without BRAF V600E). Correlation with clinical outcomes (objective response rate [ORR], overall survival [OS]) was performed using Wilcoxon signed-rank test and univariate Cox proportional hazard model, respectively, whereas correlation with tumor size prior to lenvatinib treatment was performed using the Spearman's rank correlation test. Results: Among 50 CAFs, BL angiopoietin-2 (Ang-2) correlated with tumor size (p) in DTC (0.004), MTC (0.004), EC (<0.001), melanoma [WT (<0.001), MU (<0.001)] and HCC (0.046) among multiple phase 2 trials. BL Ang-2 levels showed consistent correlation with clinical outcomes per tumor types across trials and with OS (p/hazard ratio per standard deviation) in DTC (0.001/3.2), MTC (<0.001/3.2), EC (<0.001/1.8), and melanoma [WT (0.001/1.5), MU (<0.001/2.0)]. Correlation with ORR was observed only for a minor subset of analyzed CAFs; only BL Ang-2 levels correlated with ORR in >1 tumor type, specifically in DTC (0.034*), MTC (0.025) and EC (0.001). In EC, almost 50% of BL CAFs showed a significant correlation with tumor size, potentially suggestive of an EC-specific tumor micro-environment and the contribution of Ang-2 to tumor angiogenesis in EC. Conclusions: BL Ang-2 levels correlated with tumor size and OS across majority of solid tumors in multiple lenvatinib phase 2 trials. Only BL Ang-2 levels also correlated with ORR in a subset of tumors including EC. Clinical trial information: NCT00784303,NCT01111461,NCT01136967,NCT00946153,NCT01433991,.