Background: Lenvatinib (E7080; LEN) is an oral, tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFRβ with evidence of antitumor activity in a broad range of solid tumors. Currently there is an unmet medical need for treatments in third-line or greater NSCLC patients (pts). Methods: This study was a double-blind, placebo-controlled, multicenter, randomized Phase II study of LEN 24 mg PO once daily + BSC vs. placebo (PBO) + BSC (2:1 randomization). Pts with nonsquamous NSCLC who had failed ≥ 2 two systemic anticancer regimens were enrolled. Prior erlotinib or gefitinib was required for pts with known EGFR-activating mutations. The primary endpoint was overall survival (OS). Progression free survival (PFS), overall response rate (ORR), and disease control rate (DCR) were based on investigator assessment. Efficacy endpoints were estimated via Kaplan-Meier. Results: 135 pts enrolled in the study. Per protocol, the study was unblinded and analyzed after 90 deaths. 76% received ≥ 3 prior anti-cancer regimens and 85% received prior erlotinib or gefitinib (similar rates in each arm). A summary of efficacy and safety is presented by study arm (Table). In a post hoc analysis, a similar treatment effect was observed among subjects with wild-type EGFR. Conclusions: LEN in addition to BSC demonstrated a clinically meaningful improvement in both OS and PFS (~ 3 months) in heavily pretreated patients with NSCLC, including those who received prior EGFR inhibitors. LEN was generally well-tolerated, with an AE profile consistent with observed LEN monotherapy studies. These data warrant additional evaluation of LEN in this population. Clinical trial information: NCT01529112.