3158 Background: Tumor angiogenesis remains a focal point in cancer therapeutics, necessitating innovative strategies to counter resistance mechanisms. Lenvatinib, a multitargeted tyrosine kinase inhibitor, and eribulin, a microtubule inhibitor, exhibit promise in disrupting tumor vasculature. Understanding their efficacy and safety in combination therapy is crucial, especially in heavily pretreated patients with advanced solid tumors. Methods: A single-center phase II study (NCT02640508) enrolled patients with stage IV breast carcinoma, lung carcinoma, and sarcoma, evaluating the safety and efficacy of lenvatinib and eribulin combination therapy. Eribulin was given on day 1 and day 8 at 1.4 mg/m2 and lenvatinib at a dose of 20 mg starting on day 2 of a 21-day cycle. Immunohistochemistry assessed biomarkers CD31, e-cadherin, CA-9, and vimentin. Statistical analyses included multivariate modeling and Kaplan-Meier curves. The primary endpoint of the study was the overall response rate (ORR), defined per RECIST 1.1 as assessed by investigator imaging review. Secondary endpoints included safety, progression free survival (PFS) and overall survival (OS). Results: Among 29 patients enrolled, median age was 58 years, majority were female and had at least ≥3 prior lines of chemotherapy. Treatment with lenvatinib and eribulin resulted in an ORR of 24%, as seen in the table. Median PFS was 7.4 months and OS was 8.2 months. Toxicities were manageable with grade ≥3 neutropenia seen in 34.5%, febrile neutropenia in 17.2%, and hypertension in 13.8% of patients. Treatment-related adverse events leading to study-drug discontinuation occurred in 6.8% of patients. Vimentin-negative patients exhibited significantly increased OS (fold change 4.374, p<0.001) and PFS (fold change 3.395, p<0.001) after adjusting for age, CD31, and CA9. Conclusions: Lenvatinib combined with eribulin showcased promising anti-tumor activity in heavily pretreated patients with metastatic breast carcinoma, lung carcinoma, and sarcoma. Although manageable, neutropenia emerged as a notable adverse effect. These findings underscore the potential of this combination as a therapeutic strategy for advanced solid tumors, warranting further clinical investigation. The observed significant survival benefits in Vimentin-negative patients align with the biological role of Vimentin in tumor invasiveness and metastatic potential, supporting the plausibility of these results biologically. Acknowledgement: This clinical trial was supported by Eisai. Clinical trial information: NCT02640508 . [Table: see text]