Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. In phase I studies of lenvatinib partial responses (PR) were observed in thyroid as well as melanoma, endometrial, and renal cancers. Methods: Patients (pts) with unresectable MTC and disease progression demonstrated by RECIST during the prior 12 months were enrolled. Pts may have received prior VEGFR targeted therapy. Pts were treated with a starting dose of lenvatinib 24 mg once daily in 28 day cycles until disease progression or development of unmanageable toxicities. Primary end point was Response Rate (RR) by RECIST. Tumor genetic analysis and circulating cytokine and angiogenic factors (CAF) analysis were performed. Results: 59 pts were enrolled (med age: 52; Male: 63%;) and are evaluable for response. 54% of pts required dose reduction for management of toxicity, and 22% were withdrawn from therapy due to toxicity. The most common treatment-related adverse events were proteinuria 58% (Gr3: 2%), diarrhea 56% (Gr3: 5%), hypertension 48% (Gr3: 7%), fatigue 44% (Gr3: 5%), decreased appetite 41% (Gr3: 5%), nausea 34% (Gr3: 0), and weight decreased 32% (Gr3: 3%). No Gr4 events were reported for these event categories. Confirmed PRs were observed in 21pts (RR: 36%, 95% CI: 24-49) based on independent imaging review (IIR) and 29 pts (RR: 49%, 95% CI: 36-62) based on investigator assessment. For pts who received prior VEGFR-directed treatment (n=26) RR=35% (IIR); with no prior VEGFR-directed treatment (n=33) RR=36 % (IIR). Median PFS by IRR is 9.0 mo (95% CI: 7.0-) (based on minimum 8 mo. f/u, 46% events observed). There was no clear difference in treatment response between RET-mutant (RET-mu) and RET-wild type (RET-wt) patients. Low baseline levels of ANG2, sTie-2, HGF and IL-8 were associated with greater tumor shrinkage and prolonged PFS whereas high baseline levels of VEGF and sVEGFR3 were associated with greater tumor shrinkage. Conclusions: Lenvatinib administered orally at a dose of 24 mg once daily to patients with MTC is associated with manageable toxicity and a RR of 36%, identifying lenvatinib as a promising new potential therapeutic agent for treating patients affected with this disease.