Background: Lenvatinib is a multiple receptor tyrosine kinase (RTK) inhibitor that has demonstrated meaningful benefit in radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). In SELECT, lenvatinib significantly prolonged progression-free survival (PFS) and was associated with an overall response rate (ORR) of 65% in patients with RAI-refractory DTC, with the greatest degree of tumor shrinkage occurring in the first 2 cycles. The robust activity of lenvatinib in DTC suggests that neoadjuvant treatment in patients presenting with bulky neck disease may make surgery more feasible, allows for optimal surgical outcomes and less aggressive surgical management. Neoadjuvant lenvatinib to improve surgical outcomes in locally advanced DTC has not been studied to date. This phase 2 study will examine the efficacy and safety of lenvatinib prior to thyroidectomy, with the goal of achieving more favorable surgical outcomes. Methods: This is a Simon two-stage Phase 2 open-label multicenter clinical trial for adult patients who meet the following criteria: have been diagnosed with locally advanced or persistent/recurrent thyroid and/or cervical nodal DTC, deemed at risk for R2 resection (surgical margins with macroscopic tumor) (as evident by vocal cord paralysis by laryngoscopic exam, imaging documenting extrathyroidal/extranodal extension, or major vessels involvement), have measurable disease per RECIST v1.1, have an ECOG performance status ≤ 1, and no contraindication to surgery. A total of 28 patients will be enrolled from three centers (Massachusetts General Hospital/Massachusetts Eye & Ear Infirmary (MGH/MEEI), Memorial Sloan-Kettering Cancer Center (MSKCC), and MD Anderson Cancer Center (MDACC)). Participants will receive up to 6 cycles of lenvatinib prior to surgery depending on response. Participants will undergo restaging at the end of cycle 2, 4, and 6. Participants with sufficient response to treatment who projected to achieve an R0 or R1 resection will stop lenvatinib and proceed to surgery within 7-10 days from the last dose. Participants who do not have a sufficient response who are tolerating treatment, will receive an additional 2-4 cycles of lenvatinib, followed by surgery. The primary objective is the R0 (surgical margins free from tumor)/R1 (surgical margins free from macroscopic tumor) resection rate. Secondary outcome measures include R0/R1 resection rates in each of 5 pre-specified anatomic target interfaces (perithyroid muscles, cartilage, esophagus, recurrent laryngeal nerve, major vessels), evaluation of the change in surgical morbidity complexity MGH/MEEI-MSKCC-MDACC (MMM) score and the Invasive Thyroid Class, ORR prior to surgery per RECIST v1.1, and the safety of lenvatinib in this patient population. The study is currently accruing with 11 patients enrolled at time of submission. Clinical trial information: NCT04321954.