Background: New treatment options are needed for sarcomas. Pazopanib is the only targeted agent approved for multiple soft tissue sarcoma (STS) subtypes with a response rate of 6% and a PFS of 4.6 months. Immunotherapy has a limited role in STS, as the SARC028 study of pembrolizumab demonstrated an overall response rate of 18%, with the highest response rate seen in the undifferentiated pleomorphic sarcoma (UPS) cohort at 23%. Lenvatinib is an oral, multi-tyrosine kinase inhibitor approved for the treatment of multiple cancer types including progressive, radioiodine-refractory thyroid cancer and unresectable hepatocellular carcinoma with inhibitory activity against the receptor tyrosine kinases VEGFR 1-3, FGFR 1-3, KIT, PDGFR alpha/beta, and RET. Early outcomes with the combination of lenvatinib and pembrolizumab suggest that this regimen could be broadly superior to PD-1 targeting alone for several tumor types as high rates of objective response have been noted. The rationale for this study is based on preclinical work demonstrating the immunosuppressive effects of VEGF in the tumor immune microenvironment including inhibition of dendritic cell maturation, recruitment of immunosuppressive Tregs, MDSCs and TAMs and up-regulation of PD-1 on CD8+ cells. Methods: This is a pilot study evaluating the efficacy of lenvatinib and pembrolizumab in the treatment of select metastatic and/or unresectable sarcomas. Patients will be enrolled in one of five cohorts: Cohort A: leiomyosarcoma; Cohort B: UPS; Cohort C: vascular sarcomas (including angiosarcoma and epithelioid hemangioendothelioma); Cohort D: synovial sarcoma and malignant peripheral nerve sheath tumor; and Cohort E: bone sarcomas (limited to osteosarcoma and chondrosarcoma). Eligible patients should have had at least one prior therapy for unresectable and/or metastatic disease, but no more than three prior lines of therapy. Prior treatment with angiogenesis inhibitors or immunotherapy is excluded. Archival tissue is required for eligibility. Patients enrolled in the study will be treated initially with a 2 week run-in of lenvatinib 20 mg orally daily which will be continued daily thereafter. Subsequently, they will start pembrolizumab 200 mg intravenously every 21 days. The primary endpoint for each cohort is best overall response rate documented by RECIST v1.1 Criteria at 27 weeks. A sample size of 10 patients is planned for each of the five histological cohorts. If 2 or more confirmed responses are observed among the 10 patients in an arm, the drug combination will be considered positive and worthy of further investigation for that arm. Secondary endpoints are PFS, OS, duration of response and safety/tolerability of the combination. On-treatment biopsy and blood samples will be required for correlative assessments. Accrual in all cohorts is ongoing. Clinical trial information: NCT04784247.