Background: Responses to single agent PD-1/PD-L1 inhibitors in STS remain limited with occasional responses in undifferentiated pleomorphic sarcomas (UPS), liposarcomas (LPS), and other sarcomas, and rare responses in leiomyosarcoma (LMS). Since cytotoxics and/or targeted therapies such as CDK4/6 inhibitors may alter the tumor microenvironment (TME) and potentiate the effect of immunotherapy, combination approaches may be needed to potentiate STS immunotherapy. The mechanism by which eribulin controls LPS may involve TME modification, and therefore it is attractive to test in combination with pembrolizumab in STS subtypes. This report summarizes the results from the LMS cohort from this ongoing trial. Methods: Pts treated with at least one prior therapy received eribulin 1.4mg/m2 (day 1, 8) and pembrolizumab 200mg (day 1), every 21 days. Pts continued therapy until progressive disease, death, or unacceptable toxicity. Primary endpoint was progression-free survival (PFS) at 12 weeks, with 60% PFS at 12 weeks required to deem the combination promising. Tumor assessments (RECIST 1.1) were performed at screening and every 6 weeks thereafter. Secondary endpoints included overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR). Results: Nineteen pts with LMS were enrolled from May 2019 to Sept 2019. The median age was 62 (range 48-80). Eleven (58%) patients had uterine LMS. The median # of prior therapies was 4 (range 1-7). The median follow-up was 19.7 weeks. The PFS at 12 weeks was 42.1% (90% CI: 27.0%-65.5%), with median PFS of 11.1 weeks. Median OS was not reached during the follow-up period. There was 1 partial response, and 5 confirmed stable disease for ORR of 5.3% and CBR of 26.3%, after 12 weeks. The rate of grade 3 or higher toxicity was 68% overall, most commonly neutropenia, anemia, weight loss, diarrhea, elevations of lipase, and alkaline phosphatase. These side effects were reversible. The most common adverse events were fatigue, neutropenia, anorexia, AST increase, and nausea. Conclusions: Eribulin and pembrolizumab in LMS did not meet the predefined endpoint for efficacy. The LPS and “other STS subtype” cohorts of this trial are actively enrolling. Clinical trial information: NCT03899805.