Background: The use of immune checkpoint blockade (ICB) in non-inflamed (cold) tumors is associated with limited clinical efficacy. Combination of ICB with certain molecularly targeted agents (MTA) is hypothesized to increase tumor immunogenicity by recruiting tumor infiltrating lymphocytes in cold tumors, such as LMS. Here, we present the results of LMS cohort treated on the DAPPER study (NCT03851614). Methods: LMS pts with ECOG 0-1 were randomized to either D+O (arm A), or D+C (arm B). In a 28-day cycle, D 1500mg i.v. q4w with either O 300mg bid po qd or C 20mg po qd 5d/week were administered. Overall response rates (ORR) were determined using RECISTv1.1. Evaluation of tumor kinetics (TK) was performed by calculating tumor growth rate (TGR) of target lesions on CT images at baseline and on-treatment, adjusted to account for the time difference between scans. TGR is expressed as % tumor growth/week (Ferte C et al. CCR, 2014). Additionally, paired FFPE samples (from baseline and on-treatment biopsies) were assessed using multispectral fluorescent immunohistochemistry (IHC) panel: CD3, CD8, CD20, CD68, FOXP3 and cytokeratin. Tumor areas were identified by a pathologist and immune cells were quantified using InForm image analysis software. Results: 25 metastatic LMS pts were randomized to arm A (n = 11) or B (n = 14) over 21 months. Median age was 53 years, 96% were females and 60% of pts had ≥3 lines of therapy. In 23 evaluable pts, no responses were seen, 7 pts had stable disease (SD) while 16 has progressive disease (PD). TK analysis was evaluable for 18 pts (arm A = 8, B = 10). 5/8 pts (62.5%) in arm A and 6/10 pts (60%) in arm B showed decreased TK (defined as TGR^baseline> TGR^on-treatment). In 4/5 (80%) pts who had deceleration of TK in arm A, SD was maintained for ≥6 months. The reduction in TGR on treatment, compared to baseline was significant in arm A but not in arm B (measured as median % tumor growth/week of 0.5 vs 5.1, 95% CI 0.2-4.3, p = 0.035 in arm A; and 1.3 vs 2.9, 95% CI 0.2-2.7, p = 0.088 in arm B). The median PFS of arm A and B were 9 (95% CI 3-12.8) and 4 (95% CI 2.2-4.6) months respectively. There were no statistically significant differences in tumor-infiltrating immune cells when comparing baseline and on-treatment biopsies from arm A or B. In arm A, one pt with SD > 6 months had a 2.5-fold increase in CD8 (CD3+CD8+) T cells and a 7.6-fold increase in macrophages (CD68+). Conclusions: D+O or D+C resulted in stable disease in 30% of pts, mostly on arm A (D+O). TK analysis may identify pts with prolonged SD on treatment. Although a cold-to-hot immunophenotype change was not generally seen, changes in tumor infiltrating immune cell subsets were observed in one patient with prolonged stable disease. These findings support further molecular and immunophenotype characterization in LMS patients treated with D+O or D+C. Clinical trial information: NCT03851614