Background: EMC is a rare sarcoma, marked by a specific rearrangement involving NR4A3. We reported on the activity of SM in 10 EMC pts (Eur J Cancer 2014;50:1657). We update herein this series with a longer follow-up and provide clues on the molecular bases of response. Methods: All pts with a confirmed diagnosis of progressive, advanced EMC treated since July 2007 with SM 37.5 mg/day on a named-used program were considered. Pts were treated until unacceptable toxicity or progression. SM dose was increased to 50 mg/day in pts with primary PD and acceptable toxicity while on SM 37.5 mg. Diagnosis was confirmed by the presence of NR4A3 fusion. Response was assessed by RECIST, considering treatment failure those cases who progressed while on therapy and after escalating SM to 50 mg/day. The pretreatment transcriptional profiles of 4 responsive and 2 non-responsive pts were compared. Results: Eleven pts with progressive, metastatic EMC were identified (mean age: 62 yrs - prior chemotherapy: 10). All pts were evaluable for response. Six pts stopped SM (toxicity: 3; PD: 3, of which 2 were primary, 1 secondary), while 5 pts are currently on therapy (range of time on treatment: 1-54+ mos). Best responses were: 6 PR, 3 SD, 2 PD. PR was achieved at the dose of 37.5 and 50 mg/day in 4 and 2 cases, respectively, while 2 pts progressed despite of dose escalation. One pt had a response to SM after PD while on pazopanib. Interval PD were observed in 4 pts and response was restored in all after SM rechallenge. Among pts with a PR to SM, no secondary resistance has been detected as of today, while in one pt a PD was observed after an initial SD. At a median FU of 32 mos, median PFS is 34 mos, while median OS is not reached. Unsupervised cluster analysis divided EMC into 2 major groups corresponding to responsive/EWSR1-NR4A3+ and non-responsive/TAF15-NR4A3+ cases. Conclusions: We confirm that SM is active in EMC, with responsive pts reaching prolonged progression-free intervals. We already reported that all responsive pts had the EWSR1-NR4A3 fusion variant and RNAseq analysis suggests that SM response correlates with a distinctive expression profile. The specific mechanism of action is under evaluation. A European phase II study on pazopanib in EMC is ongoing.