Background: Patients (pts) with relapsed Ewing sarcoma (ES) have a poor outcome. New therapeutic agents are needed. L is a new anticancer drug that blocks transcription and induces DNA double-strand breaks, leading to apoptosis. Moreover, in sarcomas associated with translocations, such as ES, in which the translocation produces a fusion protein that acts as a deregulated transcription factor, L might interfere with the binding of this protein to specific DNA promoters and thus with the synthesis of downstream proteins. Methods: A multicenter phase 2 trial to assess efficacy and safety of L in several types of advanced solid tumors (basket trial), including ES, is ongoing. In the ES cohort, 15 adult pts who had received no more than two prior chemotherapy regimens for advanced disease were recruited. If one confirmed response was observed, recruitment was to be increased to at least 25 evaluable patients. The study treatment was lurbinectedin 3.2 mg/m² in a 1-hour infusion every 3 weeks. Results: 28 evaluable pts were enrolled. Median age was 33 years (range, 18-74) and 16 (57%) were males. 26 (93%) had an ECOG of 0/1. ES was extraosseous in 15 pts; 7 pts had ≥3 disease sites and 27 had received ≥2 lines of prior chemotherapy. 28 pts received a median of 4 cycles of L (range, 1-12) and a median total dose of 11.9 mg/m² (range, 3.2-38.4). Efficacy: 4 pts (14.3%) had a partial response and 12 (42.8%) had disease stabilization, 6 of them for ≥4 months. Median duration of the response was 2.9 months (range, 2.9-5.5) and median progression-free survival was 2.8 months (CI 95% 1.4-4.2). Safety: Most common adverse events were related to myelosuppression: 53.6% neutropenia grade (G) 3/4, 14.3% febrile neutropenia, and 18% thrombocytopenia G 3/4; 6 pts had dose delay due to neutropenia G 2-4 or thrombocytopenia G1, and 6 pts had dose reduced because of neutropenia G2-4. G-CSF was given to 12 pts. There were no withdrawals or deaths due to toxicity. Conclusions: L as a single agent has shown activity in pretreated pts with advanced ES, with acceptable safety profile and tolerability. Myelotoxicity was well controlled with dose adjustments and G-CSF. Further and larger studies of L alone or in combination regimens are warranted for pts with advanced ES. Clinical trial information: NCT02454972