Background: A recent phase 3 study (NCT01327885, Lancet 2016, in press) comparing ERI with DTIC in pts with advanced LPS or LMS, showed a significant improvement in overall survival (OS) for the ERI arm with a manageable toxicity profile. This analysis evaluated the efficacy and safety of ERI in LPS pts. Methods: Pts aged ≥ 18 yrs with advanced dedifferentiated, myxoid, round cell, or pleomorphic LPS incurable by multimodality therapy and from 3 geographic regions were included. Pts with ECOG status ≤ 2 and ≥ 2 prior systemic treatment regimens, including an anthracycline, were randomized 1:1 to ERI (1.4 mg/m², IV on D1 and D8) or DTIC (850, 1000, or 1200 mg/m², IV on D1) every 21-D until disease progression. OS, progression free survival (PFS), and safety were analyzed in LPS pts. Results: 143 pts with LPS (38% female; 76% < 65 yrs; 45% dedifferentiated, 39% myxoid/round cell, 16% pleomorphic LPS), representing 32% of the total study population, were included in this pre-planned analysis (71 ERI; 72 DTIC). Median OS for LPS pts receiving ERI vs DTIC was 15.6 vs 8.4 mo (HR = 0.51, [95% CI 0.35 0.75]; P= 0.001). OS benefit with ERI vs DTIC was observed independent of LPS histology (dedifferentiated—18.0 vs 8.1 mo, HR = 0.43 [95% CI 0.23, 0.79]; myxoid/round cell—13.5 vs. 9.6 mo, HR = 0.79 [95% CI 0.42, 1.49]; pleomorphic—22.2 vs 6.7 mo, HR = 0.18 [95% CI 0.04, 0.85]) and independent of geographic region. PFS in LPS pts for ERI vs DTIC was also improved (2.9 vs 1.7 mo, HR = 0.52, [95% CI 0.35–0.78]; P= 0.002). The mean number of treatment cycles for ERI vs DTIC was 6.5 and 3.2, respectively. In the ERI and DTIC arms, 100% and 96% of LPS pts had adverse events (AEs). Most frequent AEs in the ERI arm were alopecia (40%), fatigue (40%), neutropenia (39%), and nausea (39%). AEs of ≥ grade (G) 3 occurred in 63% and 51% of LPS pts in the ERI and DTIC arms, respectively. Peripheral sensory neuropathy of G3 occurred in 3% of LPS pts in the ERI arm, with no incidence of G4 or G5. Conclusions: ERI was associated with a significant benefit in OS and PFS compared with DTIC in LPS pts and represents an active agent against LPS, sarcomas for which limited effective treatments are available. Clinical trial information: NCT01327885