Background: There are limited treatment options for advanced LPS and LMS, the two most common histologies in soft tissue sarcoma. Patients (pts) treated with E had an improved overall survival (OS) compared to dacarbazine but with an unsatisfactory 4% objective response rate (ORR). Early studies of L, a multi-targeted anti-angiogenic inhibitor, had suggested efficacy in sarcoma pts. We hypothesized that the L+E could potentiate the treatment efficacy in advanced LMS and LPS. Methods: LEADER was a single-arm phase Ib/II study for advanced adult LMS and LPS pts who had received no more than 2 lines of systemic chemotherapy (NCT03526679). The phase Ib part (starting dose: L 18mg/day, E 1.1mg/m²) had been reported and the recommended phase 2 dose (RP2D) was determined at L 14mg/day and E 1.1mg/m² D1, D8 every 21 days. The primary endpoint of the phase II part was ORR by RECIST 1.1, secondary endpoints included progression-free survival (PFS), 6-month PFS rate, and OS. Pts in phase Ib/II part were analyzed together for efficacy. Results: As of Nov 15 2021, 30 pts (F/M 20/10) had been treated with at least one cycle of L + E; 21 were LMS (9 uterine, 12 non-uterine) and 9 were LPS (5 dedifferentiated, 2 myxoid round cell, 2 pleomorphic). The median age was 59 (range 29-73); the median lines of treatment(s) received before enrollment was 1 (range 0-3). The ORR by RECIST 1.1 was 20 % (6/30) (95% CI 10-53%); the ORR for pts received L 18mg/day (2/6) and L 14mg/day (4/26) were not significantly different (p = 0.23). After a median FU time of 20.1 months, the median PFS and 6-month PFS rate was 8.56 mos (95% CI 4.40-not reached (NR)) and 59%, respectively. The median PFS for LMS (8.56 mos, 95% CI 4.17- NR) and LPS (11.36 mos, 95% CI 4.4-NR) were not significantly different (p = 0.73). The median OS and 12-month OS rate was 26.2 mos (95% CI 21.4-NR) and 89%, respectively, but LPS pts had significantly worse OS (HR 3.5, p = 0.04). Twenty pts experienced at-least one grade (gr) 3 or 4 adverse event (AE); gr 3 or 4 AEs occurred in > 1 pt included hypertension (n = 4); hand-foot-syndrome (HFS) (n = 5), proteinuria (n = 3), febrile neutropenia (n = 3), neutropenia (n = 11, without G-CSF support). Compared to L 18mg/day, pts treated with RP2D were associated with lower gr3/4 HFS and hypertension. There were no sustained grade 3/4 AEs for pts receiving long-term L+E. Conclusions: L + E had shown promising efficacy in advanced LMS and LPS. L at 14mg (vs 18mg) had a better AE profile without compromising activity. Future randomized study to confirm the efficacy of the combination is warranted. Clinical trial information: NCT03526679.