Anlotinib in combination with epirubicin followed by maintenance anlotinib versus placebo plus epirubicin as first-line treatment for advanced soft tissue sarcoma (STS): A randomized, double-blind, parallel-controlled, phase III study.

11501 Background: Anthracycline-based chemotherapy has been the standard first-line treatment for advanced STS for decades. The phase 3 ANNOUNCE trial failed to demonstrate an overall survival (OS) benefit with olaratumab plus doxorubicin compared to doxorubicin. Since 2020, fewer novel regimens emerged to challenge the first-line treatment. Anlotinib (ALTN), an anti-angiogenic oral multi-target tyrosine kinase inhibitor, first showed promising results in a phase II single-arm trial, the addition of ALTN to epirubicin (EH) followed by maintenance ALTN improved progression-free survival (PFS) in the first-line setting for STS patients (pts). Consequently, we conducted a nationalwide, randomized, double-blind, parallel-controlled, phase 3 trial comparing ALTN plus EH followed by ALTN maintenance versus EH combined with placebo (PBO) as first-line treatment for advanced STS pts in China. Methods: Eligible pts had previously untreated, pathologically confirmed, unresectable locally advanced or metastatic STS. Pts were randomized in a 1:1 ratio to receive either ALTN (12mg) orally once daily (2-week on/1-week off) plus EH (90 mg/m 2 ) intravenously once every 3 weeks up to 6 cycles, followed by maintenance ALTN (12mg) orally once daily (2-week on/1-week off) or PBO (0mg) orally once daily (2-week on/1-week off) plus EH(90 mg/m 2 ) intravenously once every 3 weeks up to 6 cycles, followed by maintenance PBO (0mg) orally once daily (2-week on/1-week off). The primary endpoint was PFS assessed by the blinded independent review committee according to RECIST 1.1. Secondary endpoint included OS, Objective Response Rate (ORR), Disease control rate (DCR) and safety. Results: A total of 272 pts were randomized: 135 to ALTN + EH arm, 137 to PBO + EH arm. As of February 15, 2024, after a median follow-up of 7.16 mo, ALTN + EH arm significantly improved PFS (HR 0.30 [95% CI 0.21-0.44]; P < 0.001; median 8.57 vs 3.02 mo), and ORR (17.8% vs 2.90%; P < 0.001) , DCR (79.3% vs 54.7%; P < 0.001) versus PBO + EH arm. The median OS was not reached in either arm (HR = 0.78 [95% CI: 0.49-1.25]). The benefit of ALTN + EH arm was observed across most subgroups tested, including leiomyosarcoma, synovial sarcoma and other pathological types. The incidence of Grade ≥3 adverse events (AEs) (69.6% vs 59.1%), AEs leading to discontinuation of treatment (3.7% vs 4.4%), fatal AEs (3.7% vs 3.6%) were similar between two arms. Conclusions: Anlotinib in combination with epirubicin followed by maintenance ALTN demonstrated a statistically significant and clinically meaningful PFS benefit compared to epirubicin alone in pts with previously untreated advanced STS, which could serve as a potential new first-line treatment for locally advanced or metastatic STS. The final OS outcomes are currently under ongoing follow-up. Clinical trial information: NCT05121350 .