Background: Standard treatment for patients with unresectable locally advanced or metastatic soft-tissue sarcoma is chemotherapy based on anthracyclines, while the tolerance of chemotherapy is limited. Anlotinib had demonstrated promising efficacy and favorable tolerance in the first-line treatment of these patients in the previously report (2021 ASCO). We updated the latest long-term efficacy and safety data. Methods: This multicenter, open-label, single-arm, phase II clinical trial (NCT03792542) was done at 7 hospitals in China. Patients diagnosed with locally advanced or metastatic soft-tissue sarcoma who had evaluable lesion per Response Evaluation Criteria in Solid Tumors version 1.1 were eligible for inclusion. Additional inclusion criteria were 1) 18-70 years old, 2) ECOG PS 0-2, 3) chemotherapy intolerance judged by investigators, 4) chemotherapy and anti-angiogenesis treatment naïve. All patients received 12mg anlotinib once daily for 14 days every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Safety assessment was done in patients who received at least one dose of anlotinib. Results: 39 patients (24 males and 15 females) were enrolled between April 2019 to October 2021with a median follow-up 13.4 months (IQR 6.55-19.40), and the median age is 58 (range 23-69) years old. Pathological types included liposarcoma (n = 11), fibrosarcoma (n = 8), undifferentiated pleomorphic sarcoma (n = 5), leiomyosarcoma (n = 4), synovial sarcoma (n = 4), malignant peripheral nerve sheath tumor (n = 4), and others (n = 3). At the data cutoff date on December 27, 2021, the median PFS and median overall survival (OS) were 7.1 months [95%CI 5.42-8.77], 24.3 months [95%CI 14.9-33.7], respectively. The PFS at 6 months was 60.0%, and the OS at 12 months was 76.6%. 37 patients were eligible for the evaluation of tumor response.1 achieved confirmed partial response (PR) and the objective response rate (ORR) was 2.7% (1/37). 30 had stale disease (SD) and the disease control rate (DCR) was 83.8% (31/37). The incidence of adverse events of grade 3 was 33.3%, with a higher incidence of hypertension (12.8%), proteinuria (7.7%) and fatigue (5.1%). Conclusions: Anlotinib has shown encouraging anti-tumor activity and well tolerance in the first-line treatment of locally advanced or metastatic soft-tissue sarcoma who were not suitable for chemotherapy. Clinical trial information: NCT03792542.