Background: Concurrent radiotherapy and temozolomide (TMZ) followed by adjuvant TMZ (STUPP regimen) is the standard therapy for newly diagnosed glioblastoma after resection, however, the progression-free survival (PFS) was only about 7 months (m) and the overall survival (OS) was less than 17m. This study aims to assess the efficacy and safety of adding anlotinib, a multitarget tyrosine kinase inhibitor, to the STUPP regimen for newly diagnosed glioblastoma. Methods: This was a prospective, sing-arm, multicenter, phase II study (NCT04119674). Eligible patients (pts) were diagnosed with newly diagnosed GBM and had undergone surgery within 6 weeks before enrollment. Previous exposure to other therapies was not permitted. Other key inclusion criteria included 18 to 75 years old, Karnofsky performance status ≥ 60 %, had at least one measurable lesion according to RANO criteria, and adequate bone marrow, hepatic, and renal functions. All pts received radiotherapy (54̃60 Gy administered as 1.8-2.0 Gy fractions, 5 days per week) for 6 weeks, with concurrent oral TMZ (75 mg/m2 QD) and anlotinib (8 mg QD, d1̃d14 per 3 weeks). After a 28-day treatment break, adjuvant therapy was started with six cycles of TMZ (150–200mg/m2, d1–5/4wks) and eight cycles of anlotinib (10 mg QD, d1–14/3wks) ，and followed by anlotinib monotherapy until disease progression or intolerable toxicities. The primary endpoint was progression-free survival (PFS). The adverse events (AEs) were recorded according to CTCAE 5.0. Results: From January 2019 to February 2021, 33 pts (17 males and 16 females) were enrolled from 7 hospitals in China. The median age was 52 (range: 32, 69). At the data cutoff date on January 25th, 2022, all pts had completed the concurrent treatment and 30 pts (90.0%) completed the 6 cycles of adjuvant treatment. The median treatment duration of anlotinib was 16 cycles. At the data cutoff date, 21 patients experienced disease progression and 17 pts were dead. The median PFS was 10.9m (95% CI, 6.6-15.2) and the median OS reached 18.7m (95% CI, 15.0-22.4). The PFS at 1 year was 45.5% and OS at 1 year was 72.7%. No grade 3 or worse AEs were observed during the concurrent phase and anlotinb maintenance phase. Three pts (9.1%) had grade 3 or 4 thrombocytopenia and 1 pts (3.0%) had grade 3 vomiting during the course of adjuvant therapy. Conclusions: This is the first study to explore the feasibility of adding anlotinib to the standard treatment for newly diagnosed GBM. The efficacy was impressive in that the median OS had exceeded 18m and the safety profile was favorable. The positive-controlled study was ongoing. Clinical trial information: NCT04119674.