6103 Background: Anaplastic thyroid carcinoma (ATC) is rare aggressive and fatal malignancy with poor prognosis. Antiangiogenic and multikinase inhibitors and programmed cell death protein-1 (PD-1) antibodies have conferred benefits for ATC. We aimed to assess the efficacy and safety of anlotinib plus sintilizumab in patients with locally advanced or advanced ATC. Methods: In this prospective study, patients with histologically confirmed locally advanced or metastatic ATC, received a combination therapy of anlotinib and sintilizumab. Anlotinib was started at 12 mg once daily for 14 days and combined with sintilizumab at a fixed dose of 200 mg every three weeks. The primary end point was objective response rate (ORR), assessed in patients who received at least one dose of treatment. Tumor samples were characterized by next-generation sequencing in 12 patients and PD-L1 expression levels in 14 patients. Results: Between June 1st, 2022 and August 21st, 2023, 18 patients with locally advanced or metastatic ATC were enrolled and received combination treatment. Best overall response (BOR) within all patients was 5.6% (1/18) complete remission, 38.9% partial remission (7/18), 33.3% stable disease (6/18), and 22.2% progressive disease (4/18). ORR was 44.4% for all patients and 80.0% for 5 patients with BRAF V600E mutation. The only one patient with PD-L1 negative also reached PR. Median follow up time was 14.6 months for all patients and 16.1 months for patients with BRAF V600E mutation. The median progression-free survival was 7.5 months (0.5 to 56.3 months) for all patients and 5.7 months (1.0 to 13.1 months) for patients with BRAF V600E mutation. Duration of treatment was 5.9 months (0.5 to 38.2 months), and 8 of 18 ATC patients are still on therapy. Grade III/IV toxicities were observed in 4 of 18 patients, necessitating dose reduction/discontinuation of anlotinib. The 1-year overall survival (OS) rate was 61.1% and median OS was 12.9 months (0.6 to 56.3 months), with 8 ATC patients being still alive without progression. Conclusions: The combination of anlotinib and sintilizumab demonstrated promising activity and manageable toxicity in patients with locally advanced or metastatic ATC, suggesting its potential as a viable therapeutic option for this patient population. Clinical trial information: ChiCTR2200067045. [Table: see text]