Background: Paclitaxel combined with cisplatin regimen has been the standard of care as first-line therapy in advanced ESCC for almost two decades. PD-1 blockades combined with chemotherapy as first line setting exhibited superior efficacy for patients with ESCC recently. Anlotinib was a potential second-line monotherapy for patients with ESCC in China. Therefore, this study was designed to explore the efficacy and safety of paclitaxel and cisplatin combined with anlotinib as first-line therapy in advanced ESCC. The study had been reported in 2020 ESMO (Abs 1448), 2021 ASCO-GI Symposium (Abs 181), 2021 ASCO (e16013), 2021 ESMO (Abs 1805) and 2022 ASCO-GI Symposium (Abs 315) consecutively and the update results were reported here. Methods: Patients with previously untreated metastatic or locally advanced ESCC were recruited and were given paclitaxel (135mg/m², iv, q3w) and cisplatin (60~75mg/m², iv, d1~3, q3w) plus anlotinib (10mg, po, d1~14, q3w) for 4~6 cycles as initial therapy. For those who did not have PD, maintenance treatment was adopted with anlotinib monotherapy (10mg, po, d1~14, q3w) until PD or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 using CT scans every two cycles. The predefined sample size was 47. Primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and DOR. Results: From Oct 2019 to Mar 2021, a total of 47 patients were enrolled, 46 patients included in per-protocol set analysis. The best overall response indicated that there were 4 CR (8.7%), 31 PR (67.4%), 7 SD (15.2%) and 4 NE (8.7%). Consequently, ORR was 76.1% (95%CI: 61.2%-87.4%) and DCR was 91.3% (95%CI: 79.2%-97.6%). At the data cut-off date on Jan 2022, The median PFS and median OS were 8.38 months (95% CI, 6.59-10.17) and 18.53 months (95% CI, 13.11-23.95), respectively. Additionally, safety profile exhibited that the regimen was tolerable. Common grade ≥3 adverse reactions were neutropenia (17.0%), bone marrow suppression (12.8%), nausea (10.6%), and vomiting (10.6%). Conclusions: Regimen of paclitaxel and cisplatin combined with anlotinib as first-line therapy for advanced ESCC exhibited encouraging efficacy and tolerable safety profile. And the conclusions needed to be confirmed in phase Ⅲ clinical trials. Clinical trial information: NCT04063683.