Background: Chemotherapy is the standard first-line therapy for advanced Esophageal Squamous Cell Carcinoma (ESCC). However, the poorly 5-year survival rate (4.8%) was unsatisfied. Anlotinib was an effective second-line monotherapy for ESCC in China and the combination therapy might be a promising strategy. Here we reported the update results and futhur evaluated the efficacy and safety of paclitaxel and cisplatin combined with anlotinib as first-line therapy in advanced ESCC. Methods: Pts with previously untreated metastatic or unresectable, locally advanced ESCC, who had not received (neo) adjuvant therapy/radical surgery within 6 months were recruited. Eligible patients were given paclitaxel (135mg/m2, iv, q3w) and cisplatin (60̃75mg/m2, iv, d1̃3, q3w) plus anlotinib (10mg, po, d1̃14, q3w) for 4̃6 cycles as initial therapy. Maintenance treatment was administered to those without disease progression with anlotinib monotherapy (10mg, po, d1̃14, q3w) until progression or unacceptable toxicity. The primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and DOR. The predefined sample size was 47. Tumor response was assessed by investigators according to RECIST version 1.1 criteria using CT scans every two cycles. Results: From Oct 2019 to Mar 2021, a total of 47 pts with ESCC were included and 46 pts were included in intention-to treat analysis, among whom 4 CR (8.7%), 31 PR (67.4%) and 7 SD (15.2%) were observed and 4 patients (8.7%) were not available for efficacy assessment. Consequently, ORR was 76.1% (95%CI: 61.2%-87.4%) and DCR was 91.3% (95%CI: 79.2%-97.6%). At the cut-off date on July 15, 2021, 23 pts discontinued treatment due to PD, the preliminary median PFS of ITT patients was 8.38 months (95%CI: 6.44-10.32). And the median OS was not yet available. Additionally, safety profile exhibited that the common drug-related adverse events were myelosuppression, gastrointestinal reaction, fatigue, hypertension, constipation, hypokalemia. And the common grade ≥3 adverse events were myelosuppression (29.8%), gastrointestinal reaction (10.6%), hypertension (6.3%), fatigue (4.3%) and hypokalemia (4.3%). Conclusions: The update results suggested that paclitaxel and cisplatin combined with anlotinib as first-line therapy for advanced ESCC exhibited encouraging efficacy and tolerable safety profile. And the conclusion should be validated in more pts with ESCC subsequently. Clinical trial information: NCT04063683.