Background: PD-1 inhibitors plus chemotherapy are the standard regimens of first-line treatment in advanced ESCC. Anlotinib, a multi-target TKI effectively inhibiting angiogenesis and improving tumor microenvironment, had been demonstrated to have promising efficacy and tolerable toxicity whether combined with chemotherapy as first-line treatment or monotherapy as second-line in advanced ESCC. TQB2450 is a novel humanized anti-PD-L1 monoclonal antibody. We have conducted a phase II trial to evaluate the efficacy and safety of anlotinib combined with TQB2450, cisplatin and paclitaxel as first-line therapy in advanced ESCC. Here is the update results with more enrolled patients and longer follow-up period. Methods: Eligible patients (pts) with previously untreated unresectable locally advanced or metastatic ESCC received TQB2450 (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1~14, q3w) combined with paclitaxel (135mg/m², iv, d1, q3w) and cisplatin (60~75mg/m², iv, d1~3, q3w) for 4 - 6 cycles as initial therapy. Patients without progressive disease (PD) continued to receive same dose of anlotinib plus TQB2450 as maintenance therapy until PD or unacceptable toxicity. The primary endpoint was PFS (RECIST version 1.1). Secondary endpoints included iPFS (iRECIST), ORR (RECIST version 1.1), DCR, DOR and safety. Results: From September 2021 to August 2022, 50 pts were enrolled with a median age of 64 years (range 41-74), male (39/50, 78%) and ECOG PS 1 (39/50, 78%). At the data cutoff date of January 16, 2023, 45 pts were tumor response evaluable, among whom, 3 pts achieved complete response, 34 had partial response and 8 had stable disease. The ORR was 82.2% (95% CI: 68.0%, 92.0%) and the DCR was 100.0% (95% CI: 92.1%, 100.0%). Median PFS was not reached. The incidence of grade 3-4 treatment emergent adverse events (TEAEs) was 66% (33/50), mainly included neutropenia (34%, 17/50), leukopenia (20%, 10/50) and hypertension (20%, 10/50), platelet count decreased (6%, 3/50). There was no grade 5 TRAE. 17 pts (34%, 17/50) occurred treatment related serious AEs. Conclusions: TQB2450 plus anlotinib combined with paclitaxel and cisplatin showed significant efficacy and manageable safety profile as first-line treatment in advanced ESCC, which might provide a new treatment strategy for ESCC patients. Clinical trial information: NCT05013697.