Background: To date many trials have been conducted to compare the efficacy and toxicity between TACE plus molecular targeted agents and TACE alone; all of them failed to show its clinical benefit in terms of progression free survival (PFS) or OS. In TACTICS trial (NCT01217034) TACE plus sorafenib significantly improved PFS over TACE alone in patients with unresectable HCC. (Gut 2020;69:1374-1376). Here we will report a final OS analysis from TACTICS trial with predefined mature OS events. Methods: Patients with unresectable HCC were randomized to TACE plus sorafenib (n=80) or TACE alone (n=76). Patients in the combination group received sorafenib 400 mg once daily for 2–3 weeks before TACE, followed by 800 mg twice daily during on-demand conventional TACE sessions until time to untreatable (unTACEable) progression (TTUP), defined as untreatable tumor progression, transient deterioration to Child-Pugh C or appearance of vascular invasion/extrahepatic spread. Co-primary endpoints were progression-free survival (PFS), which is defined as TTUP, or time to any cause of death and OS. Multiplicity was adjusted by gatekeeping hierarchical testing. Results: At the cut-off date of July 31, 2020, 131 OS events were observed. Median OS was 36.2 mo with TACE plus sorafenib vs 30.8 mo with TACE alone (HR, 0.861 [95%CI, 0.607, 1.223]; P=0.40). ΔOS was 5.4 mo. Updated PFS was 22.8 mo with TACE plus sorafenib vs 13.5 mo with TACE alone (HR, 0.661[95%CI, 0.466, 0.938]; P=0.02). Post-trial treatments with active procedures/agents were observed in 47 (58.8%) in TACE plus sorafenib and in 58 (76.3%) with TACE alone. Anticancer procedures in TACE alone group include resection/ablation in 14, transarterial therapy in 53 and radiation in 7. Anticancer medications in TACE alone include targeted agents in 40 (29 sorafenib, 5 regorafenib, 3 lenvatinib, 3 ramucirumab), other systemic chemotherapy in 5 and immunotherapy in 5. Safety was consistent with the primary analysis, with no new signals identified. Conclusion: In TACTICS, TACE plus sorafenib did not show OS benefit as compared with TACE alone although significantly better PFS was consistently observed. OS in TACE plus sorafenib in TACTICS trial showed the longest OS (36.2 mo) with the longest ΔOS (5.4 mo) as compared with the previous 5 TACE combination trials. The major reason for negative OS result was speculated that many post-trial active treatments were performed in control arm (76.3%), which implies that OS endpoint in TACE combination trial may not be feasible anymore in current era of sequential therapy with many active locoregional and systemic treatments. Clinical trial information: NCT01217034