TPS4200 Background: Intermediate-stage HCC represents a heterogeneous population, posing unique challenges for therapeutic management. With the advent of effective systemic therapies for unresectable HCC, the treatment landscape for intermediate-stage extends beyond LRT, particularly in patients with high tumor burden. The growing evidence about the benefit of systemic therapy in intermediate-stage HCC led to the inclusion in some recent guidelines of systemic therapy as the first choice of treatment in TACE-unsuitable patients with intermediate-stage HCC. Despite these recommendations, no randomized clinical trial has been published comparing LRT with TACE/TARE versus systemic therapy in patients with intermediate-stage HCC and high tumor burden. Methods: REPLACE is a phase III, multicenter, randomized, open-label trial that will compare the efficacy and safety of LRT with TACE/TARE versus systemic therapy, for the first-line treatment of intermediate-stage HCC with beyond up-to-7 criteria. Eligible participants will be randomized 1:1 to receive regorafenib (90 mg orally q.d. on days 1 to 21 of a 4-week cycle), and pembrolizumab (400 mg i.v. on day 1 of a 6-week cycle) or LRT with TACE or TARE, and will be stratified according to geographic region (Asia vs. non-Asia), ECOG Performance Status (0 vs 1) and Albumin-Bilirubin (ALBI) grade (1 vs 2). Patients must have intermediate-stage HCC with beyond up-to-seven criteria (Up-to-7 criteria = largest tumor diameter (cm) + number of tumors ≤7), measurable disease per RECIST 1.1, disease not amenable to curative treatment but amenable to LRT with TACE or TARE, no prior systemic or LRT for HCC, except for successful resection and/or ablation completed ≥ 6 months prior to randomization. Patients will be treated until progressive disease, unacceptable toxicity, or other treatment discontinuation criteria is met. The primary endpoint is progression free survival (PFS), assessed locally by the Investigator using mRECIST for HCC. Secondary endpoints include PFS assessed locally by the Investigator using RECIST 1.1; PFS centrally assessed using mRECIST and RECIST 1.1; overall survival; overall response rate according to RECIST v.1.1 and mRECIST based on the Investigator’s and central assessment; time to unTACEable progression; duration of response; safety and tolerability of the trial treatments, and patient reported outcomes for health-related quality of life. The estimated enrollment is 496 patients from approximately 14 countries. Recruitment started in October 2023 and is currently ongoing. Clinical trial information: NCT04777851 .