Background: The current standard of care for 1L treatment of patients with advanced/metastatic HCC is atezolizumab + BEV, which demonstrated significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to sorafenib in treatment-naïve patients. However, only 29.8% of patients show objective responses and additional therapy options are needed in the 1L setting. Programmed death-1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) are distinct inhibitory immune checkpoint pathways that synergistically reduce T-cell function. RELA is a first-in-class human immunoglobulin G4 LAG-3-blocking antibody that binds to LAG-3 and restores the effector function of T cells. Dual checkpoint inhibition of the PD-1 and LAG-3 pathways with NIVO + RELA has the potential to boost immune surveillance in HCC. Preclinical data presume that BEV, a human vascular endothelial growth factor inhibitor, reverses abnormal vascularization to allow NIVO + RELA to inhibit hypoxia-induced programmed cell death ligand 1 and LAG-3 expression and enhance depth of response and OS in HCC. Here we describe the RELATIVITY-106 study investigating the triplet therapy of NIVO + RELA + BEV in the 1L treatment of advanced/metastatic HCC. Methods: RELATIVITY-106 (NCT05337137) is a phase 1/2, randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of NIVO + RELA + BEV compared with NIVO + BEV in treatment-naïve patients with advanced/metastatic HCC. Key inclusion criteria include age ≥ 18 years; histologic confirmation of advanced/metastatic HCC in patients naïve to systemic therapy for advanced/metastatic HCC (prior neoadjuvant or adjuvant immunotherapy permitted if recurrence occurs ≥ 6 months after treatment completion); Child-Pugh A; and ECOG performance status 0 or 1. Key exclusion criteria include known fibrolamellar HCC, sarcomatoid HCC, or mixed hepatocellular cholangiocarcinoma; prior allogenic stem cell or solid organ transplantation; untreated symptomatic central nervous system metastases; clinically significant ascites; increased risk of bleeding; significant vascular disease or inadequately controlled hypertension; and major surgical procedure within 4 weeks prior to study treatment. Primary endpoints include incidence of dose-limiting toxicities assessed for up to 6 weeks and PFS by blinded independent central review (BICR) per RECIST v1.1 in all randomized patients in phase 1 and phase 2, respectively. Secondary endpoints include overall response rate (ORR) by BICR and OS in all randomized patients; ORR and PFS by BICR and OS in all randomized LAG-3-positive patients (≥ 1% by immunohistochemistry); and safety. Key exploratory endpoints include pharmacokinetics and immunogenicity assessed by antidrug antibody positivity. The study, initiated in May 2022, is currently enrolling globally. Clinical trial information: NCT05337137.