Background: The antiangiogenic tyrosine kinase inhibitor (TKI) SOR prolongs survival in advanced HCC, but responses occur in fewer than 5% of patients (pts) and median progression-free survival (PFS) is less than 6 months. Immune checkpoint inhibition (CPI) with the PD-1 inhibitor, NIVO, achieved an overall response rate (ORR) of approximately 20% in sorafenib-naïve pts enrolled on CheckMate 040 trial though most pts had progression. In preclinical studies, TKI can inhibit regulatory T cells and myeloid derived suppressor cells, immune cell subsets which may contribute to CPI resistance. CD8⁺ T cells in sorafenib-resistant tumors are characterized by PD-1 expression, providing rationale for a combined approach. The combination of TKI or the anti-angiogenic bevacizumab with CPI improves anti-tumor activity in HCC mouse models and in preliminary clinical studies. This study will examine the safety, maximum tolerated dose (MTD), and ORR of the combination of SOR plus NIVO in advanced HCC pts, along with correlative analyses of tumor and circulating immune cells. Methods: Eligible pts must have Child-Pugh A liver function and advanced HCC, without prior systemic therapy and measurable by RECIST 1.1. In Part 1 (3+3 dose escalation), SOR dose will be 400 mg QD or BID plus NIVO 240 mg IV Q2 weeks. In Part 2, Arm 1, pts will start NIVO Cycle 1, Day 1 (C1D1), with addition of SOR at MTD on C1D15; in Part 2, Arm 2, SOR is given at MTD on C1D1 with addition of NIVO on C1D15. Primary endpoints are MTD of SOR (Part 1) and ORR by RECIST 1.1 with H₀ 7.5% vs. H₁ 25% (Part 2). For expected sample size of 24 evaluable pts in Part 2, the power is 83% with 1-sided alpha 5% to determine ORR >25% by Chi-square tests. Secondary endpoints are safety, duration of response, PFS, and overall survival. Exploratory endpoints include peripheral and tumor immune cell profiling, PD-L1 expression, and alpha-fetoprotein (AFP) response. An interim safety analysis will be performed after 50% enrollment in Part 2. Optional paired biopsies in Part 2 will allow for investigation of the tumor microenvironment on SOR, NIVO, and combination. Clinical trial information: NCT03439891