Background: N is an oral, triple angiokinase inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor receptors. Two randomized, open-label, Phase II studies evaluated the efficacy and safety of N versus S in patients with advanced HCC in Europe (NCT01004003; 1199.37) and Asia (NCT00987935; 1199.39). Methods: Patients with unresectable, advanced HCC, ECOG-PS ≤ 2, Child–Pugh score A, alanine/aspartate aminotransferase (ALT/AST) ≤ 2 × upper limit of normal and ≥ 1 untreated measurable lesion or previously treated lesion with progression (by RECIST 1.0) were randomized 2:1 to N 200 mg bid or S 400 mg bid continuously in 28-day cycles, until intolerable adverse events (AEs) or disease progression (PD); treatment beyond PD was allowed if clinical benefit was perceived. The primary endpoint was time to progression (TTP) by independent central review (ICR; RECIST 1.0); secondary endpoints included overall survival (OS) and objective tumor response (OR) by ICR. Results: 188 patients received N (1199.37: n = 62; 1199.39: n = 63) or S (n = 31; n = 32). Main patient demographics/baseline characteristics were balanced between treatments in both trials except for macrovascular invasion (N vs S; 48% vs 31%) in 1199.39. TTP was comparable between N and S (median 3.7 vs 3.9 months; HR 1.31 [95% CI: 0.89–1.91]), as were OS (median 11.4 vs 11.0 months; HR 0.91 [95% CI: 0.65–1.29]) and OR rate (4% vs 5%). The rate of Grade ≥ 3 AEs (62% vs 87%) and AEs leading to dose reduction (19% vs 51%) was lower with N than S; more N-treated patients had AEs leading to drug discontinuation (34% vs 29%). The most frequent ( > 5% of patients in any group; N vs S) Grade ≥ 3 AEs were diarrhea (10% vs 5%), fatigue (7% vs 2%), increased AST (8% vs 13%) and ALT (6% vs 8%), anemia (7% vs 6%), thrombocytopenia (5% vs 8%), skin reaction (1% vs 6%) and hand-foot skin reaction (0 vs 19%). Conclusions: Pooled analysis of two trials in Caucasian and Asian patients showed similar efficacy between N and S. AEs were as expected based on the safety profile of both agents. Further studies of N in patients with advanced HCC are warranted. Clinical trial information: NCT01004003 and NCT00987935