Background: Nintedanib (N) is an oral, triple angiokinase inhibitor of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This randomized, multicenter, open-label, Phase II study (NCT00987935; 1199.39) evaluated the efficacy and safety of N versus sorafenib (S) in Asian patients with advanced HCC. Preliminary analysis showed similar time to progression (TTP) by independent central review (ICR). Methods: Asian patients with unresectable advanced HCC, Child–Pugh score 5–6, ECOG-PS ≤2, and alanine/aspartate aminotransferase (ALT/AST) ≤2× upper limit of normal were enrolled. Patients 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. Primary endpoint was TTP by ICR (RECIST 1.0) and secondary endpoints were overall survival (OS) and investigator-assessed (IA) TTP. Results: Patients (N=95) were randomized to receive N (n=63) or S (n=32); arms were balanced except for macroscopic vascular invasion (48% vs 31%). At the final cutoff date (16 Jul 14), 88% of patients had a TTP event, and 86% had an OS event; 1 patient was on treatment beyond PD. N and S had comparable IA TTP (median 2.8 vs 3.0 months; HR 1.39 [95% CI: 0.87–2.23]) and OS (median 10.2 vs 10.7 months; HR 0.94 [95% CI: 0.59–1.49]). ICR TTP data are pending. All but 1 patient reported an AE (CTCAE 3.0). More S-treated patients had Grade ≥3 AEs (56% vs 84%), serious AEs (46% vs 56%), and AEs leading to dose reduction (19% vs 59%) and drug discontinuation (24% vs 34%). Class-specific AEs of tyrosine kinase inhibitors in >15% of S-treated patients were hypertension, hand-foot skin reaction, and thrombocytopenia; only anemia was higher with N. AEs previously observed and higher with N were vomiting and nausea; ALT/AST increases and diarrhea were higher with S. Rash was reported in >15% of patients only with S. Conclusions: N shows similar efficacy to S for TTP and OS. N was better tolerated than S and AEs were generally manageable. Further studies of N in Asian patients with advanced HCC are warranted. Clinical trial information: NCT00987935