Background: C, an inhibitor of MET, VEGFR, and AXL, has previously shown clinical activity in pts with advanced HCC. This phase 3 trial (NCT01908426) evaluated C vs P in previously treated pts with advanced HCC. Methods: In this double-blind, global, phase 3 trial, pts were randomized 2:1 to C (60 mg qd) or matched P stratified by etiology, geographic region, and presence of extrahepatic spread and/or macrovascular invasion (EHS/MVI). Eligible pts had pathologic diagnosis of HCC, Child-Pugh score A, and ECOG PS ≤1. Pts must have received prior sorafenib, were allowed to receive up to 2 lines of prior systemic therapy for HCC, and must have progressed following at least one. The primary endpoint was overall survival (OS). Secondary endpoints were investigator-assessed progression-free survival (PFS) and objective response rate (ORR) per RECIST 1.1. The study was designed to detect a hazard ratio (HR) for OS of 0.76 (90% power, 2-sided α = 0.05) at the final analysis with 2 prespecified interim analyses at 50% and 75% of the planned 621 events. Results: As of 1 Jun 2017, 707 pts were randomized, and 484 deaths had occurred (317 out of 470 for C; 167 out of 237 for P). Baseline characteristics were balanced between the arms: median age was 64 years, 82% were male, 38% had HBV, 24% had HCV, 25% enrolled in Asia, 85% had EHS/MVI, and 27% had received 2 prior systemic regimens for advanced HCC. The study met the primary endpoint at the second planned interim analysis with median OS 10.2 mo for C vs 8.0 mo for P (HR 0.76, 95% CI 0.63–0.92; p = 0.0049). Median PFS was 5.2 mo for C vs 1.9 mo for P (HR 0.44, 95% CI 0.36–0.52; p < 0.0001), and ORR was 4% vs 0.4% (p = 0.0086). The most common grade 3/4 adverse events (predominantly grade 3) with higher incidence in the C vs P arm included hand-foot skin reaction (17% vs 0%), hypertension (16% vs 2%), increased aspartate aminotransferase (12% vs 7%), fatigue (10% vs 4%), and diarrhea (10% vs 2%). Subgroup analyses of OS and PFS by baseline characteristics will also be presented. Conclusions: C significantly improved OS and PFS vs P in previously treated pts with advanced HCC. Adverse events were consistent with the known safety profile of C. Clinical trial information: NCT01908426