Background: Ramucirumab (Ram) is a human IgG1 monoclonal antibody that inhibits ligand activation of the vascular endothelial growth factor receptor 2. The Phase III REACH study assessed Ram in the treatment of patients with advanced hepatocellular carcinoma (HCC) after prior sorafenib. Ram was well-tolerated. A significant improvement in overall survival (OS) in the overall population (N = 565) was not demonstrated (HR = 0.87; p = 0.14). However, a meaningful improvement in OS was observed in a prespecified subgroup of patients with baseline alpha-fetoprotein (AFP) ≥ 400 ng/mL (N = 250) (HR = 0.67, p = 0.006; median OS Ram 7.8 months vs. placebo 4.2 months). Methods: Designed to confirm the treatment effects of Ram in patients with elevated AFP, REACH-2 is a randomized, double-blind, placebo-controlled, global Phase III study of Ram and best supportive care (BSC) versus placebo and BSC in patients with HCC and elevated baseline AFP following prior therapy with sorafenib; Child-Pugh score < 7; Barcelona Clinic Liver Cancer Stage C or Stage B disease not amenable/refractory to locoregional therapy; AFP ≥ 400 ng/mL; and ECOG performance status 0‒1. Patients with a history of hepatic encephalopathy, clinically meaningful ascites, liver transplant, or hepatic locoregional therapy after sorafenib are not eligible. Eligible patients will be randomized 2:1 to receive Ram (8 mg/kg) or placebo as an intravenous infusion on day 1 of each 14-day cycle until radiographic or clinical disease progression or criterion for discontinuation are met. The primary objective is to assess the OS for patients treated with Ram versus placebo, and assumes an OS HR of 0.7 (85% power; 2-sided type I error 0.05). Target enrollment is 399 patients with a final analysis at 318 events (20% censoring). Secondary objectives include progression-free survival, objective response rate, safety, and patient-focused outcomes. Other objectives are assessments of biomarkers relevant to angiogenesis and HCC. Clinical trial information: NCT02435433