Background: Ramucirumab (RAM), a human IgG1 mAb, inhibits ligand activation of VEGFR2. In REACH, while improvement in overall survival (OS) in the overall population was not statistically significant, meaningful improvement was observed in a patient subgroup with baseline alpha-fetoprotein (AFP) ≥400 ng/mL (N = 250) (HR = 0.67, p = 0.006; median OS [months] RAM 7.8 vs placebo [pbo] 4.2). RAM treatment was generally well tolerated in patients with advanced hepatocellular carcinoma (HCC) after prior sorafenib (SOR). Methods: REACH-2 is a randomized, double-blind, pbo-controlled, global phase 3 study of RAM+best supportive care (BSC) vs pbo+BSC in patients with HCC and elevated baseline AFP following therapy with SOR. Eligibility includes Child-Pugh < 7; Barcelona Clinic Liver Cancer Stage C or B disease not amenable/refractory to locoregional therapy; AFP ≥400 ng/mL; ECOG PS 0 or 1; ≥1 measurable lesion; and disease progression during/after SOR, or SOR intolerance. Patients with history of hepatic encephalopathy, clinically meaningful ascites, liver transplant, or hepatic locoregional therapy after SOR are not eligible. Eligible patients will be randomized 2:1 to 8 mg/kg RAM or pbo (14-day cycle) and treated until radiographic/clinical disease progression or discontinuation criteria are met. The primary objective is OS; secondary objectives include progression-free survival (PFS), objective response rate, safety, and patient-focused outcomes. Recognizing expanding treatment options for HCC, a second, single arm, open-label cohort of ~44 patients will be enrolled with the same eligibility and treatment as the main cohort except a requirement for prior treatment other than SOR (eg, mTKIs, immune checkpoint inhibitors) and some exclusions of checkpoint inhibitor-related adverse events. The primary objective is safety; secondary objectives include OS, PFS, and patient-focused outcomes. Additionally, a third randomized cohort of ~65 Chinese patients will be enrolled with the same objectives, eligibility, treatment, and evaluations as the main cohort. Analysis of Open-Label and Chinese cohorts will be independent of the main REACH-2 cohort. Clinical trial information: NCT02435433