P-285 A randomized, double-blind, placebo-controlled Phase III study of ramucirumab versus placebo as second-line treatment in patients with hepatocellular carcinoma and elevated baseline alpha-fetoprotein following first-line sorafenib (REACH-2)

Abstract

Introduction: Ramucirumab (Ram) is a humanized IgG1 monoclonal antibody that inhibits VEGF-A, C and D activation of the vascular endothelial growth factor receptor 2 (VEGFR2). The Phase 3 REACH study assessed Ram versus placebo (PBO) in the treatment of patients with advanced hepatocellular carcinoma (HCC) after prior sorafenib. A significant improvement in overall survival (OS) in the overall population (N = 565) was not demonstrated (Hazard Ratio (HR) = 0.866; p = 0.1391). Ram was well tolerated. A meaningful improvement in OS was observed in a pre-specified subgroup of patients with baseline alpha-fetoprotein (AFP) >=400 ng/mL (n = 250, HR = 0.674; p = 0.0059), with significant improvements in PFS (HR = 0.699, p = 0.0106) and ORR (6.7% Ram vs 0.8% PBO, p = 0.0254). In patients with elevated AFP, a strong trend for delay in deterioration of patient reported symptoms (p = 0.054) and delay in performance status (PS) deterioration (p = 0.057) was also observed in pts treated with Ram compared to placebo. Method(s): REACH-2 is a randomized, double-blind, placebo-controlled 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. Eligible patients will be randomized 2:1 to receive Ram (8mg/kg, IV, every two weeks) until disease progression or other discontinuation criteria. Eligible patients must have a diagnosis of HCC (tissue or tumor with classical imaging characteristics); prior sorafenib; Child- Pugh score <7; Barcelona Clinic Liver Cancer Stage C or Stage B disease not suitable for locoregional therapy; AFP >=400 ng/mL; ECOG performance status <2. Patients with a history of encephalopathy, ongoing clinically meaningful ascites, liver transplant, or hepatic locoregional therapy after sorafenib are not eligible. 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 the primary analysis at 318 events (20% censoring). Secondary objectives include progression free survival, objective response rate, safety, and patient focused outcomes. Additional exploratory objectives include biomarkers relevant to angiogenesis and HCC.