710TiP - 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

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. Significant improvement in overall survival (OS) in the overall population (N = 565) was not achieved (Hazard Ratio [HR] = 0.866; 95% CI 0.717–1.046; p = 0.1391); median OS was 9.2m for RAM and 7.6m for PBO. However, a meaningful improvement in OS was observed in a pre-specified subgroup of patients with baseline alpha-fetoprotein (AFP) ≥400ng/mL (N = 250)(HR = 0.674; p = 0.0059); median OS was 7.8m for RAM and 4.2m for PBO. The safety profile of RAM in HCC patients was considered manageable. Trial design: REACH-2 is a randomized, double-blind, placebo-controlled phase III study of RAM and best supportive care (BSC) vs 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) or PBO on Day 1 of each 14-day cycle 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 5 or 6; Barcelona Clinic Liver Cancer Stage C or Stage B disease not amenable/refractory to locoregional therapy; AFP ≥400 ng/mL; ECOG performance status of 0 or 1. Patients with history of encephalopathy, ongoing clinically meaningful ascites, liver transplant, or hepatic locoregional therapy after sorafenib are not eligible. The primary objective is to assess OS for patients treated with RAM vs PBO. Target enrollment is 399 patients with final analysis at 318 events (20% censoring). Secondary objectives include progression free survival, objective response rate, safety, and patient focused outcomes. Additional objectives include assessment of biomarkers relevant to angiogenesis and HCC. Clinical trial identification: NCT02435433 Legal entity responsible for the study: Eli Lilly and Company