Ramucirumab (Ram) As Second-Line Treatment in Patients (Pts) with Advanced Hepatocellular Carcinoma (Hcc) Following First-Line Therapy with Sorafenib: Results from the Randomized Phase III Reach Study

Abstract

ABSTRACT Aim: Vascular endothelial growth factor (VEGF) and VEGF-receptor 2-mediated signaling and angiogenesis likely contribute to HCC pathogenesis. RAM is a fully human IgG1 monoclonal antibody and a VEGF-receptor 2 antagonist. Methods: Eligible pts had advanced HCC, stage BCLC C or B refractory or not amenable to locoregional therapy; Child-Pugh A; ECOG PS 0 or 1; intolerance to sorafenib despite dose reduction, or disease progression during or following sorafenib; and adequate hematologic and biochemical parameters. Pts were randomized 1:1 to receive RAM (8 mg/kg IV) plus best supportive care (BSC) or placebo (PBO) plus BSC every 2 weeks until disease progression, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. The sample size of 544 pts was calculated to enable 85% power to demonstrate statistical significance at an overall two-sided alpha of 0.05, assuming a hazard ratio (HR) of 0.75. Results: Between Nov 2010 and April 2013, 565 eligible pts were randomized (RAM 283; PBO 282). Baseline pt characteristics were balanced between arms. The OS HR was 0.866 (95% CI 0.717, 1.046; p = 0.1391); median OS was 9.2m for RAM vs 7.6m for PBO. Median PFS with RAM and PBO was 2.8m and 2.1m, respectively (HR 0.63, 95% CI 0.52–0.75; p 5% of treated RAM pts included: hypertension (12.3% RAM arm vs 3.6% PBO arm), asthenia (5.1% vs 1.8%), aspartate aminotransferase increased (5.4% vs 8.3%), and malignant neoplasm progression (6.5% vs 4.0%). In 250 pts with baseline alpha-fetoprotein (AFP) ≥400 ng/mL (pre-specified), OS HR was 0.67 (95% CI 0.51–0.90; p=0.0059) median OS was 7.8m for RAM vs 4.2m for PBO. Conclusions: No new safety signals were observed. The primary end point was not met. In a selected pt population with an elevated baseline AFP, a meaningful OS improvement in the RAM arm was observed. The relationship between AFP and RAM benefit warrants further investigation. Disclosure: J.F. Blanc: reports personal fees from Imclone systems / Lilly, during the conduct of the study; T.E. Pfiffer: reports Lilly, the sponsor of REACH trial, gave financial support to Instituto do Cancer do Estado de Sao Paulo ICESP to run part of the trial, during the conduct of the study; personal fees from Lilly, outside the submitted work; T. Okusaka: received grant money and personal fees from Eli Lilly. Relevant financial activities outside the submitted work include grant money and personal fees from several companies; J. Trojan: reports participation as a speaker and on the advisory board for Eli Lilly; J. Sastre: reports receiving personal fees for lectures from Eli Lilly, Roche, Merck, Bayer, Sanofi, and MSD; I. Chau: received research support from Eli Lilly & Co, honorarium from ImClone LLC and Eli Lilly & Co., has also been a consultant, received payment for lectures, educational presentations, and travel and meeting expenses from several other companies; S. Chang and P.B. Abada: is an employee of and has stock ownership in Eli Lilly & Co.; L. Yang: is an employee of ImClone Systems, a wholly owned subsidiary of Eli Lilly and Co., and has stock ownership in Eli Lilly and Co.; J. Schwartz: was an employee of Imclone Systems and has stock ownership in Eli Lilly. All other authors have declared no conflicts of interest.