Elsevier

The Lancet Oncology

Volume 16, Issue 7, July 2015, Pages 859-870
The Lancet Oncology

Articles
Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial

https://doi.org/10.1016/S1470-2045(15)00050-9Get rights and content

Summary

Background

VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib.

Methods

In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347.

Findings

Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0–10·6) versus 7·6 months (6·0–9·3) for the placebo group (HR 0·87 [95% CI 0·72–1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [<1%]), hyperbilirubinaemia (three [1%] vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression.

Interpretation

Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable.

Funding

Eli Lilly and Co.

Introduction

Liver cancer is the sixth most commonly diagnosed cancer worldwide and the second most common cause of cancer death.1 Hepatocellular carcinoma occurs most frequently in patients with cirrhosis from chronic hepatitis B or hepatitis C virus infection or long-standing alcohol abuse, although other causes can also contribute.2 Many factors are relevant to hepatocellular carcinoma prognosis, including cancer stage, performance status, severity of underlying disease, and tumour markers such as α-fetoprotein.

Increased concentrations of α-fetoprotein are associated with larger tumours, bilobar involvement, portal vein invasion, poorly differentiated histology, and decreased median survival.3 Thus, the concentration of α-fetoprotein has been incorporated into some hepatocellular carcinoma prognostic scoring systems.4

Sorafenib, the only drug shown to improve median overall survival, is approved globally for advanced hepatocellular carcinoma;5, 6 however, the drug is associated with major toxicities, and about 30% of patients stop it because of intolerance.7 Since the approval of sorafenib, several drugs have failed to achieve positive results in phase 3 trials in first-line or second-line treatment of hepatocellular carcinoma.8, 9 In view of the biological and clinical heterogeneity of hepatocellular carcinoma, patient enrichment strategies or selection would be crucial to show a benefit in overall survival.8

Research in context

Evidence before this study

During development of the study rationale and protocol, we systematically searched PubMed and abstracts of major oncology congresses with MeSH and full-text search terms for hepatocellular carcinoma and molecular targeted therapies, including hepatocellular carcinoma, sorafenib, hepatocellular carcinoma and angiogenesis, hepatocellular carcinoma treatment, and hepatocellular carcinoma prognostic factors. Results were limited to articles published in English and within the previous 4 years. Various signalling processes, including those involved in angiogenesis, have been implicated in the development and progression of hepatocellular cancer. Experience with sorafenib suggests that targeting angiogenesis is a valid approach. In a phase 2 study, ramucirumab, a recombinant monoclonal antibody that targets angiogenesis by specifically binding to VEGFR-2, has been shown to have a suitable safety and efficacy profile for further clinical testing in hepatocellular carcinoma after previous tyrosine-kinase inhibitor treatment.

Added value of this study

Second-line treatment with ramucirumab showed improvements in progression-free survival, time to tumour progression, and objective response, but did not improve median overall survival for the unselected population with advanced hepatocellular carcinoma when compared with placebo. An improvement in overall survival was noted in the population with a baseline concentration of α-fetoprotein of 400 ng/mL or greater. These findings, if validated, support targeting angiogenesis as a treatment strategy for advanced hepatocellular carcinoma.

Implications of all the available evidence

Our findings suggest that patients with elevated baseline α-fetoprotein might derive a survival benefit from second-line treatment with ramucirumab. However, these findings were hypothesis-generating only, and require further study and confirmation.

VEGF and VEGF receptor (VEGFR)-2-mediated signalling have an important role in angiogenesis and tumour growth.10, 11, 12 VEGF is overexpressed in hepatocellular carcinoma and associated with poorer clinical outcomes, suggesting VEGF-mediated signalling is important in hepatocellular carcinoma pathogenesis and is a therapeutic target.13

Ramucirumab is a recombinant IgG1 monoclonal antibody that specifically binds to the extracellular domain of VEGFR-2 with high affinity, preventing binding of VEGF ligands and receptor activation.14 Results of phase 2 studies showing antitumour activity of ramucirumab in first-line treatment of hepatocellular carcinoma15 and in treatment of renal cell cancer after previous tyrosine-kinase inhibitor (TKI) treatment, including sorafenib,16 provided a rationale for the development of ramucirumab in hepatocellular carcinoma after previous sorafenib treatment.

No drugs have clearly shown a survival benefit in second-line treatment after sorafenib failure in advanced hepatocellular carcinoma. In view of the unmet medical need and few treatments in this setting, an effective drug with an acceptable safety profile is needed. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib.17, 18

Section snippets

Study design and participants

In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients included in the intention-to-treat population for final analysis were aged 18 years or older, had a diagnosis of hepatocellular carcinoma and Barcelona Clinic Liver Cancer stage C or stage B that was refractory or not amenable to locoregional therapy, and had Child-Pugh A liver disease. Diagnosis of hepatocellular carcinoma was

Results

Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo (figure 1). 79 patients with Child-Pugh B disease (41 received ramucirumab and 38 received placebo) were enrolled before the protocol amendment, and were subsequently excluded from the intention-to-treat population; these patients were replaced in the intention-to-treat population with patients with Child-Pugh A disease. The data collection cutoff date

Discussion

Second-line treatment with ramucirumab did not show an improvement in overall survival for patients with advanced hepatocellular carcinoma when compared with placebo. However, improvements in the secondary endpoints of progression-free survival, time to tumour progression, and objective response were noted.

The absolute improvements in the median progression-free survival and time to tumour progression seem small for the intention-to-treat population, and are probably related to the timing of

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