ArticlesRamucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial
Introduction
Hepatocellular carcinoma is the most common primary hepatic malignancy and the third most common cause of cancer-related death worldwide.1 Many factors are clinically applicable in assessments of the prognosis of patients with hepatocellular carcinoma, including stage, performance status, severity of underlying liver disease, histopathology, and α-fetoprotein concentration.2, 3, 4, 5, 6
Sorafenib was the first drug to show improved median overall survival in patients with hepatocellular carcinoma.7, 8 Since the approval of sorafenib, only three other drugs—the first-line treatment lenvatinib and the second-line treatments regorafenib and cabozantinib—have shown clinical benefits in phase 3 clinical trials.9, 10, 11 All three drugs are oral multikinase inhibitors. In a phase 2 trial of tivantinib as second-line therapy,12 investigators selected patients with high MET-expression hepatocellular carcinoma, but there was no improvement in overall survival.
In hepatocellular carcinoma, an α-fetoprotein concentration higher than 400 ng/mL has been consistently associated with poor prognosis in several treatment settings,13, 14 and is an included parameter in several prognostic scoring systems.2, 3, 15 α-fetoprotein is a continuous variable, and a worse prognosis is associated with concentrations of α-fetoprotein higher than 400 ng/mL.16, 17, 18 VEGF and VEGFR2-mediated signalling have important roles in angiogenesis and tumour growth, including in hepatocellular carcinoma.19, 20 Increased α-fetoprotein concentrations has been associated with increased VEGFR expression and increased angiogenesis in hepatocellular carcinoma.21, 22, 23 After sorafenib therapy, roughly half of patients have α-fetoprotein concentrations of 400 ng/mL or greater, and effective and well tolerated treatments are needed in this population.18, 24
Ramucirumab is a human IgG1 monoclonal antibody that inhibits ligand activation of VEGFR2, and showed initial anti-tumour activity in a phase 2 study of advanced first-line hepatocellular carcinoma.19, 20 REACH was a global, randomised, double-blind, placebo-controlled, phase 3 study18 of the efficacy and safety of ramucirumab monotherapy after first-line sorafenib in 565 patients with advanced hepatocellular carcinoma. Ramucirumab did not significantly improve overall survival compared with placebo in the intention-to-treat population (hazard ratio [HR] 0·87 [95% CI 0·72–1·05]; p=0·14). However, a clinically meaningful and significant improvement in overall survival was noted in the ramucirumab group compared with the placebo group in the prespecified subpopulation (n=250) of patients with baseline α-fetoprotein concentrations of 400 ng/mL or greater (median overall survival 7·8 months (95% CI 5·8–9·3) vs 4·2 months (3·7–4·8; HR 0·674 [95% CI 0·508–0·895]; p=0·006).18 We aimed to investigate the efficacy and safety of ramucirumab monotherapy in patients with hepatocellular carcinoma and baseline α-fetoprotein concentration of 400 ng/mL or greater after intolerance to, or progression during, previous sorafenib therapy.
Section snippets
Study design and participants
REACH-2 was a randomised, double-blind, placebo-controlled, phase 3 study done at 92 hospitals, clinics, and medical centres in 20 countries (appendix pp 2–9). Eligible patients had a diagnosis of hepatocellular carcinoma based on either histopathological or cytological findings or, in the absence of histological confirmation, a diagnosis of cirrhosis and hepatocellular carcinoma with classical imaging characteristics (at least a three-phase liver protocol by CT or MRI and a lesion that showed
Results
Between July 26, 2015, and Aug 30, 2017, 436 patients were screened and 292 were enrolled and randomly assigned, 197 to the ramucirumab group and 95 to the placebo group (figure 1). Data cutoff for the REACH-2 analysis was March 15, 2018, by which time 281 patients were off treatment, and 11 patients in the ramucirumab group were still receiving therapy. 206 (71%) of 292 had disease progression, and 221 (76%) had died. Median duration of follow-up for overall survival was 7·6 months (IQR
Discussion
The randomised, double-blind phase 3 REACH-2 trial met its primary endpoint of improved overall survival with ramucirumab compared with placebo in patients with advanced hepatocellular carcinoma and baseline α-fetoprotein concentrations of at least 400 ng/mL who had previously been treated with sorafenib. To our knowledge, REACH-2 is the first positive phase 3 study in a biomarker-selected population of patients with hepatocellular carcinoma. Treatment with ramucirumab conferred an increase in
Data-sharing statement
Eli Lilly provides access, after anonymisation, to all individual participant data collected during the trial, except for pharmacokinetic and genetic data. Data can be requested 6 months after the indication studied has been approved in the USA and EU or after primary publication acceptance, whichever is later. No expiration date for data requests is set once the data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this
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