Research in context
Evidence before this study
We searched PubMed for articles published between Jan 1, 2008, and Oct 26, 2016, with no language restrictions, reporting on the treatment of patients with advanced hepatocellular carcinoma (HCC) who failed sorafenib treatment using the search terms (”advanced hepatocellular carcinoma” OR “advanced hepatocellular cancer”) AND “sorafenib”, filtering for articles describing phase 3 clinical trials. We also searched abstracts of the annual meeting of the American Society of Clinical Oncology, using the search term “advanced hepatocellular carcinoma”, limiting the results to phase 3 trials published or presented during the past 2 years. The search resulted in 15 articles or abstracts, of which three were excluded (two subanalyses and one report of maintenance sorafenib therapy following the combination of transcatheter arterial chemoembolisation and radiotherapy). Of the remaining 12 publications, two were reports of the pivotal trials of sorafenib for advanced HCC; five reported the first-line use of a novel drug or the novel combination of a drug with sorafenib compared with a sorafenib control; and five reported the second-line use of a novel agent in patients who had failed sorafenib. None of the trials assessing novel agents or novel combinations of agents in the first-line setting met the primary endpoint to show improved overall survival over sorafenib. Similarly, none of the drugs assessed in the second-line setting in patients previously treated with sorafenib who stopped because of disease progression or intolerance showed improvement over placebo. Therefore, new effective systemic therapies for patients with advanced HCC who fail sorafenib treatment are needed.
Added value of this study
Until now, no systemic agent has been shown to improve survival over placebo in patients with advanced HCC who fail sorafenib treatment. The results of RESORCE show that treatment with regorafenib resulted in a significant improvement in overall survival compared with placebo in patients with disease progression on sorafenib. Significant improvement over placebo was also shown for the secondary endpoints of progression-free survival, time to progression, disease control, and overall tumour response.
Implications of all the available evidence
This phase 3 trial of regorafenib is the first to show an overall survival benefit compared with placebo in patients who failed sorafenib treatment. Future trials should explore combinations of regorafenib with other systemic agents and third-line treatments for patients who fail or who do not tolerate the sequence of sorafenib and regorafenib.