Elsevier

The Lancet

Volume 389, Issue 10064, 7–13 January 2017, Pages 56-66
The Lancet

Articles
Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S0140-6736(16)32453-9Get rights and content

Summary

Background

There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment.

Methods

In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1–3 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774344.

Findings

Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50–0·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1–12·1) for regorafenib versus 7·8 months (6·3–8·8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group), hand–foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group.

Interpretation

Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on 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.

Funding

Bayer.

Introduction

The treatment of hepatocellular carcinoma (HCC) follows well established guidelines.1, 2, 3 Surgical resection, transplantation, and ablation are potential curative options for early-stage disease, whereas chemoembolisation is recommended for patients with preserved liver function and disease confined to the liver generally without vascular invasion. For patients who are not or who are no longer candidates for locoregional therapy, the oral multikinase inhibitor sorafenib is the only systemic treatment shown to provide a clinically significant improvement in overall survival.4, 5 Since the results with sorafenib were published almost 10 years ago, all phase 3 trials assessing novel systemic drugs have failed to improve outcomes over sorafenib in the first-line setting6, 7, 8, 9, 10 or in the second-line setting following sorafenib.11, 12, 13, 14 In second-line trials in patients who have failed sorafenib, overall survival in the placebo group is about 8 months.11, 12, 13, 14 Therefore, there is an unmet need for effective systemic therapies for HCC, particularly after treatment with sorafenib.

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.

Regorafenib is an oral multikinase inhibitor that blocks the activity of protein kinases involved in angiogenesis, oncogenesis, metastasis, and tumour immunity.15, 16 It has a distinct molecular target profile and had more potent pharmacological activity than sorafenib in preclinical studies.15, 17 Regorafenib is approved as monotherapy for the treatment of treatment-refractory metastatic colorectal cancer and gastrointestinal stromal tumours at a dose of 160 mg once daily for the first 3 weeks of each 4-week cycle.18, 19, 20 Based on results of a single-arm phase 2 study showing antitumour activity and acceptable tolerability,21 we aimed to assess the efficacy and safety of regorafenib in patients with HCC who progressed during sorafenib treatment.

Section snippets

Study design and participants

This randomised, double-blind, placebo-controlled international phase 3 trial was done at 152 centres in 21 countries in North America, South America, Europe, Asia, and Australia.

Eligible patients were adults with HCC confirmed by pathological assessment or non-invasive assessment according to the American Association for the Study of Liver Diseases criteria for patients with confirmed cirrhosis,1 and had to have at least one measurable lesion by modified Response Evaluation Criteria in Solid

Results

Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses; figure 1). 216 patients (38%) were from Asia. Overall, 567 patients (99%) started treatment (374 in the regorafenib group and 193 in the placebo group) and comprise the safety analysis population. Treatment groups were similar with respect to baseline demographics, tumour burden, ECOG performance status, aetiology,

Discussion

Our study shows that regorafenib provides a significant and clinically meaningful improvement in overall survival in patients with HCC progressing during sorafenib treatment. This finding was associated with an increase in median survival from 7·8 months to 10·6 months. This survival benefit was maintained in the prespecified subgroup analyses, including geographical region and aetiology, and was accompanied by significant improvements in progression-free survival, time to progression, and

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