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

Published on Jan 1, 2017in The Lancet59.102
· DOI :10.1016/S0140-6736(16)32453-9
Jordi Bruix94
Estimated H-index: 94
(University of Barcelona),
Shukui Qin31
Estimated H-index: 31
+ 21 AuthorsGuohong Han30
Estimated H-index: 30
(Fourth Military Medical University)
Sources
Abstract
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 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.
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  • References (31)
  • Citations (632)
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References31
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#1Peter R. GalleH-Index: 91
#2Alejandro Forner (European Organisation for Research and Treatment of Cancer)H-Index: 30
Last. Valérie VilgrainH-Index: 75
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Summary Liver cancer is the fifth most common cancer and the second most frequent cause of cancer-related death globally. Hepatocellular carcinoma represents about 90% of primary liver cancers and constitutes a major global health problem. The following Clinical Practice Guidelines will give up-to-date advice for the clinical management of patients with hepatocellular carcinoma, as well as providing an in-depth review of all the relevant data leading to the conclusions herein.
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#1Andrew X Zhu A X (Harvard University)H-Index: 66
#2Yoon-Koo Kang (UOU: University of Ulsan)H-Index: 54
Last. Carol Pena (Bayer AG: Bayer HealthCare Pharmaceuticals)H-Index: 15
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Purpose: Sorafenib is the current standard therapy for advanced hepatocellular carcinoma, but validated biomarkers predicting clinical outcomes are lacking. This study aimed to identify biomarkers predicting prognosis and/or response to sorafenib, with or without erlotinib, in hepatocellular carcinoma patients from the phase III SEARCH trial. Experimental Design: A total of 720 patients were randomized to receive oral sorafenib 400 mg twice daily plus erlotinib 150 mg once daily or placebo. Fift...
12 CitationsSource
#1Ghassan K. Abou-Alfa (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 38
#2Shukui QinH-Index: 31
Last. Li-Tzong Chen (NHRI: National Health Research Institutes)H-Index: 38
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4017Background: Arginine (Ar) depletion is a putative target in HCC, which lacks the citrulline (Ci) to Ar repleting enzyme argininosuccinate synthetase. A is an Ar degrading enzyme cloned from M. ...
18 CitationsSource
#1Gianluigi Mazzoccoli (Casa Sollievo della Sofferenza)H-Index: 25
#2Luca Miele (UCSC: Catholic University of the Sacred Heart)H-Index: 32
Last. Manlio Vinciguerra (NTU: Nottingham Trent University)H-Index: 36
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Sorafenib is a small molecular inhibitor of intracellular tyrosine and serine/threonine protein kinases (VEGFR, PDGFR, CRAF and BRAF), and is thought also to induce autophagy, a chief mechanism influencing tumor growth. Sorafenib shows efficacy in the management of non-resectable hepatocellular carcinoma (HCC), which is refractory to other chemotherapeutic drugs. HCC represents a major end point of chronic liver diseases and the third leading cause of cancer-related death. In HCC patients Sorafe...
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#1Jordi Bruix (University of Barcelona)H-Index: 94
#2María Reig (University of Barcelona)H-Index: 26
Last. Morris Sherman (UHN: University Health Network)H-Index: 58
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Evidence-based management of patients with hepatocellular carcinoma (HCC) is key to their optimal care. For individuals at risk for HCC, surveillance usually involves ultrasonography (there is controversy over use of biomarkers). A diagnosis of HCC is made based on findings from biopsy or imaging analyses. Molecular markers are not used in diagnosis or determination of prognosis and treatment for patients. The Barcelona Clinic Liver Cancer algorithm is the most widely used staging system. Patien...
411 CitationsSource
#1Ghassan K. Abou-Alfa (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 38
#2Donna Niedzwieski (Duke University)H-Index: 1
Last. Alan P. Venook (UCSF: University of California, San Francisco)H-Index: 64
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4003Background: An exploratory analysis of a randomized phase II study in HCC comparing doxorubicin (D) alone to doxorubicin plus sorafenib (D+S) showed a significant improvement in overall surviva...
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#1Andrew X Zhu A X (Harvard University)H-Index: 66
#2Joon Oh Park (SMC: Samsung Medical Center)H-Index: 53
Last. MasatoshiKudo (Kindai University)H-Index: 78
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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. ...
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#1Andrew X Zhu A X (Partners HealthCare)H-Index: 66
#2Olivier RosmorducH-Index: 40
Last. Yoon-Koo KangH-Index: 54
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Purpose To compare the clinical outcomes of sorafenib plus either erlotinib or placebo in patients with advanced hepatocellular carcinoma (HCC) in a multicenter, multinational, randomized, phase III trial. Patients and Methods Patients with advanced HCC and underlying Child-Pugh class A cirrhosis, who were naive to systemic treatment (N = 720), were randomly assigned to sorafenib plus either erlotinib (n = 362) or placebo (n = 358). The primary end point was overall survival (OS). Results Median...
260 CitationsSource
#1Calin CainapH-Index: 4
#2Shukui QinH-Index: 31
Last. Saied El-NowiemH-Index: 1
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Purpose This open-label phase III trial evaluated efficacy and tolerability of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC) without prior systemic therapy.
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#1MasatoshiKudo (Kindai University)H-Index: 78
#2Osamu MatsuiH-Index: 57
Last. Koichiro YamakadoH-Index: 33
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The Clinical Practice Guidelines for the Management of Hepatocellular Carcinoma proposed by the Japan Society of Hepatology was updated in June 2014 at a consensus meeting of the Liver Cancer Study Group of Japan. Three important items have been updated: the surveillance and diagnostic algorithm, the treatment algorithm, and the definition of transarterial chemoembolization (TACE) failure/refractoriness. The most important update to the diagnostic algorithm is the inclusion of gadolinium-ethoxyb...
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Abstract A liquid chromatography-tandem mass spectrometry (LC–MS/MS) method was developed and validated for the simultaneous quantification of sorafenib (SORA), its N-oxide active metabolite and of regorafenib (REGO) and its two active metabolites regorafenib N-oxide and N-desmethyl regorafenib N-oxide in hepatocellular carcinoma patients’ plasma. A proper analytes’ separation was obtained with Synergi Fusion RP column (4 μm, 80 A, 50 × 2.0 mm) using a gradient elution of 10 mM ammonium acetate ...
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#2Daiki Hira (Rits: Ritsumeikan University)H-Index: 7
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PURPOSE Severe adverse events frequently occur in patients treated with sorafenib, whereas some patients have suboptimal response to sorafenib. We aimed to evaluate the association of sorafenib-induced toxicities and clinical outcomes with the pharmacokinetics of sorafenib in patients with hepatocellular carcinoma (HCC). METHODS This was a retrospective, observational study in which 26 HCC patients who had been treated with sorafenib were enrolled between September 2010 and March 2015. The assoc...
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#1Monica MossentaH-Index: 5
#2Davide BusatoH-Index: 2
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Hepatocellular carcinoma (HCC) metabolism is redirected to glycolysis to enhance the production of metabolic compounds employed by cancer cells to produce proteins, lipids, and nucleotides in order to maintain a high proliferative rate. This mechanism drives towards uncontrolled growth and causes a further increase in reactive oxygen species (ROS), which could lead to cell death. HCC overcomes the problem generated by ROS increase by increasing the antioxidant machinery, in which key mechanisms ...
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#2Xu Yang (Peking Union Medical College Hospital)H-Index: 5
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Background:The prospect for targeted therapies in advanced hepatocellular carcinoma (HCC) has dramatically changed since several recent clinical trials have yielded promising results. The number of...
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#2Min LiH-Index: 50
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BACKGROUND Significant improvement of objective response rate and overall survival period has been achieved in several types of solid tumors by treatment with PD-1/PD-L1 inhibitors, which shed some light on hepatocellular carcinoma (HCC). Currently, a number of clinical trials concerning the application of checkpoint inhibitors in HCC are ongoing, some of which have shown favorable expectations. Hereby, we conducted a meta-analysis of existing studies to reveal the efficacy and safety of checkpo...
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Summary Background Trans-arterial chemoembolization (TACE) is one first-line option therapy for patients with hepatocellular carcinoma (HCC) not suitable for surgical resection. Aims We evaluated the effects of sunitinib plus doxorubicin-TACE on bleeding or liver failure. Methods Seventy-eight patients with HCC were included in this randomized, double-blind study. They received one to three TACE plus either sunitinib or placebo four weeks out of six for one year. The occurrence of severe bleedin...
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Introduction:Hepatocholangiocarcinoma (HCC-ICC) is a rare tumor presenting the histologic characteristics of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). As there ...
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