title: Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Bayer.
authors.affiliation: Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, IDIBAPS-Hospital Clínic de Barcelona, CIBERehd, Universitat de Barcelona, Catalonia, Spain. Electronic address: jbruix@clinic.ub.es.
authors.forename: Jordi
authors.initials: J
authors.lastname: Bruix
authors.affiliation: Chinese People's Liberation Army Cancer Center of Nanjing Bayi Hospital, Nanjing, China.
authors.forename: Shukui
authors.initials: S
authors.lastname: Qin
authors.affiliation: Groupement Hospitalier Lyon Nord, Hepatology Unit, Lyon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Merle
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Granito
authors.affiliation: Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Hsiang
authors.initials: YH
authors.lastname: Huang
authors.affiliation: St Laszlo Teaching Hospital, Budapest, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Bodoky
authors.affiliation: Service d'Oncologie Médicale, Centre Eugène Marquis, Rennes, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Pracht
authors.affiliation: Department of Gastroenterology and Nephrology, Chiba University, Chiba, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yokosuka
authors.affiliation: Department of Hepatology, Hôpital de la Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris and Université Pierre et Marie Curie, Sorbonne Universités, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rosmorduc
authors.affiliation: Russian Cancer Research Center n.a.N.Blokhin, Moscow, Russia.
authors.forename: Valeriy
authors.initials: V
authors.lastname: Breder
authors.affiliation: CHU Timone, Université de la Méditerranée, Marseille, France.
authors.forename: René
authors.initials: R
authors.lastname: Gerolami
authors.affiliation: Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Masi
authors.affiliation: King's College Hospital NHS Foundation Trust, London, UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Ross
authors.affiliation: Tianjin Medical University Cancer Hospital, Tianjin, China.
authors.forename: Tianqiang
authors.initials: T
authors.lastname: Song
authors.affiliation: INSERM 954, CHU de Nancy, Université de Lorraine, Nancy, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bronowicki
authors.affiliation: Service d'Hépatogastroentérologie, CHU, Caen, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ollivier-Hourmand
authors.affiliation: Kindai University Faculty of Medicine, Osaka, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
authors.affiliation: Department of Medical Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
authors.affiliation: Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, IDIBAPS-Hospital Clínic de Barcelona, CIBERehd, Universitat de Barcelona, Catalonia, Spain; Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finn
authors.affiliation: Bayer HealthCare SAS, Loos, France.
authors.forename: Marie-Aude
authors.initials: MA
authors.lastname: LeBerre
authors.affiliation: Bayer Pharmaceuticals, Bayer Vital GmbH, Leverkusen, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Baumhauer
authors.affiliation: Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA.
authors.forename: Gerold
authors.initials: G
authors.lastname: Meinhardt
authors.affiliation: The First Affiliated Hospital (Xijing Hospital) of the Fourth Military Medical University, Xi'an, China.
authors.forename: Guohong
authors.initials: G
authors.lastname: Han
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib; D009536:Niacinamide; D000077157:Sorafenib