title: Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial.
abstract: OBJECTIVE
  Aside from the multikinase inhibitor sorafenib, there are no effective systemic therapies for the treatment of advanced hepatocellular carcinoma.
  
  
  OBJECTIVE
  To assess the efficacy of everolimus in patients with advanced hepatocellular carcinoma for whom sorafenib treatment failed.
  
  
  METHODS
  EVOLVE-1 was a randomized, double-blind, phase 3 study conducted among 546 adults with Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were intolerant of sorafenib. Patients were enrolled from 17 countries between May 2010 and March 2012. Randomization was stratified by region (Asia vs rest of world) and macrovascular invasion (present vs absent).
  
  
  METHODS
  Everolimus, 7.5 mg/d, or matching placebo, both given in combination with best supportive care and continued until disease progression or intolerable toxicity. Per the 2:1 randomization scheme, 362 patients were randomized to the everolimus group and 184 patients to the placebo group.
  
  
  METHODS
  The primary end point was overall survival. Secondary end points included time to progression and the disease control rate (the percentage of patients with a best overall response of complete or partial response or stable disease).
  
  
  RESULTS
  No significant difference in overall survival was seen between treatment groups, with 303 deaths (83.7%) in the everolimus group and 151 deaths (82.1%) in the placebo group (hazard ratio [HR], 1.05; 95% CI, 0.86-1.27; P = .68; median overall survival, 7.6 months with everolimus, 7.3 months with placebo). Median time to progression with everolimus and placebo was 3.0 months and 2.6 months, respectively (HR, 0.93; 95% CI, 0.75-1.15), and disease control rate was 56.1% and 45.1%, respectively (P = .01). The most common grade 3/4 adverse events for everolimus vs placebo were anemia (7.8% vs 3.3%, respectively), asthenia (7.8% vs 5.5%, respectively), and decreased appetite (6.1% vs 0.5%, respectively). No patients experienced hepatitis C viral flare. Based on central laboratory results, hepatitis B viral reactivation was experienced by 39 patients (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy.
  
  
  CONCLUSIONS
  Everolimus did not improve overall survival in patients with advanced hepatocellular carcinoma whose disease progressed during or after receiving sorafenib or who were intolerant of sorafenib.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01035229.
authors: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston.
authors: Andrew X
authors: AX
authors: Zhu
authors: Kinki University School of Medicine, Osaka, Japan.
authors: Masatoshi
authors: M
authors: Kudo
authors: ICM Val d'Aurelle, Montpellier, France.
authors: Eric
authors: E
authors: Assenat
authors: University Nord De France, Lille, France.
authors: Stéphane
authors: S
authors: Cattan
authors: Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Yoon-Koo
authors: YK
authors: Kang
authors: Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors: Ho Yeong
authors: HY
authors: Lim
authors: University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
authors: Ronnie T P
authors: RT
authors: Poon
authors: Hôpital Saint André, Bordeaux, France.
authors: Jean-Frederic
authors: JF
authors: Blanc
authors: Medical School Hannover, Hannover, Germany.
authors: Arndt
authors: A
authors: Vogel
authors: Kaohsiung Chang Gung Memorial Hospital, Taiwan.
authors: Chao-Long
authors: CL
authors: Chen
authors: CHRU de Tours, Tours, France.
authors: Etienne
authors: E
authors: Dorval
authors: Medical University of Vienna, Vienna, Austria.
authors: Markus
authors: M
authors: Peck-Radosavljevic
authors: Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy.
authors: Armando
authors: A
authors: Santoro
authors: G Rummo Hospital, Benevento, Italy.
authors: Bruno
authors: B
authors: Daniele
authors: Kyorin University School of Medicine, Tokyo, Japan.
authors: Junji
authors: J
authors: Furuse
authors: Novartis Pharma, Basel, Switzerland.
authors: Annette
authors: A
authors: Jappe
authors: Novartis Pharma, Basel, Switzerland.
authors: Kevin
authors: K
authors: Perraud
authors: Novartis Pharma, Basel, Switzerland.
authors: Oezlem
authors: O
authors: Anak
authors: Novartis Pharmaceuticals, East Hanover, New Jersey.
authors: Dalila B
authors: DB
authors: Sellami
authors: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan19National Cheng Kung University Hospital, Tainan, Taiwan20Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Li-Tzong
authors: LT
authors: Chen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D018450:Disease Progression; D004311:Double-Blind Method; D000068338:Everolimus; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000009:adverse effects* / Q000627:therapeutic use; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000077157:Sorafenib; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib; D020123:Sirolimus