title: Sorafenib with or without everolimus in patients with advanced hepatocellular carcinoma (HCC): a randomized multicenter, multinational phase II trial (SAKK 77/08 and SASL 29).
abstract: Sorafenib (S), a multitargeted tyrosine kinase inhibitor, is the standard of care for first-line systemic treatment of advanced hepatocellular carcinoma (HCC). Everolimus (E) is a potent inhibitor of mTOR, a pathway frequently activated in HCC. Preclinical data suggest that the combination S + E has additive effects compared with single-agent S.
  
  
  
  Patients with unresectable or metastatic HCC and Child-Pugh ≤7 liver dysfunction were randomized to receive daily S 800 mg alone or with E 5 mg until progression or unacceptable toxicity. The primary end point was progression-free survival at 12 weeks (PFS12). The secondary end points included response rate, PFS, time to progression (TTP), overall survival (OS), duration of disease stabilization (DDS), safety, and quality-of-life (QoL) assessments.
  
  
  
  A total of 106 patients were randomized: 46 patients received S and 60 patients received S + E. Ninety-three patients were assessable for the primary end point and 105 patients for the safety analysis. The PFS12 rate was 70% [95% confidence interval (CI) 54-83] and 68% (95% CI 53-81) in patients randomized to S and S + E, respectively. The RECIST (mRECIST) response rate was 0% (23%) in the S arm and 10% (35%) in the S + E arm. Median PFS (6.6 versus 5.7 months), TTP (7.6 versus 6.3 months), DDS (6.7 versus 6.7 months), and OS (10 versus 12 months) were similar in the S and S + E arms, respectively. Grade 3/4 adverse events occurred in 72% and 86% of patients in arm S and arm S + E, respectively. Patients had similar QoL scores over time, except for a greater worsening in physical well-being and mood in the arm S + E.
  
  
  
  No evidence was found that S + E improves the efficacy compared with S alone. Combining 5 mg E with full-dose S is feasible, but more toxic than S alone. Further testing of this drug combination in molecularly unselected HCCs appears unwarranted.
  
  
  
  NCT01005199.
authors.affiliation: Department of Medical Oncology, Kantonsspital St Gallen, St Gallen dieter.koeberle@claraspital.ch.
authors.forename: D
authors.initials: D
authors.lastname: Koeberle
authors.affiliation: Department of Hepatology, University Hospital Bern, Bern, Switzerland.
authors.forename: J-F
authors.initials: JF
authors.lastname: Dufour
authors.affiliation: Department of Medical Oncology, St László Teaching Hospital, Budapest, Hungary.
authors.forename: G
authors.initials: G
authors.lastname: Demeter
authors.affiliation: SAKK Coordinating Center, Berne.
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.affiliation: Quality of life Office, International Breast Cancer Study Group, Bern.
authors.forename: K
authors.initials: K
authors.lastname: Ribi
authors.affiliation: Department of Medical Oncology, University Hospital Zurich, Zürich.
authors.forename: P
authors.initials: P
authors.lastname: Samaras
authors.affiliation: Department of Medical Oncology, Istituto Oncologico della Svizzera Italiana, Bellinzona.
authors.forename: P
authors.initials: P
authors.lastname: Saletti
authors.affiliation: Department of Medical Oncology, University Hospital of Geneva, Geneva.
authors.forename: A D
authors.initials: AD
authors.lastname: Roth
authors.affiliation: Department of Medical Oncology, Kantonsspital St Gallen, St Gallen.
authors.forename: D
authors.initials: D
authors.lastname: Horber
authors.affiliation: Department of Medical Oncology, University Hospital Bern, Bern.
authors.forename: M
authors.initials: M
authors.lastname: Buehlmann
authors.affiliation: Department of Medical Oncology, University Hospital Lausanne, Lausanne.
authors.forename: A D
authors.initials: AD
authors.lastname: Wagner
authors.affiliation: Department of Medical Oncology, University Hospital Lausanne, Lausanne.
authors.forename: M
authors.initials: M
authors.lastname: Montemurro
authors.affiliation: Department of Medical Oncology, St László Teaching Hospital, Budapest, Hungary.
authors.forename: G
authors.initials: G
authors.lastname: Lakatos
authors.affiliation: Department of Medical Oncology, Hôpital du Valais (RSV)-CHCVs, Lausanne, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Feilchenfeldt
authors.affiliation: Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Peck-Radosavljevic
authors.affiliation: Department of Medical Oncology, Spital STS AG, Bern, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Rauch
authors.affiliation: SAKK Coordinating Center, Berne.
authors.forename: B
authors.initials: B
authors.lastname: Tschanz
authors.affiliation: Department of Medical Oncology, St László Teaching Hospital, Budapest, Hungary.
authors.forename: G
authors.initials: G
authors.lastname: Bodoky
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D000068338:Everolimus / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D000077157:Sorafenib
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib
keywords: everolimus; hepatocellular carcinoma; sorafenib; tyrosine kinase inhibitor