title: Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial.
abstract: OBJECTIVE
  The AVAglio (Avastin in Glioblastoma) and RTOG-0825 randomized, placebo-controlled phase III trials in newly diagnosed glioblastoma reported prolonged progression-free survival (PFS), but not overall survival (OS), with the addition of bevacizumab to radiotherapy plus temozolomide. To establish whether certain patient subgroups derived an OS benefit from the addition of bevacizumab to first-line standard-of-care therapy, AVAglio patients were retrospectively evaluated for molecular subtype, and bevacizumab efficacy was assessed for each patient subgroup.
  
  
  METHODS
  A total of 349 pretreatment specimens (bevacizumab arm, n = 171; placebo arm, n = 178) from AVAglio patients (total, N = 921) were available for biomarker analysis. Samples were profiled for gene expression and isocitrate dehydrogenase 1 (IDH1) mutation status and classified into previously identified molecular subtypes. PFS and OS were assessed within each subtype.
  
  
  RESULTS
  A multivariable analysis accounting for prognostic covariates revealed that bevacizumab conferred a significant OS advantage versus placebo for patients with proneural IDH1 wild-type tumors (17.1 v 12.8 months, respectively; hazard ratio, 0.43; 95% CI, 0.26 to 0.73; P = .002). This analysis also revealed an interaction between the proneural subtype biomarker and treatment arm (P = .023). The group of patients with mesenchymal and proneural tumors derived a PFS benefit from bevacizumab compared with placebo; however, this translated to an OS benefit in the proneural subset only.
  
  
  CONCLUSIONS
  Retrospective analysis of AVAglio data suggests that patients with IDH1 wild-type proneural glioblastoma may derive an OS benefit from first-line bevacizumab treatment. The predictive value of the proneural subtype observed in AVAglio should be validated in an independent data set.
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sandmann
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Bourgon
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom.
authors.forename: Josep
authors.initials: J
authors.lastname: Garcia
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom.
authors.forename: Congfen
authors.initials: C
authors.lastname: Li
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Cloughesy
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom.
authors.forename: Olivier L
authors.initials: OL
authors.lastname: Chinot
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom.
authors.forename: Ryo
authors.initials: R
authors.lastname: Nishikawa
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom.
authors.forename: Warren
authors.initials: W
authors.lastname: Mason
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom.
authors.forename: Roger
authors.initials: R
authors.lastname: Henriksson
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom.
authors.forename: Frank
authors.initials: F
authors.lastname: Saran
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom.
authors.forename: Albert
authors.initials: A
authors.lastname: Lai
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Moore
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom.
authors.forename: Samir
authors.initials: S
authors.lastname: Kharbanda
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom.
authors.forename: Franklin
authors.initials: F
authors.lastname: Peale
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom.
authors.forename: Priti
authors.initials: P
authors.lastname: Hegde
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Abrey
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom.
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Phillips
authors.affiliation: Thomas Sandmann, Richard Bourgon, Congfen Li, Samir Kharbanda, Franklin Peale, Priti Hegde, Heidi S. Phillips, and Carlos Bais, Genentech, South San Francisco; Timothy Cloughesy and Albert Lai, University of California Los Angeles, Los Angeles, CA; Josep Garcia, Nicola Moore, and Lauren E. Abrey F. Hoffmann-La Roche, Basel, Switzerland; Olivier L. Chinot, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseille, France; Wolfgang Wick, University Medical Center, Heidelberg, Germany; Ryo Nishikawa, Saitama Medical University, Saitama, Japan; Warren Mason, Princess Margaret Hospital, Toronto, Ontario, Canada; Roger Henriksson, Regional Cancer Center Stockholm, Stockholm; and Umeå University, Umeå, Sweden; and Frank Saran, Royal Marsden National Health Service Foundation Trust, Surrey, United Kingdom. bais.carlos@gene.com.
authors.forename: Carlos
authors.initials: C
authors.lastname: Bais
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000532:radiotherapy; D017326:Clinical Trials, Phase III as Topic; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality* / Q000532:radiotherapy; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D018714:Radiotherapy, Adjuvant; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D000068258:Bevacizumab; D003606:Dacarbazine; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D000077204:Temozolomide