title: Randomized phase II trial comparing molecularly targeted therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer: cross-over analysis from the SHIVA trial.
abstract: Several studies used the ratio of progression-free survival (PFS) on genotype-matched treatment to PFS on genotype-unmatched treatment to assess the efficacy of therapy guided by patients' tumor molecular profiling. We evaluated the PFS ratio from patients who cross-over in the SHIVA trial.
  
  
  
  The primary end point of the SHIVA trial was to compare PFS on molecularly targeted agents (MTAs) based on tumor molecular profiling and treatment at physician's choice (TPC) in patients with any kind of cancer who had failed standard-of-care therapy. The experimental treatment included only marketed MTAs given outside their indications according to a pre-specified treatment algorithm. Patients were allowed to cross-over at disease progression in both arms. Response was evaluated according to RECIST 1.1 at randomization and at cross-over. We evaluated the ratio of PFS on MTA (PFSMTA) to PFS on TPC (PFSTPC) in patients who crossed-over.
  
  
  
  Among 741 patients enrolled in the SHIVA trial, 197 were randomized, and 95 crossed-over, including 70 patients from the TPC to the MTA arm and 25 patients from the MTA to the TPC arm. Two patients crossed-over in the TPC arm without disease progression. The PFSMTA/PFSTPC ratio exceeded 1.3 in 37% of patients who crossed-over from the TPC to the MTA arm. The PFSMTA/PFSTPC ratio exceeded 1.3 in 61% of patients who crossed-over from the MTA arm to the TPC arm.
  
  
  
  The cross-over analysis of the SHIVA trial identified 37% of patients who crossed-over from TPC to MTA with a PFSMTA/PFSTPC ratio exceeding 1.3.
authors.affiliation: Department of Biostatistics, Institut Curie, Paris.
authors.forename: L
authors.initials: L
authors.lastname: Belin
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud.
authors.forename: M
authors.initials: M
authors.lastname: Kamal
authors.affiliation: Department of Biostatistics, Institut Curie, Paris.
authors.forename: C
authors.initials: C
authors.lastname: Mauborgne
authors.affiliation: Department of Biostatistics, Institut Curie, Paris.
authors.forename: C
authors.initials: C
authors.lastname: Plancher
authors.affiliation: Clinical Trial Management Unit, Institut Curie, Paris.
authors.forename: F
authors.initials: F
authors.lastname: Mulot
authors.affiliation: Department of Medical Oncology, Institut Claudius Régaud, Toulouse.
authors.forename: J-P
authors.initials: JP
authors.lastname: Delord
authors.affiliation: Department of Medical Oncology, Institut Paoli-Calmettes, Marseille.
authors.forename: A
authors.initials: A
authors.lastname: Gonçalves
authors.affiliation: Department of Medical Oncology, Centre Alexis Vautrin, Nancy.
authors.forename: C
authors.initials: C
authors.lastname: Gavoille
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud.
authors.forename: C
authors.initials: C
authors.lastname: Dubot
authors.affiliation: Department of Medical Oncology, Centre Georges-François Leclerc, Dijon.
authors.forename: N
authors.initials: N
authors.lastname: Isambert
authors.affiliation: Department of Medical Oncology, Centre René Gauducheau, Nantes.
authors.forename: M
authors.initials: M
authors.lastname: Campone
authors.affiliation: Department of Medical Oncology, Centre Léon Bérard, Lyon.
authors.forename: O
authors.initials: O
authors.lastname: Trédan
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud.
authors.forename: F
authors.initials: F
authors.lastname: Ricci
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud.
authors.forename: M
authors.initials: M
authors.lastname: Alt
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud.
authors.forename: D
authors.initials: D
authors.lastname: Loirat
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud.
authors.forename: M-P
authors.initials: MP
authors.lastname: Sablin
authors.affiliation: Department of Biostatistics, Institut Curie, Paris.
authors.forename: X
authors.initials: X
authors.lastname: Paoletti
authors.affiliation: Department of Radiology, Institut Curie, Paris.
authors.forename: V
authors.initials: V
authors.lastname: Servois
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud.|Saint-Quentin-en-Yvelines University, Montigny-le Bretonneux.|INSERM U900, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Le Tourneau
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018592:Cross-Over Studies; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018579:Patient Selection; D057285:Precision Medicine; D059039:Standard of Care
keywords: PFS ratio; SHIVA; cross-over; outcome; precision medicine