title: FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer.
abstract: BACKGROUND
  BRAF V600E mutation plays a negative prognostic role in metastatic colorectal cancer (mCRC), leading to a median Progression Free Survival (PFS) of 4-6months with first-line conventional treatments. Our group recently reported in a retrospective exploratory analysis of a phase II trial that FOLFOXIRI (5-FU/LV+Oxaliplatin+Irinotecan) plus bevacizumab might allow to achieve remarkable results in terms of PFS and Overall Survival (OS) also in this poor-prognosis subgroup. The aim of this work was to prospectively validate our retrospective finding.
  
  
  METHODS
  This phase II trial was designed to detect an increase in 6month-Progression Free Rate (6m-PFR) from 45% to 80% in a population of BRAF mutant mCRC patients treated with first-line FOLFOXIRI plus bevacizumab. Secondary end-points were PFS, OS, response rate (RR) and the analysis of outcome parameters in the pooled population consisting of both retrospectively and prospectively included patients. This trial is registered with ClinicalTrials.gov, number NCT01437618.
  
  
  RESULTS
  Two-hundred-fourteen potentially eligible mCRC patients were screened for BRAF mutational status. Fifteen BRAF mutant patients (7%) were included in the validation cohort. At a median follow up of 25.7months, 6m-PFR was 73%. Median PFS and OS were 9.2 and 24.1months, respectively. In the pooled population, at a median follow up of 40.4months, 6m-PFR was 84%. Median PFS and OS were 11.8 and 24.1months, respectively. Overall RR and disease control rate were 72% and 88%, respectively.
  
  
  CONCLUSIONS
  Lacking randomised trials in this specific molecular subgroup, FOLFOXIRI plus bevacizumab might be a reasonable option for the first-line treatment of BRAF mutant mCRC patients.
authors.affiliation: Unit of Medical Oncology 2, Azienda Ospedaliera-Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy. Electronic address: fotiosloupakis@gmail.com.
authors.forename: F
authors.initials: F
authors.lastname: Loupakis
authors.affiliation: Unit of Medical Oncology 2, Azienda Ospedaliera-Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Cremolini
authors.affiliation: Unit of Medical Oncology 2, Azienda Ospedaliera-Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Salvatore
authors.affiliation: Unit of Medical Oncology 2, Azienda Ospedaliera-Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Masi
authors.affiliation: Division of Pathology, Department of Surgery, University of Pisa, Via Roma 67, 56126 Pisa, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Sensi
authors.affiliation: Unit of Medical Oncology 2, Azienda Ospedaliera-Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Schirripa
authors.affiliation: Unit of Medical Genetics, Azienda Ospedaliera-Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Michelucci
authors.affiliation: Unit of Medical Oncology 2, Azienda Ospedaliera-Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Pfanner
authors.affiliation: Unit of Medical Oncology 1, Azienda Ospedaliera-Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Brunetti
authors.affiliation: Division of Pathology, Department of Surgery, University of Pisa, Via Roma 67, 56126 Pisa, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Lupi
authors.affiliation: Unit of Medical Oncology 2, Azienda Ospedaliera-Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Antoniotti
authors.affiliation: Unit of Medical Oncology 1, Oncology Institute of Veneto, Via Gattamelata 64, 35138 Padua, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Bergamo
authors.affiliation: Unit of Medical Oncology 1, Oncology Institute of Veneto, Via Gattamelata 64, 35138 Padua, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Lonardi
authors.affiliation: Unit of Medical Oncology 1, Oncology Institute of Veneto, Via Gattamelata 64, 35138 Padua, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Zagonel
authors.affiliation: Unit of Medical Genetics, Azienda Ospedaliera-Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Simi
authors.affiliation: Division of Pathology, Department of Surgery, University of Pisa, Via Roma 67, 56126 Pisa, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Fontanini
authors.affiliation: Unit of Medical Oncology 2, Azienda Ospedaliera-Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy; Division of Medical Oncology, Department of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Falcone
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D011379:Prognosis; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D000068258:Bevacizumab; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: BRAF; Bevacizumab; Chemotherapy; Colorectal cancer; FOLFOXIRI