title: Characteristics of pyrexia in BRAFV600E/K metastatic melanoma patients treated with combined dabrafenib and trametinib in a phase I/II clinical trial.
abstract: BACKGROUND
  Pyrexia is a frequent adverse event with combined dabrafenib and trametinib therapy (CombiDT), but little is known of its clinical associations, etiology, or appropriate management.
  
  
  METHODS
  All patients on the BRF133220 phase I/II trial of CombiDT treated at the standard dose (150/2) were included for assessment of pyrexia (n = 201). BRAF and MEK inhibitor-naïve patients (n = 117) were included for efficacy analyses. Pyrexia was defined as temperature ≥38°C (≥100.4(°)F) or related symptoms.
  
  
  RESULTS
  Fifty-nine percent of patients developed pyrexia during treatment, 24% of which had pyrexia symptoms without a recorded elevation in body temperature. Pyrexia was grade 2+ in 60% of pyrexia patients. Median time to onset of first pyrexia was 19 days, with a median duration of 9 days. Pyrexia patients had a median of two pyrexia events, but 21% had three or more events. Various pyrexia management approaches were conducted in this study. A trend was observed between dabrafenib and hydroxy-dabrafenib exposure and pyrexia. No baseline clinical characteristics predicted pyrexia, and pyrexia was not statistically significantly associated with treatment outcome.
  
  
  CONCLUSIONS
  Pyrexia is a frequent and recurrent toxicity with CombiDT treatment. No baseline features predict pyrexia, and it is not associated with clinical outcome. Dabrafenib and metabolite exposure may contribute to the etiology of pyrexia. The optimal secondary prophylaxis for pyrexia is best studied in a prospective trial.
authors.affiliation: Melanoma Institute Australia and The University of Sydney, Sydney, Australia alexander.menzies@sydney.edu.au.
authors.forename: A M
authors.initials: AM
authors.lastname: Menzies
authors.affiliation: University of California San Francisco, San Francisco.
authors.forename: M T
authors.initials: MT
authors.lastname: Ashworth
authors.affiliation: Clinical Statistics, GlaxoSmithKline, Collegeville, USA.
authors.forename: S
authors.initials: S
authors.lastname: Swann
authors.affiliation: Melanoma Institute Australia and The University of Sydney, Sydney, Australia Westmead Hospital, University of Sydney, Sydney Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: R F
authors.initials: RF
authors.lastname: Kefford
authors.affiliation: Massachusetts General Hospital Center, Boston.
authors.forename: K
authors.initials: K
authors.lastname: Flaherty
authors.affiliation: Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa.
authors.forename: J
authors.initials: J
authors.lastname: Weber
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville.
authors.forename: J R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: California Pacific Medical Center, San Francisco.
authors.forename: K B
authors.initials: KB
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology, The University of Colorado Cancer Center, Aurora.
authors.forename: R
authors.initials: R
authors.lastname: Gonzalez
authors.affiliation: Department of Oncology, The Angeles Clinic and Research Institute, Santa Monica.
authors.forename: O
authors.initials: O
authors.lastname: Hamid
authors.affiliation: Penn Medicine, The University of Pennsylvania, Philadelphia, USA.
authors.forename: L
authors.initials: L
authors.lastname: Schuchter
authors.affiliation: Oncology Unit, Ludwig Institute for Cancer Research, Heidelberg, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Cebon
authors.affiliation: Department of Oncology, Vanderbilt University Medical Centre, Nashville, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Sosman
authors.affiliation: Clinical Statistics, GlaxoSmithKline, Collegeville, USA.
authors.forename: S
authors.initials: S
authors.lastname: Little
authors.affiliation: Clinical Statistics, GlaxoSmithKline, Collegeville, USA.
authors.forename: P
authors.initials: P
authors.lastname: Sun
authors.affiliation: Clinical Statistics, GlaxoSmithKline, Collegeville, USA.
authors.forename: G
authors.initials: G
authors.lastname: Aktan
authors.affiliation: Clinical Statistics, GlaxoSmithKline, Collegeville, USA.
authors.forename: D
authors.initials: D
authors.lastname: Ouellet
authors.affiliation: Clinical Statistics, GlaxoSmithKline, Collegeville, USA.
authors.forename: F
authors.initials: F
authors.lastname: Jin
authors.affiliation: Melanoma Institute Australia and The University of Sydney, Sydney, Australia Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: G V
authors.initials: GV
authors.lastname: Long
authors.affiliation: University of California San Francisco, San Francisco.
authors.forename: A
authors.initials: A
authors.lastname: Daud
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D005260:Female; D005334:Fever / Q000139:chemically induced* / Q000453:epidemiology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D010091:Oximes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011744:Pyrimidinones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D007093:Imidazoles; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib
keywords: BRAF; dabrafenib; fever; melanoma; pyrexia; trametinib