title: Combined therapy with dabrafenib and trametinib in BRAF-mutated metastatic melanoma in a real-life setting: the INT Milan experience.
abstract: OBJECTIVE
  Combination therapy with dabrafenib and trametinib is safer and more effective than BRAF inhibitor-based monotherapy for metastatic melanoma.
  
  
  METHODS
  We retrospectively analyzed BRAF-mutated metastatic melanoma patients treated at our institution with daily oral dabrafenib 300 mg and trametinib 2 mg from November 2013 to April 2016. This clinical record included both untreated and previously treated stage IV melanomas. Physical examination and laboratory examinations were performed monthly and disease re-evaluations were performed every 3 months.
  
  
  RESULTS
  A total of 48 patients (24 male, 24 female) with BRAF-mutated metastatic melanoma received dabrafenib and trametinib; median age was 48 years (range 23-75). Median follow-up was 362.5 days (range 72-879). Best overall response rate consisted of 6.2% (3 patients) complete response, 64.6% (31) partial response, and 25% (12) stable disease; median time to best response was 11 weeks (range 5.7-125.5). Progression of disease was seen in 19 patients (39.6%), with median time to progression (TTP) of 26 weeks (range 8-54). A total of 15 patients (31.2%) died due to progression of disease. Median progression-free survival and median overall survival were not reached. To date, 30 patients (62.5%) are still under treatment. A total of 27 (56.2%) patients had at least one adverse event (AE); grade 3-4 AEs were seen in 4 cases (8.3%). The main toxicities were fever (25%), skin rash (14.6%), arthralgias (10.4%), and aspartate aminotransferase/alanine aminotransferase increase (8.3%). Treatment dose was reduced in 7 subjects (14.6%), with only one case of discontinuation due to AE.
  
  
  CONCLUSIONS
  Our data, using combined targeted therapy, are in line with the scientific literature in terms of both safety and effectiveness in a real-life setting.
authors.affiliation:  Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cavalieri
authors.affiliation:  Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Di Guardo
authors.affiliation:  Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
authors.forename: Carolina
authors.initials: C
authors.lastname: Cimminiello
authors.affiliation:  Day Surgery Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Bono
authors.affiliation:  Day Surgery Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Tolomio
authors.affiliation:  Laser Therapy Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Colombetti
authors.affiliation:  Pathology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Valeri
authors.affiliation:  Radiology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Tolla
authors.affiliation:  Medical Oncology Department, University of Milan, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: de Braud
authors.affiliation:  Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Del Vecchio
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000556:secondary; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010091:Oximes / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011728:Pyridones / Q000008:administration & dosage; D011744:Pyrimidinones / Q000008:administration & dosage; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib