title: Functional and symptom impact of trametinib versus chemotherapy in BRAF V600E advanced or metastatic melanoma: quality-of-life analyses of the METRIC study.
abstract: BACKGROUND
  In a randomized phase III study, trametinib prolonged progression-free survival and improved overall survival versus chemotherapy in patients with BRAF V600 mutation-positive melanoma.
  
  
  METHODS
  Patients' quality of life (QOL) was assessed at baseline and follow-up visits using the European Organisation for Research and Treatment of Cancer Core QOL questionnaire.
  
  
  RESULTS
  In the primary efficacy population (BRAF V600E+, no brain metastases) from baseline to weeks 6 and 12, patients' global health status scores worsened by 4-5 points with chemotherapy but improved by 2-3 points with trametinib. Rapid and substantive reductions in QOL functionality (e.g. role functioning, 8-11 points at weeks 6 and 12) and symptom exacerbation (e.g. fatigue, 4-8 points; nausea and vomiting, 5 points, both at weeks 6 and 12) were observed in chemotherapy-treated patients. In contrast, trametinib-treated patients reported small improvements or slight worsening from baseline at week 12, depending on the functional dimension and symptom. The mean symptom-scale scores for chemotherapy-treated patients increased from baseline (symptoms worsened) for seven of eight symptoms at week 6 (except insomnia) and six of eight symptoms at week 12 (except dyspnea and insomnia). In contrast, at weeks 6 and 12, the mean symptom-scale scores for trametinib decreased from baseline (symptoms improved) for pain (11-12 points), insomnia (10-12 points), and appetite loss (1-5 points), whereas those for diarrhea worsened (15-16 points). Mixed-model repeated-measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements (small to moderate) from baseline in favor of trametinib for global health; physical, role, and social functioning; fatigue; pain; insomnia; nausea and vomiting; constipation; dyspnea; and appetite at weeks 6 and/or 12. QOL results for the intent-to-treat population were consistent.
  
  
  CONCLUSIONS
  This first QOL assessment for a MEK inhibitor in metastatic melanoma demonstrated that trametinib was associated with less functional impairment, smaller declines in health status, and less exacerbation of symptoms versus chemotherapy.
authors: Department of Dermatology, University Hospital Essen, Essen, Germany. Electronic address: dirk.schadendorf@uk-essen.de.
authors: D
authors: D
authors: Schadendorf
authors: Global Health Outcomes, Oncology Research and Development, and Clinical Statistics, GlaxoSmithKline, Collegeville.
authors: M M
authors: MM
authors: Amonkar
authors: Department of Internal Medicine, University of Iowa Hospital and Clinics, Iowa City, USA.
authors: M
authors: M
authors: Milhem
authors: Global Health Outcomes, Oncology Research and Development, and Clinical Statistics, GlaxoSmithKline, Collegeville.
authors: K
authors: K
authors: Grotzinger
authors: Department of Tumor Biotherapy, N.N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation.
authors: L V
authors: LV
authors: Demidov
authors: Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors: P
authors: P
authors: Rutkowski
authors: Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.
authors: C
authors: C
authors: Garbe
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors: R
authors: R
authors: Dummer
authors: Department of Dermatology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
authors: J C
authors: JC
authors: Hassel
authors: Department of General Medical Oncology and Laboratory of Experimental Oncology, University Hospitals, Leuven Cancer Institute, Leuven, Belgium.
authors: P
authors: P
authors: Wolter
authors: Department of Dermato-Oncology, Elbekliniken, Buxtehude.
authors: P
authors: P
authors: Mohr
authors: Department of Dermatology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors: U
authors: U
authors: Trefzer
authors: Department of Medical Oncology, Centre Eugène Marquis, Rennes, France.
authors: C
authors: C
authors: Lefeuvre-Plesse
authors: Department of Oncology, Sint-Augustinus, Wilrijk, Belgium.
authors: A
authors: A
authors: Rutten
authors: The Wellcome Trust Clinical Research Facility, The Queen Elizabeth Hospital, Birmingham, UK.
authors: N
authors: N
authors: Steven
authors: Department of Oncology, Uppsala University, Uppsala, Sweden.
authors: G
authors: G
authors: Ullenhag
authors: Global Health Outcomes, Oncology Research and Development, and Clinical Statistics, GlaxoSmithKline, Collegeville.
authors: L
authors: L
authors: Sherman
authors: Global Health Outcomes, Oncology Research and Development, and Clinical Statistics, GlaxoSmithKline, Collegeville.
authors: F S
authors: FS
authors: Wu
authors: Global Health Outcomes, Oncology Research and Development, and Clinical Statistics, GlaxoSmithKline, Collegeville.
authors: K
authors: K
authors: Patel
authors: Global Health Outcomes, Oncology Research and Development, and Clinical Statistics, GlaxoSmithKline, Collegeville.
authors: M
authors: M
authors: Casey
authors: Department of Dermatology and U 981, Institut Gustave Roussy, Villejuif-Paris-Sud, France.
authors: C
authors: C
authors: Robert
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003606:Dacarbazine / Q000009:adverse effects / Q000627:therapeutic use; D018572:Disease-Free Survival; D006304:Health Status; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D017239:Paclitaxel / Q000009:adverse effects / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011728:Pyridones / Q000009:adverse effects / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000009:adverse effects / Q000627:therapeutic use*; D011788:Quality of Life; D011795:Surveys and Questionnaires
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D003606:Dacarbazine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases; D017239:Paclitaxel
keywords: BRAF; MEK; chemotherapy; melanoma; quality of life; trametinib