title: Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial.
abstract: BACKGROUND
  In the COMBI-v trial, patients with previously untreated BRAF Val600Glu or Val600Lys mutant unresectable or metastatic melanoma who were treated with the combination of dabrafenib and trametinib had significantly longer overall and progression-free survival than those treated with vemurafenib alone. Here, we present the effects of treatments on health-related quality of life (HRQoL), an exploratory endpoint in the COMBI-v study.
  
  
  METHODS
  COMBI-v was an open-label, randomised phase 3 study in which 704 patients with metastatic melanoma with a BRAF Val600 mutation were randomly assigned (1:1) by an interactive voice response system to receive either a combination of dabrafenib (150 mg twice-daily) and trametinib (2 mg once-daily) or vemurafenib monotherapy (960 mg twice-daily) orally as first-line therapy. The primary endpoint was overall survival. In this pre-specified exploratory analysis, we prospectively assessed HRQoL in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer quality of life (EORTC QLQ-C30), EuroQoL-5D (EQ-5D), and Melanoma Subscale of the Functional Assessment of Cancer Therapy-Melanoma (FACT-M), completed at baseline, during study treatment, at disease progression, and after progression. We used a mixed-model, repeated measures ANCOVA to assess differences in mean scores between groups with baseline score as covariate; all p-values are descriptive. The COMBI-v trial is registered with ClinicalTrials.gov, number NCT01597908, and is ongoing for the primary endpoint, but is not recruiting patients.
  
  
  RESULTS
  From June 4, 2012, to Oct 7, 2013, 1645 patients at 193 centres worldwide were screened for eligibility, and 704 patients were randomly assigned to dabrafenib plus trametinib (n=352) or vemurafenib (n=352). Questionnaire completion rates for both groups were high (>95% at baseline, >80% at follow-up assessments, and >70% at disease progression) with similar HRQoL and symptom scores reported at baseline in both treatment groups for all questionnaires. Differences in mean scores between treatment groups were significant and clinically meaningful in favour of the combination compared with vemurafenib monotherapy for most domains across all three questionnaires during study treatment and at disease progression, including EORTC QLQ-C30 global health (7·92, 7·62, 6·86, 7·47, 5·16, 7·56, and 7·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·005 at week 40), EORTC QLQ-C30 pain (-13·20, -8·05, -8·82, -12·69, -12·46, -11·41, and -10·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001), EQ-5D thermometer scores (7·96, 8·05, 6·83, 11·53, 7·41, 9·08, and 10·51 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·006 at week 32), and FACT-M Melanoma Subscale score (3·62, 2·93, 2·45, 3·39, 2·85, 3·00, and 3·68 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001).
  
  
  CONCLUSIONS
  From the patient's perspective, which integrates not only survival advantage but also disease-associated and adverse-event-associated symptoms, treatment with the combination of a BRAF inhibitor plus a MEK inhibitor (dabrafenib plus trametinib) adds a clear benefit over monotherapy with the BRAF inhibitor vemurafenib and supports the combination therapy as standard of care in this population.
authors.affiliation: Service de Dermatologie, Aix Marseille University, and Assistance Publique Hôpitaux de Marseille (APHM), University Hospital Timone, Marseille, France. Electronic address: jean-jacques.grob@ap-hm.fr.
authors.forename: Jean Jacques
authors.initials: JJ
authors.lastname: Grob
authors.affiliation: GlaxoSmithKline Oncology Research and Development, Collegeville, PA, USA.
authors.forename: Mayur M
authors.initials: MM
authors.lastname: Amonkar
authors.affiliation: Przychodnia Lekarska Komed, Konin, Poland.
authors.forename: Boguslawa
authors.initials: B
authors.lastname: Karaszewska
authors.affiliation: Sheba Medical Center, Ramat Gan, Ramat, Israel.
authors.forename: Jacob
authors.initials: J
authors.lastname: Schachter
authors.affiliation: Department of Dermatology, Universität Zürich, Zurich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Oncology Division, Poznan University of Medical Sciences, Med-Polonia, Poznan, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Mackiewicz
authors.affiliation: Moscow City Oncology Hospital #62, Stepanovskoye, Moscow, Russia.
authors.forename: Daniil
authors.initials: D
authors.lastname: Stroyakovskiy
authors.affiliation: Swissmed Centrum Zdrowia and Gdansk Medical University, Gdansk, Poland.
authors.forename: Kamil
authors.initials: K
authors.lastname: Drucis
authors.affiliation: Centre Hospitalier Universitairede Reims-Hôpital Robert Debré, Reims, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Grange
authors.affiliation: Istituto Oncologico Veneto Istituto Di Ricovero e Cura a Carattere Scientifico, Padua, Italy.
authors.forename: Vanna
authors.initials: V
authors.lastname: Chiarion-Sileni
authors.affiliation: Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Rutkowski
authors.affiliation: N N Blokhin Russian Cancer Research Center, Moscow, Russia.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Lichinitser
authors.affiliation: Petrov Research Institute of Oncology, Saint Petersburg, Russia.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Levchenko
authors.affiliation: University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium.
authors.forename: Pascal
authors.initials: P
authors.lastname: Wolter
authors.affiliation: Universitätsklinikum Schleswig-Holstein (UKSH), Department of Dermatology, Kiel, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Hauschild
authors.affiliation: Melanoma Institute Australia, The University of Sydney and The Mater Hospital, Sydney, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: Mount Vernon Cancer Centre, Northwood, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Nathan
authors.affiliation: University of California Los Angeles (UCLA) Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Flaherty
authors.affiliation: GlaxoSmithKline Oncology Research and Development, Collegeville, PA, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.affiliation: GlaxoSmithKline Oncology Research and Development, Collegeville, PA, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Legos
authors.affiliation: GlaxoSmithKline Oncology Research and Development, Collegeville, PA, USA.
authors.forename: Diane Opatt
authors.initials: DO
authors.lastname: McDowell
authors.affiliation: GlaxoSmithKline Oncology Research and Development, Collegeville, PA, USA.
authors.forename: Bijoyesh
authors.initials: B
authors.lastname: Mookerjee
authors.affiliation: Department of Dermatology, University Hospital Essen, Essen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Gustave Roussy, Département de Médecine oncologique, Service de Dermatologie et Université Paris-Sud, Faculté de Médecine, Villejuif, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
mesh_terms: D000284:Administration, Oral; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D020022:Genetic Predisposition to Disease; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D057194:Intention to Treat Analysis; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000556:secondary; D009154:Mutation; D010091:Oximes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010641:Phenotype; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011788:Quality of Life; D012307:Risk Factors; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011795:Surveys and Questionnaires; D013997:Time Factors; D016896:Treatment Outcome; D000077484:Vemurafenib
chemical_list: D014408:Biomarkers, Tumor; D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases; C561627:dabrafenib