Evidence map›Paper›PMID 28475671›Full record

Trial reportAnnals of oncology : official journal of the European Society for Medical Oncology2017

Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study.

G V Long, K T Flaherty, D Stroyakovskiy, H Gogas, E Levchenko, F de Braud, J Larkin, C Garbe, T Jouary, A Hauschild and 21 more

Erratum issued Registry-linked trialAbstract readClinical Trial, Phase IIIComparative StudyRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Annals of oncology : official journal of the European Society for Medical Oncology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. It is linked to trial NCT01584648 (A Phase III, Randomized, Double-blinded Study Comparing the Combination of the BRAF Inhibitor, Dabrafenib and the MEK Inhibitor, Trametinib to Dabrafenib and Placebo as First-line Therapy in Subjects With Unresectable), which is not on this map. Cited by 307 papers, 8 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
307citing papers in PubMed, 8 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT01584648 phase3completednot on this map

A Phase III, Randomized, Double-blinded Study Comparing the Combination of the BRAF Inhibitor, Dabrafenib and the MEK Inhibitor, Trametinib to Dabrafenib and Placebo as First-line Therapy in Subjects With Unresectable (Stage IIIC) or Metastatic (Stage IV) BRAF V600E/K Mutation-positive Cutaneous Melanoma

TypeinterventionalSponsorNovartis PharmaceuticalsRan2012 to 2019Enrolled423ConditionsMelanomaArmsDabrafenib, Trametinib, Trametinib placebo
3 · Its place in the literature

Who cites it

307 citing papers in PubMed, 8 syntheses or guidelines pooled it.

  1. Pooled it
  2. Pooled it
  3. Guideline
  4. Pooled it
  5. Neoadjuvant treatment for stage III and IV cutaneous melanoma.The Cochrane database of systematic reviews · 2023
    Pooled it
  6. Pooled it
  7. Pooled it
  8. Pooled it
  9. Contribution of MEK Inhibition to BRAF/MEK Inhibitor Combination Treatment ofJournal of clinical oncology : official journal of the American Society of Clinical Oncology · 2023
    Trial
  10. COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients WithJournal of clinical oncology : official journal of the American Society of Clinical Oncology · 2022
    Trial
  11. Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib forJournal of clinical oncology : official journal of the American Society of Clinical Oncology · 2022
    Trial
  12. Article
  13. PredictedInternational journal of molecular sciences · 2026
    Article
  14. Article
  15. Review
  16. Review
  17. Review
  18. Review
  19. Article
  20. Article

247 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

31 authors.

G V LongMelanoma Institute Australia, The University of Sydney, and Royal North Shore and Mater Hospitals, North Sydney, Australia.
K T FlahertyDevelopmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, Boston, USA.
D StroyakovskiyMoscow City Oncology Hospital #62, Moscow, Russia.
H GogasFirst Department of Medicine, "Laiko" General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
E LevchenkoPetrov Research Institute of Oncology, Saint Petersburg, Russia.
F de BraudDipartimento di Medicina Oncologica, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
J LarkinRoyal Marsden NHS Foundation Trust, London, UK.
C GarbeDepartment of Dermatology, University of Tübingen, Tübingen, Germany.
T JouaryService D'oncologie Médicale, Hopital Francois Mitterrand, Pau, France.
A HauschildDepartment of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany.
V Chiarion-SileniMelanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padova, Italy.
C LebbeAPHP Dermatology and CIC Departments, INSERM U976, University Paris Diderot, Paris, France.
M MandalàDepartment of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy.
M MillwardMedical Oncology Department, Sir Charles Gairdner Hospital, Perth, Australia.
A AranceDepartment of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain.
I BondarenkoDnipropetrovsk State Medical Academy, Clinical Hospital #4, Dnipropetrovsk, Ukraine.
J B A G HaanenNetherlands Cancer Institute, Amsterdam, The Netherlands.
J HanssonDepartment of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
J UtikalSkin Cancer Unit, German Cancer Research Center (DKFZ) and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim and Heidelberg, Germany.
V FerraresiDepartment of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy.
P MohrDermatologisches Zentrum Buxtehude, Elbe Kliniken Buxtehude, Buxtehude, Germany.
V ProbachaiDnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council, Dnipropetrovsk, Ukraine.
D SchadendorfDepartment of Dermatology, University Hospital Essen, Essen, Germany.
P NathanMount Vernon Cancer Centre, Northwood, UK.
C RobertGustave Roussy, Département de Médecine Oncologique, Service de Dermatologie et Université Paris-Sud, Faculté de Médecine, Villejuif, France.
A RibasDepartment of Medicine, Hematology/Oncology, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, USA.
M A DaviesMelanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, USA.
S R LaneNovartis Pharmaceuticals Corporation, East Hanover, USA.
J J LegosNovartis Pharmaceuticals Corporation, East Hanover, USA.
B MookerjeeNovartis Pharmaceuticals Corporation, East Hanover, USA.
J-J GrobService de Dermatologie, Centre Hospitalo-Universitaire Timone, Aix-Marseille Université, Marseille, France.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundPrevious analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients. PATIENTS AND

methodsThis double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics.

resultsBetween 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use.

conclusionsThese data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.

Indexed as

MutationAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorDisease-Free SurvivalDisease ProgressionDouble-Blind MethodDrug Administration ScheduleHumansImidazolesKaplan-Meier EstimateMelanomaOximesProtein Kinase InhibitorsProto-Oncogene Proteins B-rafPyridonesPyrimidinonesBiomarkers, TumorBRAF protein, humandabrafenibImidazolesOximesProtein Kinase InhibitorsProto-Oncogene Proteins B-rafPyridonesPyrimidinonestrametinibBRAFdabrafenibdurable outcomesmelanomametastatictrametinib

Identifiers

PMID28475671
PMCPMC5834102

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.