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.

Autor:	Long GV; Melanoma Institute Australia, The University of Sydney, and Royal North Shore and Mater Hospitals, North Sydney, Australia., Flaherty KT; Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, Boston, USA., Stroyakovskiy D; Moscow City Oncology Hospital #62, Moscow, Russia., Gogas H; First Department of Medicine, 'Laiko' General Hospital, National and Kapodistrian University of Athens, Athens, Greece., Levchenko E; Petrov Research Institute of Oncology, Saint Petersburg, Russia., de Braud F; Dipartimento di Medicina Oncologica, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Larkin J; Royal Marsden NHS Foundation Trust, London, UK., Garbe C; Department of Dermatology, University of Tübingen, Tübingen, Germany., Jouary T; Service D'oncologie Médicale, Hopital Francois Mitterrand, Pau, France., Hauschild A; Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany., Chiarion-Sileni V; Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padova, Italy., Lebbe C; APHP Dermatology and CIC Departments, INSERM U976, University Paris Diderot, Paris, France., Mandalà M; Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy., Millward M; Medical Oncology Department, Sir Charles Gairdner Hospital, Perth, Australia., Arance A; Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain., Bondarenko I; Dnipropetrovsk State Medical Academy, Clinical Hospital #4, Dnipropetrovsk, Ukraine., Haanen JBAG; Netherlands Cancer Institute, Amsterdam, The Netherlands., Hansson J; Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Utikal J; Skin 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., Ferraresi V; Department of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy., Mohr P; Dermatologisches Zentrum Buxtehude, Elbe Kliniken Buxtehude, Buxtehude, Germany., Probachai V; Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council, Dnipropetrovsk, Ukraine., Schadendorf D; Department of Dermatology, University Hospital Essen, Essen, Germany.; German Cancer Consortium, Heidelberg, Germany., Nathan P; Mount Vernon Cancer Centre, Northwood, UK., Robert C; Gustave Roussy, Département de Médecine Oncologique, Service de Dermatologie et Université Paris-Sud, Faculté de Médecine, Villejuif, France., Ribas A; Department of Medicine, Hematology/Oncology, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, USA., Davies MA; Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, USA., Lane SR; Novartis Pharmaceuticals Corporation, East Hanover, USA., Legos JJ; Novartis Pharmaceuticals Corporation, East Hanover, USA., Mookerjee B; Novartis Pharmaceuticals Corporation, East Hanover, USA., Grob JJ; Service de Dermatologie, Centre Hospitalo-Universitaire Timone, Aix-Marseille Université, Marseille, France.
Jazyk:	angličtina
Zdroj:	Annals of oncology : official journal of the European Society for Medical Oncology [Ann Oncol] 2017 Jul 01; Vol. 28 (7), pp. 1631-1639.
DOI:	10.1093/annonc/mdx176
Abstrakt:	Background: Previous 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 Methods: This 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. Results: Between 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. Conclusions: These 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. (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)
Databáze:	MEDLINE
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