Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma.
Caroline Robert,Jean J. Grob,Daniil Stroyakovskiy,Boguslawa Karaszewska,Axel Hauschild,Evgeny Levchenko,Vanna Chiarion Sileni,Jacob Schachter,Claus Garbe,Igor Bondarenko,Helen Gogas,Mario Mandalà,John B A G Haanen,C. Lebbé,Andrzej Mackiewicz,Piotr Rutkowski,Paul Nathan,Antoni Ribas,Michael A. Davies,Keith T. Flaherty,Paul Burgess,Monique Tan,Eduard Gasal,Maurizio Voi,Dirk Schadendorf,Georgina V. Long +25 more
TLDR
First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.Abstract:
Background Patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients remain undefined. To determine 5-year survival rates and clinical characteristics of the patients with durable benefit, we sought to review long-term data from randomized trials of combination therapy with BRAF and MEK inhibitors. Methods We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively. Results A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years. Conclusions First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline and Novartis; COMBI-d ClinicalTrials.gov number, NCT01584648; COMBI-v ClinicalTrials.gov number, NCT01597908.).read more
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References
More filters
Journal ArticleDOI
Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma
Jedd D. Wolchok,Vanna Chiarion-Sileni,Rene Gonzalez,Piotr Rutkowski,Jean-Jacques Grob,C. Lance Cowey,Christopher D. Lao,John Wagstaff,Dirk Schadendorf,Pier Francesco Ferrucci,Michael Smylie,Reinhard Dummer,Andrew F. Hill,David Hogg,John B. A. G. Haanen,Matteo S. Carlino,Oliver Bechter,Michele Maio,Ivan Marquez-Rodas,Massimo Guidoboni,Grant A. McArthur,Céleste Lebbé,Paolo A. Ascierto,Georgina V. Long,Jonathan Cebon,Jeffrey A. Sosman,Michael A. Postow,Margaret K. Callahan,Dana Walker,Linda Rollin,Rafia Bhore,F. Stephen Hodi,James Larkin,James Larkin +33 more
TL;DR: Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with n ivolumAB alone than with ipil optimumab alone.
Journal ArticleDOI
Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib
Caroline Robert,Boguslawa Karaszewska,Jacob Schachter,Piotr Rutkowski,Andrzej Mackiewicz,Daniil Stroiakovski,Michael Lichinitser,Reinhard Dummer,Florent Grange,Laurent Mortier,Vanna Chiarion-Sileni,Kamil Drucis,Ivana Krajsová,Axel Hauschild,Paul Lorigan,Pascal Wolter,Georgina V. Long,Keith T. Flaherty,Paul Nathan,Antoni Ribas,Antoni Ribas,Anne-Marie Martin,Peng Sun,Wendy A. Crist,Jeff Legos,Stephen D. Rubin,Shonda M Little,Dirk Schadendorf +27 more
TL;DR: Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity.
Journal ArticleDOI
Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma
Georgina V. Long,Daniil Stroyakovskiy,Helen Gogas,Evgeny Levchenko,F. de Braud,James Larkin,Claus Garbe,T. Jouary,Axel Hauschild,Jean-Jacques Grob,V. Chiarion Sileni,Céleste Lebbé,Mario Mandalà,Michael Millward,Ana Arance,Igor Bondarenko,John B. A. G. Haanen,Johan Hansson,Jochen Utikal,Virginia Ferraresi,Nadezhda Kovalenko,Peter Mohr,V. Probachai,Dirk Schadendorf,Paul Nathan,Caroline Robert,Antoni Ribas,Douglas J. DeMarini,Jhangir G. Irani,Michelle Casey,Daniele Ouellet,Anne-Marie Martin,Ngocdiep T. Le,Kiran Patel,Keith T. Flaherty +34 more
TL;DR: A combination of dabraenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations.
Journal ArticleDOI
Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial
Georgina V. Long,Georgina V. Long,Daniil Stroyakovskiy,Helen Gogas,Evgeny Levchenko,Filippo de Braud,James Larkin,Claus Garbe,Thomas Jouary,Axel Hauschild,Jean-Jacques Grob,Vanna Chiarion-Sileni,Céleste Lebbé,Mario Mandalà,Michael Millward,Ana Arance,Igor Bondarenko,John B. A. G. Haanen,Johan Hansson,Jochen Utikal,Jochen Utikal,Virginia Ferraresi,Nadezhda Kovalenko,Peter Mohr,Volodymr Probachai,Dirk Schadendorf,Paul Nathan,Caroline Robert,Caroline Robert,Antoni Ribas,Douglas J Demarini,Jhangir G. Irani,Suzanne Swann,Jeffrey J. Legos,Fan Jin,Bijoyesh Mookerjee,Keith T. Flaherty +36 more
TL;DR: The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma.
Journal ArticleDOI
Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.
F.S. Hodi,Vanna Chiarion-Sileni,Rene Gonzalez,Jean-Jacques Grob,Piotr Rutkowski,Charles Lance Cowey,Christopher D. Lao,Dirk Schadendorf,John Wagstaff,Reinhard Dummer,Pier Francesco Ferrucci,Michael Smylie,Andrew F. Hill,David Hogg,Ivan Marquez-Rodas,Joel Jiang,Jasmine I. Rizzo,James Larkin,Jedd D. Wolchok,Jedd D. Wolchok +19 more
TL;DR: The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018.
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