Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial

被引：1072

作者：

Long, Georgina V. ^{[1
,2
]}

Stroyakovskiy, Daniil ^{[3
]}

Gogas, Helen ^{[4
]}

Levchenko, Evgeny ^{[5
]}

de Braud, Filippo ^{[6
]}

Larkin, James ^{[7
]}

Garbe, Claus ^{[8
]}

Jouary, Thomas ^{[9
]}

Hauschild, Axel ^{[10
]}

Grob, Jean-Jacques ^{[11
,12
]}

Chiarion-Sileni, Vanna ^{[13
]}

Lebbe, Celeste ^{[14
]}

Mandala, Mario ^{[15
]}

Millward, Michael ^{[16
]}

Arance, Ana ^{[17
,18
]}

Bondarenko, Igor ^{[19
]}

Haanen, John B. A. G. ^{[20
]}

Hansson, Johan ^{[21
]}

Utikal, Jochen ^{[22
,23
]}

Ferraresi, Virginia ^{[24
]}

Kovalenko, Nadezhda ^{[25
]}

Mohr, Peter ^{[26
]}

Probachai, Volodymr ^{[27
]}

Schadendorf, Dirk ^{[28
]}

Nathan, Paul ^{[29
]}

Robert, Caroline ^{[30
,31
]}

Ribas, Antoni ^{[32
]}

DeMarini, Douglas J. ^{[33
]}

Irani, Jhangir G. ^{[33
]}

Swann, Suzanne ^{[33
]}

Legos, Jeffrey J. ^{[33
]}

Jin, Fan ^{[34
]}

Mookerjee, Bijoyesh ^{[33
]}

Flaherty, Keith ^{[35
]}

机构：

[1] Univ Sydney, Melanoma Inst Australia, Sydney, NSW 2006, Australia

[2] Mater Hosp, Sydney, NSW, Australia

[3] Moscow City Oncol Hosp, Moscow, Russia

[4] Univ Athens, Sch Med, Dept Med, GR-11527 Athens, Greece

[5] Petrov Res Inst Oncol, St Petersburg, Russia

[6] Fdn IRCCS Ist Nazl Tumori, Milan, Italy

[7] Royal Marsden Hosp, London SW3 6JJ, England

[8] Univ Hosp Tuebingen, Dept Dermatol, Tubingen, Germany

[9] CHU Bordeaux, Hop St Andre, Dept Dermatol, Bordeaux, France

[10] Univ Hosp Schleswig Holstein, Kiel, Germany

[11] Aix Marseille Univ, Marseille, France

[12] APHM Hosp CHU Timone, Marseille, France

[13] Veneto Oncol Inst IRCCS, Melanoma & Oesophageal Oncol Unit, Padua, Italy

[14] Univ Paris Diderot, INSERM U976, APHP Dermatol CIC Hop St Louis, Paris, France

[15] Papa Giovanni XXIII Canc Ctr Hosp, Bergamo, Italy

[16] Sir Charles Gairdner Hosp, Perth, WA, Australia

[17] Hosp Clin Barcelona, Dept Med Oncol, Barcelona, Spain

[18] Translat Genom & Targeted Therapeut Solid Tumors, Barcelona, Spain

[19] Dnepropetrovsk State Med Acad, Dnepropetrovsk, Ukraine

[20] Netherlands Canc Inst, Amsterdam, Netherlands

[21] Karolinska Inst, Karolinska Univ Hosp Solna, Stockholm, Sweden

[22] Heidelberg Univ, Univ Med Ctr Mannheim, Mannheim, Germany

[23] German Canc Res Ctr, Heidelberg, Germany

[24] Ist Nazl Tumori Regina Elena, Rome, Italy

[25] Volograd Reg Oncol Dispensary 3, Volzhsky, Russia

[26] Elbe Klinikum Stade, Stade, Germany

[27] Dnipropetrovsk State Council, Dnipropetrovsk Clin Oncol Ctr, Dnepropetrovsk, Ukraine

[28] Univ Hosp Essen, Essen, Germany

[29] Mt Vernon Canc Ctr, Northwood, Middx, England

[30] Gustave Roussy, Villejuif Paris Sud, France

[31] Univ Paris Sud, F-94275 Le Kremlin Bicetre, France

[32] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA

[33] Novartis Pharmaceut, E Hanover, NJ USA

[34] Merck & Co Inc, Kenilworth, NJ USA

[35] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA

来源：

LANCET | 2015年 / 386卷 / 9992期

关键词：

CLINICAL-TRIALS; MEK INHIBITION; VEMURAFENIB; COBIMETINIB; MUTATIONS;

D O I：

10.1016/S0140-6736(15)60898-4

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article. Methods We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648. Findings Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25.1 months (95% CI 19.2-not reached) in the dabrafenib and trametinib group versus 18.7 months (15.2-23.7) in the dabrafenib only group (hazard ratio [HR] 0.71, 95% CI 0.55-0.92; p=0.0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11.0 months (95% CI 8.0-13.9) in the dabrafenib and trametinib group and 8.8 months (5.9-9.3) in the dabrafenib only group (HR 0.67, 95% CI 0.53-0.84; p=0.0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group. Interpretation The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing.

引用

页码：444 / 451

页数：8

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