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

被引：498

作者：

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

Flaherty, K. T. ^{[3
]}

Stroyakovskiy, D. ^{[4
]}

Gogas, H. ^{[5
]}

Levchenko, E. ^{[6
]}

de Braud, F. ^{[7
]}

Larkin, J. ^{[8
]}

Garbe, C. ^{[9
]}

Jouary, T. ^{[10
]}

Hauschild, A. ^{[11
]}

Chiarion-Sileni, V. ^{[12
]}

Lebbe, C. ^{[13
,14
]}

Mandala, M. ^{[15
]}

Millward, M. ^{[16
]}

Arance, A. ^{[17
]}

Bondarenko, I. ^{[18
]}

Haanen, J. B. A. G. ^{[19
]}

Hansson, J. ^{[20
]}

Utikal, J. ^{[21
,22
,23
,24
]}

Ferraresi, V. ^{[25
]}

Mohr, P. ^{[26
]}

Probachai, V. ^{[27
]}

Schadendorf, D. ^{[28
,29
]}

Nathan, P. ^{[30
]}

Robert, C. ^{[31
,32
]}

Ribas, A. ^{[33
]}

Davies, M. A. ^{[34
]}

Lane, S. R. ^{[35
]}

Legos, J. J. ^{[35
]}

Mookerjee, B. ^{[35
]}

Grob, J. -J. ^{[36
]}

机构：

[1] Univ Sydney, Melanoma Inst Australia, 40 Rocklands Rd, Sydney, NSW 2060, Australia

[2] Royal North Shore & Mater Hosp, Sydney, NSW, Australia

[3] Massachusetts Gen Hosp, Ctr Canc, Dev Therapeut & Melanoma Program, Boston, MA USA

[4] Moscow City Oncol Hosp 62, Moscow, Russia

[5] Univ Athens, Laiko Gen Hosp, Dept Med 1, Athens, Greece

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

[7] Fdn IRCCS, Ist Nazl Tumori, Dipartimento Med Oncol, Milan, Italy

[8] Royal Marsden NHS Fdn Trust, London, England

[9] Univ Tubingen, Dept Dermatol, Tubingen, Germany

[10] Hop Francois Mitterand, Serv Oncol Med, Pau, France

[11] Univ Hosp Schleswig Holstein, Dept Dermatol, Kiel, Germany

[12] IRCCS, Vereto Oncol Inst, Melanoma & Oesophageal Oncol Unit, Padua, Italy

[13] Univ Paris Diderot, INSERM U976, APHP Dermatol Dept, Paris, France

[14] Univ Paris Diderot, INSERM U976, CIC Dept, Paris, France

[15] Papa Giovanni XXIII Hosp, Dept Oncol & Hematol, Bergamo, Italy

[16] Sir Charles Gairdner Hosp, Med Oncol Dept, Perth, WA, Australia

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

[18] Clin Hosp 4, Dnipropetrovsk State Med Acad, Dripropetrovsk, Ukraine

[19] Netherlands Canc Inst, Amsterdam, Netherlands

[20] Karolinska Univ Hosp, Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden

[21] Heidelberg Univ, Univ Med Ctr Mannheim, German Canc Res Ctr DKEZ, Skin Canc Unit, Mannheim, Germany

[22] Heidelberg Univ, Univ Med Ctr Mannheim, Dept Dermatol Venereol & Allergol, Mannheim, Germany

[23] Heidelberg Univ, Univ Med Ctr Mannheim, German Canc Res Ctr DKEZ, Skin Canc Unit, Heidelberg, Germany

[24] Heidelberg Univ, Univ Med Ctr Mannheim, Dept Dermatol Venereol & Allergol, Heidelberg, Germany

[25] Regina Elena Inst Canc Res, Dept Med Oncol A, Rome, Italy

[26] Elbe Kliniken Buxtehude, Dermatol Zentrum Buxtehude, Buxtehude, Germany

[27] Dnipropetrovsk Clin Oncol Ctr Dnipropetrovsk Stat, Dnepropetrovsk, Ukraine

[28] Univ Hosp Essen, Dept Dermatol, Essen, Germany

[29] German Canc Consortium, Heidelberg, Germany

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

[31] Gustave Roussy, Dept Med Oncol, Serv Dermatol, Villejuif, France

[32] Univ Paris Sud, Fac Med, Villejuif, France

[33] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Dept Med Hematol Oncol, Los Angeles, CA 90095 USA

[34] Univ Texas MD Anderson Canc Ctr, Melanoma Med Oncol & Syst Biol, Houston, TX 77030 USA

[35] Nova Pharmaceut Corp, E Hanover, NJ USA

[36] Aix Marseille Univ, Ctr Hosp Univ Timone, Serv Dermatol, Marseille, France

来源：

ANNALS OF ONCOLOGY | 2017年 / 28卷 / 07期

关键词：

melanoma; metastatic; BRAF; dabrafenib; trametinib; durable outcomes; POOLED ANALYSIS; MEK INHIBITION; DOUBLE-BLIND; OPEN-LABEL; COMBINATION; IPILIMUMAB; MULTICENTER; VEMURAFENIB; NIVOLUMAB; 2-YEAR;

D O I：

10.1093/annonc/mdx176

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 (150mg twice daily) plus trametinib (2mg 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.

引用

页码：1631 / 1639

页数：9

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