Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial

被引：2366

作者：

Hauschild, Axel ^{[1
]}

Grob, Jean-Jacques ^{[2
]}

Demidov, Lev V. ^{[3
]}

Jouary, Thomas ^{[4
]}

Gutzmer, Ralf ^{[5
]}

Millward, Michael ^{[6
,7
]}

Rutkowski, Piotr ^{[8
,9
]}

Blank, Christian U. ^{[10
]}

Miller, Wilson H., Jr. ^{[11
]}

Kaempgen, Eckhart ^{[12
]}

Martin-Algarra, Salvador ^{[13
]}

Karaszewska, Boguslawa ^{[14
]}

Mauch, Cornelia ^{[15
,16
]}

Chiarion-Sileni, Vanna ^{[17
]}

Martin, Anne-Marie ^{[18
]}

Swann, Suzanne ^{[18
]}

Haney, Patricia ^{[18
]}

Mirakhur, Beloo ^{[18
]}

Guckert, Mary E. ^{[18
]}

Goodman, Vicki ^{[18
]}

Chapman, Paul B. ^{[19
]}

机构：

[1] Univ Hosp, Dept Dermatol, D-24105 Kiel, Germany

[2] Aix Marseille Univ, Hop Timone, Assistance Publ Hop Marseille, Marseille, France

[3] NN Blokhin Russian Canc Res Ctr, Moscow, Russia

[4] Hop St Andre, Dept Dermatol, Skin Canc Unit, Bordeaux, France

[5] Hannover Med Sch, Skin Canc Ctr, Dept Dermatol & Allergy, Hannover, Germany

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

[7] Univ Western Australia, Perth, WA 6009, Australia

[8] Maria Sklodowska Curie Mem Canc Ctr, Dept Soft Tissue Bone Sarcoma & Melanoma, Warsaw, Poland

[9] Inst Oncol, Warsaw, Poland

[10] Antoni van Leeuwenhoek Hosp NKI AVL, Netherlands Canc Inst, Div Med Oncol, Amsterdam, Netherlands

[11] Sir Mortimer B Davis Jewish Hosp, Lady Davis Inst Med Res, Montreal, PQ, Canada

[12] Univ Hosp Erlangen, Skin Canc Ctr, Dept Dermatol, Erlangen, Germany

[13] Univ Navarra Clin, Dept Med Oncol, Pamplona, Spain

[14] Przychodnia Lekarska KOMED, Konin, Poland

[15] Univ Hosp Cologne, Dept Dermatol & Venereol, Cologne, Germany

[16] Univ Hosp Cologne, CIO KolnBonn, Cologne, Germany

[17] Ist Oncol Veneto, Melanoma & Skin Canc Unit, Padua, Italy

[18] GlaxoSmithKline, Collegeville, PA USA

[19] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA

来源：

LANCET | 2012年 / 380卷 / 9839期

关键词：

SOLID TUMORS; RESISTANCE; VEMURAFENIB; INHIBITION; SURVIVAL; CANCER;

D O I：

10.1016/S0140-6736(12)60868-X

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a manageable safety profile in studies of phase 1 and 2 in patients with BRAF(V600)-mutated metastatic melanoma. We studied the efficacy of dabrafenib in patients with BRAF(V600E)-mutated metastatic melanoma. Methods We enrolled patients in this open-label phase 3 trial between Dec 23, 2010, and Sept 1, 2011. This report is based on a data cutoff date of Dec 19, 2011. Patients aged 18 years or older with previously untreated, stage IV or unresectable stage III BRAF(V600E) mutation-positive melanoma were randomly assigned (3:1) to receive dabrafenib (150 mg twice daily, orally) or dacarbazine (1000 mg/m(2) intravenously every 3 weeks). Patients were stratified according to American Joint Committee on Cancer stage (unresectable III+IVM1a+IVM1b vs IVM1c). The primary endpoint was investigator-assessed progression-free survival and was analysed by intention to treat; safety was assessed per protocol. This study is registered with ClinicalTrials.gov, number NCT01227889. Findings Of the 733 patients screened, 250 were randomly assigned to receive either dabrafenib (187 patients) or dacarbazine (63 patients). Median progression-free survival was 5.1 months for dabrafenib and 2.7 months for dacarbazine, with a hazard ratio (HR) of 0.30 (95% CI 0.18-0.51; p<0.0001). At data cutoff, 107 (57%) patients in the dabrafenib group and 14 (22%) in the dacarbazine group remained on randomised treatment. Treatment-related adverse events (grade 2 or higher) occurred in 100 (53%) of the 187 patients who received dabrafenib and in 26 (44%) of the 59 patients who received dacarbazine. The most common adverse events with dabrafenib were skin-related toxic effects, fever, fatigue, arthralgia, and headache. The most common adverse events with dacarbazine were nausea, vomiting, neutropenia, fatigue, and asthenia. Grade 3-4 adverse events were uncommon in both groups. Interpretation Dabrafenib significantly improved progression-free survival compared with dacarbazine.

引用

页码：358 / 365

页数：8

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