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

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• 作者：Axel Hauschild ; Jean-Jacques Grob ; Lev V Demidov ; Thomas Jouary ; Ralf Gutzmer ; Michael Millward ; Piotr Rutkowski ; Christian U Blank ; Wilson H Miller Jr ; Eckhart Kaempgen ; Salvador Mart¨ªn-Algarra ; Boguslawa Karaszewska ; Cornelia Mauch ; Vanna Chiarion-Sileni ; Anne-Marie Martin ; Suzanne Swann ; Patricia Haney ; Beloo Mirakhur ; Mary E Guckert ; Vicki Goodman ; et al.
• 刊名：The Lancet
• 出版年：2012
• 出版时间：28 July-3 August, 2012
• 年：2012
• 卷：380
• 期：9839
• 页码：358-365
• 全文大小：258 K

文摘

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Summary

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/m² 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 , number .

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.

Funding

GlaxoSmithKline.