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

作者：Hauschild, Axel^*; Grob, Jean-Jacques; Demidov, Lev V.; Jouary, Thomas; Gutzmer, Ralf; Millward, Michael; Rutkowski, Piotr; Blank, Christian U.; Miller, Wilson H., Jr.; Kaempgen, Eckhart; Martin-Algarra, Salvador; Karaszewska, Boguslawa; Mauch, Cornelia; Chiarion-Sileni, Vanna; Martin, Anne-Marie; Swann, Suzanne; Haney, Patricia; Mirakhur, Beloo; Guckert, Mary E.; Goodman, Vicki; Chapman, Paul B.

来源：Lancet, 2012, 380(9839): 358-365.

DOI：10.1016/S0140-6736(12)60868-X

• SOLID TUMORS
• RESISTANCE
• VEMURAFENIB
• INHIBITION
• SURVIVAL
• CANCER

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.

• 出版日期2012-7-28
• 单位河北医科大学