Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial.
Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial.
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DOI：
10.1016/s1470-2045(17)30429-1
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发表时间：
2017-07
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通讯作者：
Long GV
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作者：
Davies MA;Saiag P;Robert C;Grob JJ;Flaherty KT;Arance A;Chiarion-Sileni V;Thomas L;Lesimple T;Mortier L;Moschos SJ;Hogg D;Márquez-Rodas I;Del Vecchio M;Lebbé C;Meyer N;Zhang Y;Huang Y;Mookerjee B;Long GV
达普拉非尼联合曲美替尼(D+T)可改善无脑转移的BRAF V600突变转移性黑色素瘤的预后；然而，D+T在活动性黑色素瘤脑转移(MBM)中的活性尚未被研究。在这里，我们报告第二阶段试验COMBI-MB的结果。我们的目的是通过对BRAF V600突变黑色素瘤脑转移患者的D+T进行评估，建立在黑色素瘤脑转移靶向治疗的现有证据的基础上。这项正在进行的开放标签第二阶段研究(NCT02039947)评估了以下四个黑色素瘤患者队列：(A)BRAF V600E，无症状MBM，既往无局部脑部治疗；(B)BRAF V600E，无症状MBM，既往局部脑部治疗；(C)BRAF V600D/K/R，无症状MBM，是否有既往局部脑部治疗；以及(D)BRAF V600D/E/K/R，有症状MBM，是否接受过局部脑部治疗。主要目标是评估所有治疗对象人群中队列A的颅内反应率(IRR)。次要终点包括B-D队列中的IRR；颅外和总体反应率；疾病控制率；颅内、颅外和总体反应持续时间；无进展生存率；总体生存率；以及安全性。共纳入125例患者(A：n=76；B：n=16；C：n=16；D：n=17)。在数据截止日(2016年11月28日；中位数随访8.5个月)，调查者评估的IRR在A组为58%(n=44/76)，B组16名患者中有9名(56%)，C组16名患者中有7名(44%)，D组17名患者中有10名(59%)，B组16名患者中有9名(56%)，D组17名患者中有10名(59%)。队列中最常见的严重不良事件是发热(n=9/125；7%)和射血分数降低(n=5/125；4%)。在BRAF V600突变的MBMS患者中，D+T是活跃的，安全性可控，但中位反应持续时间相对较短。这些结果提供了D+T的临床益处的证据，并支持进一步研究以进一步改善MBMS患者预后的必要性。诺华公司。
Dabrafenib plus trametinib (D+T) improves outcomes in BRAF V600–mutant metastatic melanoma without brain metastases; however, activity of D+T has not been studied in active melanoma brain metastases (MBM). Here, we report results from the phase 2 trial COMBI-MB. Our aim was to build upon the current body of evidence of targeted therapy in melanoma brain metastases through an evaluation of D+T in patients with BRAF V600–mutant melanoma brain metastases. This ongoing open-label, phase 2 study (NCT02039947) evaluated dabrafenib 150 mg twice daily plus trametinib 2 mg once daily in four melanoma patient cohorts: (A) BRAF V600E, asymptomatic MBM, no prior local brain therapy; (B) BRAF V600E, asymptomatic MBM, prior local brain therapy; (C) BRAF V600D/K/R, asymptomatic MBM, with or without prior local brain therapy; and (D) BRAF V600D/E/K/R, symptomatic MBM, with or without prior local brain therapy. The primary objective was to assess intracranial response rate (IRR) in cohort A in the all-treated-subjects population. Secondary endpoints included IRR in cohorts B–D; extracranial and overall response rates; disease control rates; duration of intracranial, extracranial, and overall response; progression-free survival; overall survival; and safety. A total of 125 patients were enrolled (A: n=76; B: n=16; C: n=16; D: n=17). At the data cutoff (November 28, 2016; median follow-up 8·5 months) investigator-assessed IRR was 58% (n=44/76) in cohort A. Intracranial response by investigator assessment was also achieved in 9 (56%) of 16 patients in cohort B, 7 (44%) of 16 patients in cohort C, and 10 (59%) of 17 patients in cohort D. Safety results were consistent with prior D+T studies, with 60 (48%) of 125 patients across cohorts experiencing grade 3/4 adverse events. The most common serious adverse events across cohorts were pyrexia (n=9/125; 7%) and ejection fraction decreased (n=5/125; 4%). D+T was active with a manageable safety profile in patients with BRAF V600–mutant MBMs, but the median duration of response was relatively short. These results provide evidence of clinical benefit with D+T and support the need for additional research to further improve outcomes in patients with MBMs. Novartis.