Upstream mitogen-activated protein kinase (MAPK) pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients
Upstream mitogen-activated protein kinase (MAPK) pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients
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DOI：
10.1016/j.ejca.2013.09.014
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发表时间：
2014-01-01
影响因子：
8.4
通讯作者：
Dummer, Reinhard
中科院分区：
文献类型：
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作者：
Goldinger, Simone M.;Zimmer, Lisa;Dummer, Reinhard
BRAF突变型黑色素瘤可以通过BRAF激酶抑制剂（BRAFi）和MEK激酶抑制剂（MEKi）成功治疗。然而，BRAFi加MEKi并没有产生令人满意的缓解率（RR）。本研究的目的是评估BRAF突变黑色素瘤患者的进展时间（TTP）与丝裂原活化蛋白激酶（MAPK）途径上游抑制策略。BRAF突变阳性的转移性黑色素瘤患者在皮肤肿瘤学合作组（DeCOG）网络中被确定，并首先使用MEKi治疗，在进展时使用选择性BRAFi治疗。回顾性分析23例黑色素瘤患者（6例女性，17例男性，年龄47-80岁）的TTP。总中位TTP为8.9个月。MEKi患者的中位TTP为4.8（1.2-23.2）个月，BRAFi患者的中位TTP为4.5（1.2-15.7）个月。MEKi的RR（39%， 9个部分缓解和0个完全缓解）比先前报道的更高。我们的分析表明，在BRAF突变的黑色素瘤中，MAPK通路的反向抑制是可行的。中位TTP（8.9个月）接近有前景的BRAF- MEKi联合治疗（中位无进展生存期（PFS） 9.4个月）。首先给予MEKi时，MAPK抑制的总治疗持续时间与相反的顺序相似，但TTP倾向于MEKi。该方法在合理的容忍度下是可行的。这项临床研究鼓励在前瞻性临床试验中进一步研究，以确定MAPK途径抑制的最佳治疗方案，并应伴随使用重复活检的分子监测。(C) 2013 Elsevier Ltd.版权所有。
BRAF-mutant melanoma can be successfully treated by BRAF kinase inhibitors (BRAFi) and MEK kinase inhibitors (MEKi). However, the administration of BRAFi followed by MEKi did not generate promising response rate (RR). The purpose of this investigation was to evaluate the time to progression (TTP) with a mitogen-activated protein kinase (MAPK) pathway upstream inhibition strategy in BRAF mutated melanoma patients.BRAF mutation positive metastatic melanoma patients were identified within the Dermatology Cooperative Oncology Group (DeCOG) network and were treated first with a MEKi and upon progression with a selective BRAFi.A total of 23 melanoma patients (six females, 17 males, aged 47-80 years) were retrospectively analysed for TTP. The total median TTP was 8.9 months. The median TTP for MEKi was 4.8 (1.2-23.2) and subsequent for BRAFi 4.5 (1.2-15.7) months, respectively. A higher RR for MEKi (39%, nine partial responses and 0 complete responses) than previously reported was observed.Our analysis suggests that the reversed inhibition of the MAPK pathway is feasible in BRAF mutated melanoma. The median TTP (8.9 months) is close to the promising BRAF- and MEKi combination therapy (median progression-free survival (PFS) 9.4 months). The total treatment duration of the MAPK inhibition when a MEKi is administered first is similar compared to the reversed sequence, but TTP shifts in favour to the MEKi. This approach is feasible with reasonable tolerability. This clinical investigation encourages further studies in prospective clinical trials to define the optimal treatment schedule for the MAPK pathway inhibition and should be accompanied by molecular monitoring using repeated biopsies. (C) 2013 Elsevier Ltd. All rights reserved.