MEK inhibition may increase survival of NRAS-mutated melanoma patients treated with checkpoint blockade: Results of a retrospective multicentre analysis of 364 patients
MEK inhibition may increase survival of NRAS-mutated melanoma patients treated with checkpoint blockade: Results of a retrospective multicentre analysis of 364 patients
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DOI：
10.1016/j.ejca.2018.04.010
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发表时间：
2018-07-01
影响因子：
8.4
通讯作者：
Heinzerling, Lucie
中科院分区：
文献类型：
--
作者：
Kirchberger, Michael Constantin;Ugurel, Selma;Heinzerling, Lucie
背景：黑色素瘤存在基因突变，如BRAF、NRAS和KIT。激活NRAS突变存在于大约20%的黑色素瘤中。尽管BRAF突变可以通过特定的抑制剂有效地靶向，但事实证明，这种方法在NRAS突变的情况下更具挑战性。研究对象和方法：在这项研究中，364例转移性黑色素瘤患者接受了抗PD-1单抗(nivolumab，pembrolizumab)和抗CTLA-4(Ipilimumab)治疗，比较了236例NRAS突变患者和128例NRAS野生型黑色素瘤患者的总体生存率和对抗CTLA-4(Ipilimumab)治疗的反应。结果：与野生型相比，NRAS突变型黑色素瘤患者对检查点抑制剂治疗的有效率分别为15%和13%(P=0.731)，抗PD-1单抗治疗有效率分别为21%和13%(P=0.210)，联合治疗有效率为40%和39%(P=0.859)。然而，NRAS突变黑色素瘤患者的中位总生存期为21个月，显著低于NRAS野生型黑色素瘤患者的33个月(P=0.034)。在NRAS突变型黑色素瘤患者接受检查点抑制剂治疗之前或之后口服MEK抑制剂的治疗显示出对生存有利的趋势。结论：免疫检查点抑制在NRAS突变黑色素瘤和NRAS野生型黑色素瘤中显示出相似的应答率，尽管在NRAS突变的情况下生存不那么有利。加用MEK抑制药可能会提高临床疗效。(C)2018爱思唯尔有限公司。保留所有权利。
Background: Melanoma harbours genetic alterations in genes such as BRAF, NRAS and KIT. Activating NRAS mutations are present in about 20% of melanomas. Even though BRAF mutations can be effectively targeted with specific inhibitors, this approach has proven more challenging in cases of NRAS mutations. Previous reports suggested that immunotherapy might be more successful in NRAS-mutated compared to BRAF-mutated or BRAF/NRAS wildtype melanoma.Patients and methods: In this study, overall survival and response to anti-PD-1 (nivolumab, pembrolizumab) and anti-CTLA-4 (ipilimumab) therapy of 364 patients with metastatic melanoma were assessed comparing 236 NRAS-mutated patients with 128 NRAS wildtype patients. Subtyping of NRAS mutation in 211 cases revealed 12 different genotypes of which Q61 mutations were predominant (95%).Results: Patients with NRAS mutant melanoma showed similar response rates to checkpoint inhibitor therapy compared to NRAS wildtype patients with 15% versus 13% for ipilimumab (P = 0.731), 21% versus 13% for anti-PD-1 monotherapy (P = 0.210) and 40% versus 39% for ipilimumab and anti-PD-1 therapy in combination or sequence (P = 0.859). Nevertheless, median overall survival of patients with NRAS mutant melanoma was significantly lower with 21 months compared to 33 months in NRAS wildtype melanoma patients (P = 0.034). Therapy with oral MEK inhibitors before or after checkpoint inhibitor therapy showed a trend toward a survival benefit in patients with NRAS mutant melanoma.Conclusions: Immune checkpoint inhibition shows comparable response rates in NRAS-mutated and NRAS wildtype melanoma even though survival is less favourable in case of NRAS mutation. Additional MEK inhibition might improve clinical benefit. (C) 2018 Elsevier Ltd. All rights reserved.