免疫检查点抑制剂和靶向药物辅助治疗可切除黑素瘤疗效的网状Meta分析

Efficacy of immune checkpoint inhibitors and targeted therapy in adjuvant treatment of resectable melanoma:a network meta-analysis

目的通过贝叶斯网状Meta分析评估免疫检查点抑制剂和靶向药物对可切除黑素瘤的治疗效果。方法通过PubMed、Embase和Cochrane数据库检索可切除黑素瘤辅助治疗的随机对照试验。基于风险比,应用贝叶斯固定效应模型对无复发生存期进行网状Meta分析来评估相对治疗效果。通过StataSE 15和OpenBUGS 3.2.3软件对数据进行综合分析。结果共纳入6篇文章,包括5587例患者和7种治疗方法。其中Ⅲ期亚组5019例,存在溃疡亚组2085例,不存在溃疡亚组2629例,BRAF突变亚组2054例;7种治疗分别为手术+观察或安慰剂、手术+dabrafenib联合trametinib辅助治疗、手术+nivolumab辅助治疗、手术+ipilimumab辅助治疗、手术+pembrolizumab辅助治疗、手术+bevacizumab辅助治疗以及手术+vemurafenib辅助治疗。在网状Meta分析中,dabrafenib联合trametinib(HR 0.47,95%CI 0.39~0.57)、nivolumab(HR 0.49,95%CI 0.36~0.65)和pembrolizumab(HR 0.57,95%CI 0.43~0.75)辅助治疗在改善无复发生存期上明显比单纯手术治疗更有效;Ⅲ期和存在溃疡的可切除黑素瘤患者亚组分析结果与上述网状Meta分析相同。不存在溃疡的可切除黑素瘤亚组分析中,vemurafenib(HR 0.48,95%CI 0.29~0.79)、dabrafenib联合trametinib(HR 0.48,95%CI 0.33~0.70)和nivolumab(HR 0.50,95%CI 0.31~0.79)辅助治疗较单纯手术治疗可显著延长患者的无复发生存期,但pembrolizumab(HR 0.69,95%CI 0.45~1.06)并没有比单纯手术治疗效果更好。在BRAF突变的黑素瘤亚组分析中,与单纯手术相比,bevacizumab(HR 0.60,95%CI 0.43~0.85)、dabrafenib联合trametinib(HR 0.47,95%CI 0.38~0.57)、pembrolizumab(HR 0.59,95%CI 0.38~0.92)和vemurafenib(HR 0.65,95%CI 0.50~0.85)辅助治疗均能明显延长患者的无复发生存期。采用网状Meta分析对各种辅助治疗进行排序,dabrafenib联合trametinib在网状Meta分析中以及Ⅲ期亚组、存在溃疡亚组和BRAF突变亚组中排第一的可能性最大,而不存在溃疡的亚组分析中,vemurafenib排第一的可能性最大。结论对于存在溃疡或BRAF突变的可切除黑素瘤患者,dabrafenib联合trametinib是最佳辅助治疗;对于BRAF突变状态未知或野生型的可切除黑素瘤患者,nivolumab是最佳辅助治疗。

Objective To assess the efficacy of immune checkpoint inhibitors and targeted therapy in the treatment of resectable melanoma by Bayesian network meta-analysis.Methods PubMed,Embase and Cochrane databases were searched for randomized controlled trials on adjuvant therapy of resectable melanoma.Based on hazard ratios,a network meta-analysis of relapse-free survival was performed using a Bayesian fixed-effect model to assess therapeutic effect of adjuvant therapy on resectable melanoma.Data were comprehensively analyzed by using StataSE 15 and OpenBUGS 3.2.3 softwares.Results Six eligible articles involving 5587 patients assigned to 7 treatment regimens were included.There were 5019 patients in the stageⅢsubgroup,2085 in the ulcerated subgroup,2629 in the non-ulcerated subgroup,and 2054 in the BRAF-mutated subgroup;the 7 treatment regimens included surgery+observation or placebo,surgery+adjuvant dabrafenib plus trametinib,surgery+adjuvant nivolumab,surgery+adjuvant ipilimumab,surgery+adjuvant pembrolizumab,surgery+adjuvant bevacizumab,and surgery+adjuvant vemurafenib.In the network meta-analysis,surgery+adjuvant dabrafenib plus trametinib(HR=0.47,95%CI:0.39-0.57),surgery+adjuvant nivolumab(HR=0.49,95%CI:0.36-0.65)and surgery+adjuvant pembrolizumab(HR=0.57,95%CI:0.43-0.75)were more effective for the improvement of relapse-free survival than surgery alone;the subgroup analysis of stageⅢand ulcerated resectable melanoma showed the same results as the above-mentioned network meta-analysis.In the subgroup analysis of non-ulcerated resectable melanoma,surgery+adjuvant vemurafenib(HR=0.48,95%CI:0.29-0.79),surgery+adjuvant dabrafenib plus trametinib(HR=0.48,95%CI:0.33-0.70),and surgery+adjuvant nivolumab(HR=0.50,95%CI:0.31-0.79)could significantly prolong the relapse-free survival compared with surgery alone,but surgery+adjuvant pembrolizumab(HR=0.69,95%CI:0.45-1.06)was not superior to surgery alone.In the subgroup analysis of BRAF-mutated melanoma,surgery+adjuvant bevacizumab(HR=0.60,95%CI:0.43-0.85),surgery+adjuvant dabrafenib plus trametinib(HR=0.47,95%CI:0.38-0.57),surgery+adjuvant pembrolizumab(HR=0.59,95%CI:0.38-0.92)and surgery+adjuvant vemurafenib(HR=0.65,95%CI:0.50-0.85)could significantly prolong the relapse-free survival compared with surgery alone.The network meta-analysis was carried out for ranking of these adjuvant treatments,and adjuvant dabrafenib plus trametinib was most likely to rank first in the network meta-analysis and subgroup analysis of stageⅢ,ulcerated or BRAF-mutated resectable melanoma,while adjuvant vemurafenib was most likely to rank first in the subgroup analysis of non-ulcerated resectable melanoma.Conclusion For ulcerated or BRAF-mutated resectable melanoma,dabrafenib plus trametinib may be the optimal adjuvant therapy;for resectable melanoma with unknown BRAF status or wild-type BRAF,nivolumab may be the optimal adjuvant therapy.