中华皮肤科杂志 ›› 2022, Vol. 55 ›› Issue (7): 603-609.doi: 10.35541/cjd.20200767

• Meta分析 • 上一篇    下一篇

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

张宁,李舒,李敬   

  1. 郑州市第七人民医院皮肤科，郑州  450016
  • 收稿日期:2020-08-03 修回日期:2021-08-09 发布日期:2022-07-05
  • 通讯作者: 张宁 E-mail:282532797@qq.com

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

Zhang Ning, Li Shu, Li Jing    

  1. Department of Dermatology, The Seventh People′s Hospital of Zhengzhou, Zhengzhou 450016, China
  • Received:2020-08-03 Revised:2021-08-09 Published:2022-07-05
  • Contact: Zhang Ning E-mail:282532797@qq.com

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摘要： 【摘要】 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5 587例患者和7种治疗方法。其中Ⅲ期亚组5 019例，存在溃疡亚组2 085例，不存在溃疡亚组2 629例，BRAF突变亚组2 054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。

关键词: 黑色素瘤, 分子靶向治疗, Meta分析, 免疫检查点抑制剂, 可切除黑素瘤

Abstract: 【Abstract】 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 5 587 patients assigned to 7 treatment regimens were included. There were 5 019 patients in the stage Ⅲ subgroup, 2 085 in the ulcerated subgroup, 2 629 in the non-ulcerated subgroup, and 2 054 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 stage Ⅲ and 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 stage Ⅲ, 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 patients with ulcerated or BRAF-mutated resectable melanoma, dabrafenib plus trametinib may be the optimal adjuvant therapy; for those with BRAF-unknown or wild-type resectable melanoma, nivolumab may be the optimal adjuvant therapy.

Key words: Melanoma, Molecular targeted therapy, Meta-analysis, Immune checkpoint inhibitors, Resected melanoma