Abstract：
Available evidence suggests that in patients with advanced BRAF V600-mutant melanoma treated with the combination of BRAF and MEK inhibitors, gender could be associated with survival outcome. We performed a systematic review and meta-analysis of all randomized clinical trials (RCTs) testing the combination of BRAF and MEK inhibitors, to assess the interaction between treatment effect and patients\' gender. We searched PubMed, MEDLINE, Embase, and Scopus, for phase II and III RCTs up to January 30, 2022. We included all RCTs that enrolled patients with BRAF V600-mutant advanced cutaneous melanoma and assessed combinations of BRAF and MEK inhibitors versus BRAF inhibitor monotherapy. Our aim was to assess differences if any in treatment efficacy between men and women, measured in terms of the differences in progression-free survival (PFS) and overall survival (OS) log-hazard ratios (log-HRs). We calculated the pooled PFS- and OS-HRs with 95% confidence intervals (CIs) in men and women using a random-effects model and assessed the heterogeneity between the estimates using an interaction test. Five RCTs that enrolled a total of 2,113 patients were included in the analysis. In women, the combination of BRAF and MEK inhibitors halved the risk of progression or death as compared with BRAF inhibitor monotherapy with a pooled PFS-HR of 0.50 (95%CI 0.41-0.61). In men, the benefit obtained with BRAF and MEK inhibitors was smaller with a pooled PFS-HR of 0.63 (95%CI 0.54-0.74), P-heterogeneity = .05. A similar trend was observed for OS where the pooled OS-HR was 0.62 (95%CI 0.48-0.80) in women and only 0.78, (95%CI 0.67-0.92) in men, P-heterogeneity = 0.11. These results support meaningful gender-based heterogeneity of response to combination of BRAF and MEK inhibitors targeted therapy in patients with advanced BRAF-mutant melanoma, that should be considered in future research to improve treatment effectiveness.
摘要：
现有证据表明，在BRAF和MEK抑制剂联合治疗的晚期BRAFV600突变黑色素瘤患者中，性别可能与生存结果相关。我们对所有测试BRAF和MEK抑制剂组合的随机临床试验（RCT）进行了系统评价和荟萃分析。评估治疗效果与患者性别之间的相互作用。我们搜索了PubMed,MEDLINE,Embase,还有Scopus,截至2022年1月30日的II期和III期RCT。我们纳入了所有纳入BRAFV600突变晚期皮肤黑色素瘤患者的RCT，并评估了BRAF和MEK抑制剂的组合与BRAF抑制剂单一疗法的组合。我们的目的是评估男女之间治疗效果的差异，根据无进展生存期（PFS）和总生存期（OS）对数风险比（log-HRs）的差异进行测量。我们使用随机效应模型计算了男性和女性中具有95％置信区间（CI）的合并PFS和OS-HR，并使用交互检验评估了估计值之间的异质性。共纳入2,113名患者的5个RCT被纳入分析。在女性中，与BRAF抑制剂单药治疗相比,BRAF和MEK抑制剂联合治疗的进展或死亡风险减半,合并PFS-HR为0.50(95CI0.41~0.61).在男人中，BRAF和MEK抑制剂获得的益处较小，合并的PFS-HR为0.63（95CI0.54-0.74），P异质性=0.05。OS也观察到了类似的趋势，女性的合并OS-HR为0.62（95CI0.48-0.80），男性仅为0.78（95CI0.67-0.92），P-异质性=0.11。这些结果支持晚期BRAF突变黑色素瘤患者对BRAF和MEK抑制剂联合靶向治疗的有意义的基于性别的异质性反应。这应该在未来的研究中考虑，以提高治疗效果。
