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.

现有证据表明，在接受 BRAF 和 MEK 抑制剂联合治疗的晚期 BRAF V600 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) 进行了系统回顾和荟萃分析，以评估治疗效果与患者性别之间的相互作用。我们在 PubMed、MEDLINE、 Embase和 Scopus 中搜索了截至 2022 年 1 月 30 日的 II 期和 III 期随机对照试验。我们纳入了所有纳入 BRAF V600 突变晚期皮肤黑色素瘤患者的随机对照试验并评估了 BRAF 和 MEK 抑制剂的组合与 BRAF 抑制剂单一疗法的对比。我们的目的是评估男性和女性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-HR) 的差异来衡量。我们使用随机效应模型计算了男性和女性合并的 PFS-HR 和 OS-HR 以及 95% 置信区间 (CI)，并使用交互检验评估了估计值之间的异质性。共纳入 2,113 名患者的五项随机对照试验被纳入分析。在女性中，与 BRAF 抑制剂单一疗法相比，BRAF 和 MEK 抑制剂的组合使进展或死亡的风险减半，合并的 PFS-HR 为 0.50 (95%CI 0.41–0.61)。在男性中，P-异质性 = .05。对于 OS 观察到类似的趋势，其中合并的 OS-HR 在女性中为 0.62 (95%CI 0.48–0.80)，而在男性中仅为 0.78 (95%CI 0.67–0.92)，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反应具有有意义的基于性别的异质性，在未来的研究中应考虑这一点以提高治疗效果。