Lengyel Anna Sára, Meznerics Fanni Adél, Galajda Noémi Ágnes, Gede Noémi, Kói Tamás, Mohammed Alzahra Ahmed, Péter Petra Nikolett, Lakatos Alexandra It, Krebs Máté, Csupor Dezső, Bánvölgyi András, Hegyi Péter, Holló Péter, Kemény Lajos V
Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary.
Centre for Translational Medicine, Semmelweis University, 1085 Budapest, Hungary.
Int J Mol Sci. 2024 Nov 28;25(23):12821. doi: 10.3390/ijms252312821.
The combinations of BRAF inhibitor-based targeted therapies with immune checkpoint inhibitors currently represent less common therapeutic approaches in advanced melanoma. The aim of this study was to assess the safety and efficacy of currently available melanoma treatments by conducting a systematic review and network meta-analysis. Four databases were systematically searched for randomized clinical studies that included patients with advanced/metastatic melanoma receiving chemotherapy, immune checkpoint inhibitors, BRAF/MEK inhibitor therapy, or combinations thereof. The primary endpoints were treatment-related adverse events (TRAE), serious adverse events (SAE) of grade ≥ 3 adverse events, therapy discontinuation, progression-free survival (PFS), as well as objective response rate (ORR) and complete response rate (CRR). A total of 63 articles were eligible for our systematic review; 59 of them were included in the statistical analysis. A separate subgroup analysis was conducted to evaluate the efficacy outcomes, specifically in BRAF-positive patients. Triple combination therapy or triple therapy (inhibiting BRAF, MEK and PD1/PDL1 axis) showed significantly longer progression-free survival compared to BRAF + MEK combination therapies (HR = 0.76; 95% CI 0.64-0.9), but similar objective and complete response rates in BRAF-mutated melanoma. This safety analysis suggests that triple therapy is not inferior to combined immune checkpoint inhibitors (ICI) and BRAF/MEK therapies in terms of serious adverse events and therapy discontinuation rates. However, monotherapies and BRAF/MEK combinations showed notable advantage over triple therapy in terms of treatment-related adverse events. Combination strategies including BRAF/MEK-targeted therapies with ICI therapies are effective first-line options for advanced, BRAF-mutant melanoma; however, they are associated with more frequent side effects. Therefore, future RCTs are required to evaluate and identify high-risk subpopulations where triple therapy therapies should be considered.
基于BRAF抑制剂的靶向治疗与免疫检查点抑制剂的联合应用目前在晚期黑色素瘤中是不太常见的治疗方法。本研究的目的是通过进行系统评价和网状荟萃分析来评估当前可用的黑色素瘤治疗方法的安全性和有效性。系统检索了四个数据库，以查找随机临床研究，这些研究纳入了接受化疗、免疫检查点抑制剂、BRAF/MEK抑制剂治疗或其组合的晚期/转移性黑色素瘤患者。主要终点包括治疗相关不良事件（TRAE）、≥3级不良事件的严重不良事件（SAE）、治疗中断、无进展生存期（PFS）以及客观缓解率（ORR）和完全缓解率（CRR）。共有63篇文章符合我们的系统评价标准；其中59篇纳入了统计分析。进行了一项单独的亚组分析以评估疗效结果，特别是在BRAF阳性患者中。与BRAF+MEK联合治疗相比，三联组合疗法或三联疗法（抑制BRAF、MEK和PD1/PDL1轴）显示出显著更长的无进展生存期（HR=0.76；95%CI 0.64-0.9），但在BRAF突变的黑色素瘤中客观缓解率和完全缓解率相似。该安全性分析表明，在严重不良事件和治疗中断率方面，三联疗法不劣于联合免疫检查点抑制剂（ICI）和BRAF/MEK疗法。然而，在治疗相关不良事件方面，单药治疗和BRAF/MEK联合治疗比三联疗法具有显著优势。包括BRAF/MEK靶向治疗与ICI治疗的联合策略是晚期BRAF突变黑色素瘤有效的一线选择；然而，它们与更频繁的副作用相关。因此，需要未来的随机对照试验来评估和确定应考虑三联疗法的高风险亚组人群。
