DataSheet_1_Acceptability of Drugs in the Treatment of Unresectable/Metastatic BRAF V600-Mutant Melanoma: A Systematic Review and Network Meta-Analysis.docx

BackgroundAlthough many novel regimens have entered the treatment paradigm for unresectable/metastatic BRAF V600-mutant melanoma, there is still a lack of head-to-head comparison in terms of security. We conducted a network meta-analysis to compare the risk of adverse events (AEs) across different treatments and to provide an acceptability ranking for patients.
MethodsA systematic literature review was conducted in Embase, PubMed, WHO International Clinical Trials Registry Platform, and Clinical Trials.gov with a time frame from database inception to December 24, 2021. We retrieved evidence on the cumulative incidence of any-grade AEs means grades 1-5 AEs (regardless of severity) and severe AEs based on the pooled risk ratios (RRs) and 95% credible intervals (95% CrI).
ResultsTwelve publications and thirteen treatments enrolling 5,803 patients were included. For any-grade AEs, the acceptability of combined dabrafenib and trametinib is superior to the combination of vemurafenib and cobimetinib (RR: 0.94; Crl: 0.89, 0.98). Furthermore, nivolumab combined with ipilimumab increases any-grade AEs than single-agent ipilimumab (RR: 0.90; Crl: 0.83, 0.96) or nivolumab (RR: 0.90; Crl: 0.84, 0.97). For severe AEs, dabrafenib has the best acceptability than single-agent vemurafenib (RR: 0.66; Crl: 0.50, 0.87) or encorafenib (RR: 0.64; Crl: 0.43, 0.94). In addition, ipilimumab (SUCRA: 0.87) ranks first in the acceptability for any-grade AEs, and nivolumab (SUCRA: 0.95) ranks first in the acceptability for severe AEs. The ranking of the combination of vemurafenib and cobimetinib (SUCRA: 0.66) is superior to encorafenib in combination with binimetinib (SUCRA: 0.39) and combination of vemurafenib and cobimetinib (SUCRA: 0.18).
ConclusionsWe identified the lowest AE risk treatment options for BRAF V600-mutant melanoma patients. In general, immunotherapy (ipilimumab or nivolumab) has better acceptability than most targeted therapies, and triplet therapies are related with the worst acceptability. Moreover, single-agent dabrafenib can be used as the first choice in monotherapy, and the combination of dabrafenib and trametinib is the preferred combination therapy. Overall, the combination of immunotherapy drugs increases any-grade and severe AEs than a single agent, whereas the condition of targeted therapy drugs cannot be simply generalized. Therefore, this information can facilitate evidence-based decision-making and support optimizing treatment and outcomes in clinical practice.

背景：尽管诸多新型治疗方案已纳入不可切除/转移性BRAF V600突变型黑色素瘤的治疗范式，但目前仍缺乏针对其安全性的头对头比较研究。本研究开展了网状Meta分析（network meta-analysis），以对比不同治疗方案的不良事件（Adverse Events, AEs）发生风险，并为患者提供治疗可接受性排序。
方法：本研究在Embase、PubMed、世界卫生组织国际临床试验注册平台（WHO International Clinical Trials Registry Platform）以及ClinicalTrials.gov中开展系统文献检索，检索时限为各数据库建库起至2021年12月24日。本研究基于合并风险比（Risk Ratios, RRs）及95%可信区间（95% credible intervals, 95% CrI），提取任意级别不良事件（即1~5级不良事件，无论严重程度）及严重不良事件的累积发生率相关证据。
结果：本研究共纳入12项文献报道，涉及13种治疗方案，累计纳入5803例患者。针对任意级别不良事件，达拉非尼（dabrafenib）联合曲美替尼（trametinib）的治疗可接受性优于维莫非尼（vemurafenib）联合考比替尼（cobimetinib）（RR：0.94；95% CrI：0.89~0.98）。此外，纳武利尤单抗（nivolumab）联合伊匹木单抗（ipilimumab）的任意级别不良事件发生率高于单药伊匹木单抗（RR：0.90；95% CrI：0.83~0.96）或单药纳武利尤单抗（RR：0.90；95% CrI：0.84~0.97）。针对严重不良事件，单药达拉非尼的治疗可接受性优于单药维莫非尼（RR：0.66；95% CrI：0.50~0.87）或单药康奈非尼（encorafenib）（RR：0.64；95% CrI：0.43~0.94）。此外，伊匹木单抗（表面下累积排序概率，Surface Under the Cumulative Ranking Order, SUCRA：0.87）在任意级别不良事件的治疗可接受性中排名第一，而纳武利尤单抗（SUCRA：0.95）在严重不良事件的治疗可接受性中排名第一。维莫非尼联合考比替尼（SUCRA：0.66）的可接受性排序优于康奈非尼联合比美替尼（SUCRA：0.39）及维莫非尼联合考比替尼（SUCRA：0.18）。
结论：本研究明确了BRAF V600突变型黑色素瘤患者的最低不良事件风险治疗方案。总体而言，免疫治疗（伊匹木单抗或纳武利尤单抗）的可接受性优于多数靶向治疗方案，而三联治疗方案的可接受性最差。此外，单药达拉非尼可作为单药治疗的首选方案，达拉非尼联合曲美替尼则为首选联合治疗方案。总体而言，免疫治疗药物联合方案的任意级别及严重不良事件发生率高于单药治疗，但靶向治疗药物的相关规律无法简单推广。上述研究结果可为临床实践中的循证决策提供参考，助力优化治疗方案及患者临床结局。