Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
Clin Cancer Res. 2023 Feb 1;29(3):521-531. doi: 10.1158/1078-0432.CCR-22-2581.
This study aimed to identify baseline clinical features associated with the outcomes of patients enrolled in the COMBI-MB phase II study of dabrafenib and trametinib treatment in patients with V600 BRAF-mutant metastatic melanoma with melanoma brain metastases (MBM). Exploratory biomarker analysis was also conducted as part of the synergistic COMBI-BRV trial (BRV116521), to identify molecular and immunologic changes associated with dabrafenib in MBMs and extracranial metastases (ECM).
Post hoc analysis was performed for baseline features of patients (n = 125) enrolled in COMBI-MB. Analyses were performed to identify baseline clinical features associated with intracranial response rate (ICRR), progression-free survival (PFS), and overall survival (OS).
Exploratory biomarker analysis was performed on biospecimen collected in the COMBI-BRV trial in which patients with BRAF-mutant, resectable MBM were treated with dabrafenib for 10 to 14 days prior to craniotomy. Accessible ECM were resected or biopsied at the time of craniotomy. Biospecimens underwent molecular and immunologic profiling for comparative analyses.
In COMBI-MB baseline treatment with corticosteroids was independently associated with lower ICRR [39% vs. 63%; OR, 0.323; 95 % confidence interval (CI), 0.105-0.996; P = 0.049] and shorter PFS (HR, 1.93; 95% CI, 1.06-3.51; P = 0.031). Additional significant associations identified in the multivariate analysis were improved PFS in patients with a BRAFV600E genotype (HR, 0.565; 95% CI, 0.321-0.996; P = 0.048) and improved OS in patients with Eastern Cooperative Oncology Group 0 (HR, 0.44; 95% CI, 0.25-0.78; P = 0.005).
Corticosteroid treatment was associated with reduced ICRR and PFS in COMBI-MB, similar to results with immunotherapy for MBMs. Baseline corticosteroid treatment is a key factor to consider in MBM patient management and clinical trial design/interpretation.
本研究旨在确定与接受达拉非尼和曲美替尼治疗的 V600 BRAF 突变型转移性黑色素瘤伴脑转移（MBM）患者的 COMBI-MB 二期研究结果相关的基线临床特征。作为协同 COMBI-BRV 试验（BRV116521）的一部分，还进行了探索性生物标志物分析，以确定与 MBM 和颅外转移（ECM）中达拉非尼相关的分子和免疫变化。
对 COMBI-MB 入组的 125 例患者的基线特征进行了事后分析。进行了分析以确定与颅内反应率（ICRR）、无进展生存期（PFS）和总生存期（OS）相关的基线临床特征。
在 COMBI-BRV 试验中对生物标志物进行了探索性分析，其中 BRAF 突变型、可切除的 MBM 患者在开颅手术前接受了 10-14 天的达拉非尼治疗。开颅时切除或活检可切除的 ECM。对生物标本进行了分子和免疫分析以进行比较分析。
在 COMBI-MB 中，基线皮质类固醇治疗与较低的 ICRR[39%比 63%；OR，0.323；95%置信区间（CI），0.105-0.996；P=0.049]和较短的 PFS（HR，1.93；95%CI，1.06-3.51；P=0.031）相关。多变量分析中确定的其他显著相关性是 BRAFV600E 基因型患者的 PFS 改善（HR，0.565；95%CI，0.321-0.996；P=0.048）和 ECOG 0 患者的 OS 改善（HR，0.44；95%CI，0.25-0.78；P=0.005）。
皮质类固醇治疗与 COMBI-MB 中的 ICRR 和 PFS 降低相关，与 MBM 的免疫治疗结果相似。基线皮质类固醇治疗是 MBM 患者管理和临床试验设计/解释中需要考虑的关键因素。
