Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial
Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial
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DOI：
10.1016/s1470-2045(20)30062-0
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发表时间：
2020-03-01
期刊：
影响因子：
51.1
通讯作者：
Long, Georgina, V
中科院分区：
文献类型：
--
作者：
Dummer, Reinhard;Brase, Jan C.;Long, Georgina, V
背景在3期COMBI-AD试验中，与安慰剂相比，辅助药物达拉非尼加曲美替尼降低了切除的BRAP（V600）突变III期黑色素瘤患者的复发风险。这种预先指定的探索性生物标志物分析的目的是评估潜在的预后或预测因素和机制的阻力辅助靶向therapy.Methods COMBI-AD是一个随机，双盲，安慰剂对照，3期试验比较达拉非尼150毫克口服每日两次加曲美替尼2毫克口服每日一次与两个匹配的安慰剂。研究参与者至少18岁，并且根据美国癌症联合委员会第7版标准，经历了具有BRAF（V600）或BRAF（V600）突变的IIIA期（淋巴结转移>1 mm）、IIIB或IIIC皮肤黑素瘤的完全切除。通过交互式语音应答系统将患者随机（1：1）分配至两个治疗组，并按突变类型和疾病分期分层。患者、医生和分析数据的研究者均对治疗分配设盲。主要结局是无复发生存期，定义为从随机化到疾病复发或任何原因死亡的时间。生物标志物评估是试验预先规定的探索性结局。我们通过使用下一代DNA测序评估了固有的肿瘤基因组特征，并通过使用NanoString RNA检测评估了肿瘤微环境的特征，这可能提供预后和预测信息。该试验在ClinicalTrials.gov注册，编号NCT 01682083，正在进行中，但不再招募参与者。在数据截止日期（2018年4月30日），达拉非尼+曲美替尼组的中位随访时间为44个月（IQR 38-49），安慰剂组为42个月（21-49）。在368例患者中评估了内在肿瘤基因组特征（DNA测序集），在507例患者中评估了肿瘤微环境特征（NanoString生物标志物集）。基线时MAPK通路基因组改变不影响治疗获益或临床结局。在两个治疗组中，高于中位数的IFN γ基因表达特征是延长无复发生存期的预后指标。肿瘤突变负荷是安慰剂组无复发生存期的独立预后因素（高TM B，前三分之一;风险比[HR] 0.56，95% CI 0.37-0.85，p= 0.001）。达拉菲尼+曲美替尼组（0-83，95% CI 0-53-1-32，p=0 - 44）。肿瘤突变负荷低于2个百分位数的患者似乎从靶向治疗中获得了实质性的长期无复发生存获益（HR [与安慰剂相比] 0.49，95%CI 0-35-0-68，p
Background Adjuvant dabrafenib plus trametinib reduced the risk of relapse versus placebo in patients with resected, BRAP(V600)-tnutant, stage III melanoma in the phase 3 COMBI-AD trial. This prespecified exploratory biomarker analysis aimed to evaluate potential prognostic or predictive factors and mechanisms of resistance to adjuvant targeted therapy.Methods COMBI-AD is a randomised, double-blind, placebo-controlled, phase 3 trial comparing dabrafenib 150 mg orally twice daily plus trametinib 2 mg orally once daily versus two matched placebos. Study participants were at least 18 years of age and underwent complete resection of stage IIIA (lymph node metastases >1 mm), IIIB, or IIIC cutaneous melanoma, per American Joint Committee on Cancer 7th edition criteria, with a BRAF(V600) or BRAF(V600) mutation. Patients were randomly assigned (1:1) to the two treatment groups by an interactive voice response system, stratified by mutation type and disease stage. Patients, physicians, and the investigators who analysed data were masked to treatment allocation. The primary outcome was relapse-free survival, defined as the time from randomisation to disease recurrence or death from any cause. Biomarker assessment was a prespecified exploratory outcome of the trial. We assessed intrinsic tumour genomic features by use of next-generation DNA sequencing and characteristics of the tumour microenvironment by use of a NanoString RNA assay, which might provide prognostic and predictive infoiniation. This trial is registered with ClinicalTrials.gov, number NCT01682083, and is ongoing but no longer recruiting participants.Findings Between Jan 31, 2013, and Dec 11, 2014, 870 patients were enrolled in the trial. Median follow-up at data cutoff (April 30, 2018) was 44 months (IQR 38-49) in the dabrafenib plus trametinib group and 42 months (21-49) in the placebo group. Intrinsic tumour genomic features were assessed in 368 patients (DNA sequencing set) and tumour microenvironment characteristics were assessed in 507 patients (NanoString biomarker set). MAPK pathway genomic alterations at baseline did not affect treatment benefit or clinical outcome. An IFN gamma gene expression signature higher than the median was prognostic for prolonged relapse-free survival in both treatment groups. Tumour mutational burden was independently prognostic for relapse-free survival in the placebo group (high TM B, top third; hazard ratio [HR] 0.56, 95% CI 0.37-0.85, p=0. 0056), but not in the dabrafenib plus trametinib group (0-83, 95% CI 0-53-1-32, p=0 44). Patients with tumour mutational burden in the lower two terciles seem to derive a substantial long-term relapse-free survival benefit from targeted therapy (HR [versus placebo] 0.49, 95% CI 0-35-0-68, p