Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study.
Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study.
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达拉非尼或达拉非尼加曲美替尼治疗晚期黑色素瘤患者的循环肿瘤DNA：一项临床验证研究
DOI：
10.1016/s1470-2045(20)30726-9
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发表时间：
2021-03
期刊：
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通讯作者：
Polsky D
中科院分区：
文献类型：
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作者：
Syeda MM;Wiggins JM;Corless BC;Long GV;Flaherty KT;Schadendorf D;Nathan PD;Robert C;Ribas A;Davies MA;Grob JJ;Gasal E;Squires M;Marker M;Garrett J;Brase JC;Polsky D
黑色素瘤缺乏有效的血液生物标记物来监测和预测治疗效果。无细胞循环肿瘤DNA(CtDNA)是一种很有前景的生物标志物；然而，人们已经使用了各种检测方法，到目前为止，还没有大型研究检验ctDNA的系列变化与BRAF和/或MEK抑制剂治疗后的生存之间的关系。我们的目的是评估基线ctDNA水平和动力学是否可以预测生存结果。我们使用分析验证的Droplet数字聚合酶链式反应分析方法，检测了参加两项临床试验的18岁≥患者的治疗前和治疗中血浆样本中BRAF V600突变的ctDNA。COMII-D(NCT01584648)是一项随机双盲的3期研究，试验对象为DRAF V600突变阳性、无法切除或转移性黑色素瘤的患者，分别是达普拉非尼加曲美替尼和达普拉非尼加安慰剂。患者的东部合作肿瘤组表现状态(ECOG PS)为0或1。主要终点为无进展生存。COMBI-MB(NCT02039947)是一项开放标签的第二阶段研究，评估达普拉非尼联合曲美替尼治疗BRAF V600突变阳性转移性黑色素瘤和脑转移的患者。接受COMBI-MB治疗的A组患者有无症状的脑转移，以前没有进行过脑局部定向治疗，ECOG评分为0或1。主要结果是A组患者的颅内反应。生物标记物分析是预先指定的探索性终点，在COMBI-d和COMBI-MB的意向治疗人群中进行。我们调查了突变拷贝数(基线或第4周或零转换状态)与疗效终点(无进展存活率、总体存活率和最佳总体反应)之间的关系。我们使用Cox模型、Kaplan-Meier图和对数等级检验来探索与无进展生存率和总体生存率的关系。除了突变拷贝数外，还研究了乳酸脱氢酶等其他预后变量的影响。在COMBI-d中，423例患者中有345例(82%)在治疗前和治疗中(第4周)有血浆样本可用，423例患者中有224例(53%)有血浆样本可用。在COMBI-MB的队列A中，76名颅内外转移性黑色素瘤患者中多达38名(50%)可获得治疗前和治疗中的样本。345例患者中有320例(93%；COMBI-d)和38例患者中有34例(%；COMBI-MB)在治疗前标本中检出CTDNA。当评估为连续变量时，COMBI-d患者基线BRAF V600突变阳性ctDNA水平升高预示着较差的总体生存结果，与基线乳酸脱氢酶水平无关。的ctDNA切割点在COMBI-d组登记的血浆分层患者中复制/毫升的生存结果，并在COMBI-MB队列中得到验证。在COMBI-d中，在第4周检测不到ctDNA与延长无进展和总体生存显著相关，特别是在乳酸脱氢酶水平升高的患者中。治疗前和治疗中BRAF V600突变的ctDNA检测可以作为靶向治疗临床结果的独立的、预测的生物标志物。诺华公司。
Melanoma lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy. Cell-free circulating tumour DNA (ctDNA) is a promising biomarker; however, various detection methods have been used, and, to date, there have been no large studies examining the association between serial changes in ctDNA and survival after BRAF and/or MEK inhibitor therapy. We aimed to evaluate whether baseline ctDNA levels and kinetics could predict survival outcomes. We used analytically validated droplet digital polymerase chain reaction assays to measure BRAF V600–mutant ctDNA in pretreatment and on-treatment plasma samples from patients aged ≥ 18 years old enrolled in two clinical trials. COMBI-d (NCT01584648) is a double-blind, randomised phase 3 study of dabrafenib plus trametinib vs dabrafenib plus placebo in previously untreated patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. Patients had Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. The primary endpoint was progression-free survival. COMBI-MB (NCT02039947) is an open-label, phase 2 study evaluating dabrafenib plus trametinib in patients with BRAF V600 mutation-positive metastatic melanoma and brain metastases. Patients in cohort A of COMBI-MB had asymptomatic brain metastases, no previous local brain-directed therapy, and an ECOG PS 0 or 1. The primary outcome was intracranial response in cohort A. Biomarker analysis was a prespecified exploratory endpoint and performed in the intention-to-treat population in COMBI-d and COMBI-MB. We investigated the relationship between mutant copy number (baseline or week 4 or zero conversion status) and efficacy endpoints (progression-free survival, overall survival, and best overall response). We used Cox models, Kaplan-Meier plots, and log-rank tests to explore the relationship with progression-free survival and overall survival. The impact of additional prognostic variables such as lactate dehydrogenase were also investigated in addition to the mutant copy number. In COMBI-d, pretreatment and on-treatment (week 4) plasma samples were available from 345 of 423 (82%) and 224 of 423 (53%) patients, respectively. In cohort A of COMBI-MB, pretreatment and on-treatment samples were available from up to 38 of 76 patients (50%) with intracranial and extracranial metastatic melanoma. ctDNA was detected in pretreatment samples from 320 of 345 patients (93%; COMBI-d) and 34 of 38 patients (89%; COMBI-MB). When assessed as a continuous variable, elevated baseline BRAF V600 mutation-positive ctDNA levels predicted worse overall survival outcomes, independent of baseline lactate dehydrogenase levels, in COMBI-d. A ctDNA cut point of 64 copies/mL of plasma stratified patients enrolled in COMBI-d with respect to survival outcomes and was validated in the COMBI-MB cohort. In COMBI-d, undetectable ctDNA at week 4 was significantly associated with extended progression-free and overall survival, particularly in patients with elevated lactate dehydrogenase levels. Pretreatment and on-treatment BRAF V600–mutant ctDNA measurements may serve as independent, predictive biomarkers of clinical outcome with targeted therapy. Novartis.