Early change in plasma tumor DNA as a patient and trial-level diagnostic in advanced lung cancer

项目摘要 标题：晚期肺癌患者循环肿瘤DNA的早期变化--和试验水平的诊断 主要调查者：杰弗里·R·奥克斯纳德，医学博士 血浆循环肿瘤DNA(CtDNA)的基因组分析正在改变晚期非肿瘤患者的护理 小细胞肺癌(NSCLC)。血浆ctDNA基因分型方法(也称为“液体活组织检查”)是 现在常规用于非侵入性检测关键癌症基因类型(EGFR、KRAS、ALK、ROS1等)，两者都 指导最初的系统治疗或有效地针对耐药性。这是数量上的本质 诊断为监测治疗反应的非侵入性工具创造了明显的潜力 我们和其他人回顾地展示了一种现象，但这种方法是不充分的 在临床上起杠杆作用。我们的初步数据表明，血浆ctDNA反应是一个高度动态的标记物， 提供对治疗效果的快速洞察，比标准反应更早，而且可能更敏感 成像。在一个癌症治疗方法越来越多和多样化的时代，灵活的评估工具 治疗福利可能有助于我们更好地评估治疗方法，并让患者接受最好的治疗。 我们DFCI的团队在将血浆基因组学转化为临床反应方面具有独特的地位 非小细胞肺癌护理的生物标记物。我们领导了许多ctdna基因分型分析的临床验证，同时 同时描述了ctDNA基因组学的复杂性和局限性。同时，我们有一个 在作为翻译工具和试验终点研究放射学响应方面有良好的记录。我们的小组是 其独特之处在于其专注于临床应用的新型诊断方法，具有对临床的深刻理解 决策点和必要的诊断性能。在此体验的基础上，我们拥有 现在有机会解决关键的科学差距，并向科学界通报(1)什么构成 血浆反应，(2)血浆反应意味着什么，以及(3)血浆反应应如何用作 患者级和试验级诊断。 在这项应用中，我们首先计划量化非小细胞肺癌患者ctdna水平的临床变化。 开始新的治疗，并利用现有的试验和临床队列，识别和验证血浆反应 切点，可靠而有力地预测从治疗中受益。同时，我们将进行一次试用级 EGFR-和KRAS-8个临床试验的11个扩展队列中的血浆反应分析 突变型NSCLC，所有血浆都储存在DFCI，以了解血浆反应的最佳时间 以及其预测试验结果的能力(放射学应答率)。最后，我们将启动一项治疗试验 在晚期非小细胞肺癌一线免疫治疗中使用血浆反应评估自适应指导 强化治疗，这是一种范式转变的方法，如果成功，有可能激励 使用血浆ctDNA监测的新一代试验有效地发展了癌症患者的治疗。 总之，这些研究将为基于ctdna的反应评估奠定基础，使其成为一种广泛可用的 指导病人护理和临床试验分析的工具。

Project Summary Title: Early change in circulating tumor DNA as a patient- and trial-level diagnostic in advanced lung cancer Primary Investigator: Geoffrey R. Oxnard, MD Genomic analysis of plasma circulating tumor DNA (ctDNA) is transforming the care of advanced non- small cell lung cancer (NSCLC). Plasma ctDNA genotyping approaches (also known as “liquid biopsies”) are now used routinely to noninvasively test for key cancer genotypes (EGFR, KRAS, ALK, ROS1, etc), both to guide initial systemic treatment or to effectively target drug resistance. The quantitative nature of this diagnostic creates obvious potential for use as a noninvasive tool for monitoring treatment response, a phenomenon we and others have shown retrospectively but an approach which is inadequately being leveraged clinically. Our preliminary data suggests that plasma ctDNA response is a highly dynamic marker, offering rapid insight into treatment effect, earlier and potentially more sensitively than standard response imaging. In an era with an increasing number and variety of cancer therapies, nimble tools for evaluating treatment benefit may help us better assess therapies and get patients onto the best treatments. Our group at DFCI is uniquely positioned to translate plasma genomics into a clinical response biomarker for NSCLC care. We have led the clinical validation of numerous ctDNA genotyping assays, while simultaneously characterizing the complexities and limitations of ctDNA genomics. In parallel, we have a strong track record in studying radiographic response as a translational tool and trial endpoint. Our group is unique in its focus on the clinical application of novel diagnostics, with a deep understanding of the clinical decision points and the necessary diagnostic performance. Building off this experience, we have an opportunity now to address a critical scientific gap and inform the scientific community on (1) what constitutes a plasma response, (2) what does a plasma response signify, and (3) how should plasma response be used as a patient-level and trial-level diagnostic. In this application, we first plan to quantify the clinical variation of ctDNA levels in patients with NSCLC starting a new therapy and, using existing trial and clinical cohorts, identify and validate a plasma response cutpoint which reliably and robustly predicts for benefit from therapy. In parallel, we will perform a trial-level analysis of plasma response in a cohort of 11 expansion cohorts from 8 clinical trials in EGFR- and KRAS- mutant NSCLC, all with plasma being banked at DFCI, to understand the optimal timing of plasma response as well as its ability to predict trial outcome (radiographic response rate). Finally, we will launch a therapeutic trial of first-line immunotherapy in advanced NSCLC which uses plasma response assessment to adaptively guide intensification of treatment, a paradigm-shifting approach which, if successful, has the potential to motivate a new generation of trials using plasma ctDNA monitoring to effectively evolve the treatment of cancer patients. Together, these studies will lay the groundwork for ctDNA-based response assessment as a widely available tool for guiding patient care and for clinical trial analysis.