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

患者血浆肿瘤 DNA 的早期变化以及晚期肺癌的试验水平诊断

• 批准号: 9973740
• 负责人: Cloud Peter Paweletz
• 金额: $ 52.08万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9973740
• 关键词: Address; Adopted; Advanced Malignant Neoplasm; Biological; Biological Assay; Biological Markers; Biopsy; Blood; Blood Tests; Cancer Patient; Caring; Clinical; Clinical Trials; Communities; Complement; DNA analysis; Dana-Farber Cancer Institute; Data; Development; Diagnostic; Diagnostic radiologic examination; Drug Targeting; Drug resistance; Effectiveness; Epidermal Growth Factor Receptor; FDA approved; Generations; Genomics; Genotype; Grant; Image; Immuno-Chemotherapy; Immunotherapy; Intuition; Investigational Therapies; KRAS2 gene; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Measures; Methods; Molecular; Monitor; Mutation; Nature; Non-Small-Cell Lung Carcinoma; Oncogenes; Oral; Outcome; Patient Care; Patients; Performance; Pharmaceutical Preparations; Plasma; Positioning Attribute; ROS1 gene; Research Personnel; Specimen; Test Result; Testing; Therapeutic Trials; Translating; Treatment outcome; Validation; Variant; base; cancer care; cancer imaging; cancer therapy; chemotherapy; clinical application; clinical trial analysis; cohort; effective therapy; experience; improved; innovation; insight; liquid biopsy; mutant; next generation sequencing; novel diagnostics; novel therapeutics; response; response biomarker; targeted treatment; therapy outcome; tool; treatment effect; treatment response; tumor; tumor DNA

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.

项目摘要 循环肿瘤DNA的早期变化作为晚期肺癌患者和试验水平的诊断 主要研究者：Geoffrey R.医学博士奥克斯纳德 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“液体活检”）是 现在常规用于非侵入性检测关键癌症基因型（EGFR、KRAS、ALK、ROS 1等）， 指导初始全身治疗或有效地针对耐药性。这种定量的性质 诊断创造了明显的潜力，作为一种非侵入性的工具，用于监测治疗反应， 我们和其他人已经回顾了这种现象，但这种方法并不充分， 在临床上使用。我们的初步数据表明，血浆ctDNA反应是一个高度动态的标志物， 提供对治疗效果的快速洞察，比标准反应更早且可能更敏感 显像在一个癌症治疗数量和种类不断增加的时代， 治疗效益可以帮助我们更好地评估治疗方法，并让患者接受最佳治疗。 我们在DFCI的团队具有独特的优势，可以将血浆基因组学转化为临床反应 NSCLC治疗的生物标志物。我们领导了众多ctDNA基因分型检测的临床验证， 同时表征ctDNA基因组学的复杂性和局限性。同时，我们有一个 在研究放射学反应作为转化工具和试验终点方面有良好的记录。我们集团 独特之处在于其专注于新型诊断的临床应用，对临床 决策点和必要的诊断性能。基于这一经验，我们有一个 现在有机会解决一个关键的科学差距，并告知科学界（1）什么是一个 血浆反应，（2）血浆反应意味着什么，以及（3）如何将血浆反应用作 患者级和试验级诊断。 在本申请中，我们首先计划定量NSCLC患者中ctDNA水平的临床变化， 开始新的治疗，并使用现有的试验和临床队列，确定和验证血浆应答 可靠且稳健地预测治疗获益的临界点。与此同时，我们将执行一个试验级 EGFR-和KRAS-的8项临床试验的11个扩展队列的血浆缓解分析 突变型NSCLC，所有患者的血浆均储存在DFCI，以了解血浆缓解的最佳时间， 以及其预测试验结果的能力（放射学反应率）。最后，我们将启动一项治疗试验， 晚期NSCLC的一线免疫治疗，使用血浆反应评估自适应地指导 强化治疗，这是一种范式转变方法，如果成功，有可能激发一种 使用血浆ctDNA监测的新一代试验，以有效地发展癌症患者的治疗。 总之，这些研究将为基于ctDNA的反应评估奠定基础， 用于指导患者护理和临床试验分析的工具。