Integration of Imaging and Circulating Plasma Cell-Free DNA Sequencing Using MSK-ACCESS to Monitor Treatment Response and Predict Progression in Patients With Multiple Cancers on Targeted Therapy

项目摘要 新疗法的开发是改善全球癌症预后的核心。但目前 用于获取这些新疗法的临床获益的指标可能并不总是获取治疗成功， 失败拟议研究的总体目标是通过利用以下指标来提高精度， 将成像与其他肿瘤反应测量（如血浆循环肿瘤DNA的变化）相结合 在接受新疗法的患者中检测ctDNA。拟议的研究建立在临床原理验证的基础上， 研究小组使用下一代ctDNA测序（NGS）， 选择性改变的频率（VAF）可以在常规放射学反应之前观察到， VAF的增加通常发生在放射学进展前几周到几个月。建立在基础之上 作为NGS的一部分，MSK-ACCESS是一种高度敏感的深度测序液体活检检测方法，最近由美国国家生物技术研究所开发， 研究小组基于其FDA授权的对应MSK-IMPACT对肿瘤组织进行了研究， 能够识别可以用药物靶向的可操作的遗传改变。另夕h 研究建立在调查小组在“篮子试验”方面的广泛经验基础上， 精确的基因组驱动和免疫调节治疗，其中招募标准是一个假定的 生物标志物，无论癌症类型如何，这使得连续收集共同临床试验ctDNA变得更加重要 沿着对肿瘤组织的MSK-IMPACT检测，提供基线基因组图谱，以指导 基于ctDNA的疾病监测。前瞻性收集的ctDNA样本的多样性和广泛性 这些试验提供了可以与监管级别治疗前、治疗中 以及通过计算机断层扫描（CT）和/或磁共振成像进行的进展后成像评估 (MRI)和正电子发射断层扫描（PET）。具体目标1：评估早期 ctDNA变异等位基因频率（VAF）的变化，对常规和先进治疗的最佳反应 早期靶向或免疫调节临床试验中的成像评估。具体目标2：确定 血浆ctDNA趋势可以更精确地预测纵向临床益处（通过无进展性 生存期），在早期阶段通过RECIST属于疾病稳定的广泛缓解类别的患者中 临床试验具体目标3：确定ctDNA水平升高预示最终死亡的中位时间 最初受益于靶向或免疫调节治疗的患者的放射学进展（即， 完全/部分反应或稳定的疾病作为最佳总体反应）。影响：The 这项研究的见解将为整合先进的成像和基于ctDNA的生物标志物奠定基础 在未来，地球仪的监管机构可能会使用这些信息来评估和 批准新的精确治疗，并最终实现个性化精确医疗的可能性。

PROJECT SUMMARY The development of novel therapies is at the core of improving cancer outcomes worldwide. However, currently used metrics to capture clinical benefit of these novel therapies may not always capture treatment success or failure. The overarching goal of the proposed research is to increase precision by leveraging metrics that integrate imaging with other measures of tumor response such as changes in plasma circulating tumor DNA (ctDNA) in patients undergoing novel therapies. The proposed research builds on clinical proof-of-principle by the investigative team using next-generation sequencing (NGS) of ctDNA that decreases in variant allele frequency (VAF) of selected alterations can be observed prior to conventional radiologic response, and that increases in VAF often occur several weeks to months before radiologic progression. Building on the foundation of NGS, MSK-ACCESS, a highly sensitive deep sequencing liquid biopsy assay, was recently developed by the investigative team based on its FDA-authorized counterpart MSK-IMPACT performed on tumor tissue, which enables the identification of actionable genetic alterations that can be targeted with drugs. Additionally, the research builds upon extensive experience of the investigative team with “basket trials” evaluating the activity of precision genome-driven and immunomodulatory therapies, whereby the enrolling criterion is a putative biomarker regardless of cancer type, which has put a premium on serially collecting co-clinical trial ctDNA samples along with MSK-IMPACT testing on the tumor tissue, providing a baseline genomic profile to guide ctDNA-based disease monitoring. The diverse and extensive collection of prospectively collected ctDNA samples within these trials provides timepoints that can be compared to regulatory grade pre-treatment, on-treatment, and post-progression imaging assessments via computed tomography (CT) and/or magnetic resonance imaging (MRI), and positron emission tomography (PET). Specific Aim 1: To evaluate the correlation between early changes in ctDNA variant allele frequencies (VAF) with best response to therapy via conventional and advanced imaging assessments in early-phase targeted or immunomodulatory clinical trials. Specific Aim 2: To identify if plasma ctDNA trends can more precisely predict longitudinal clinical benefit (measured by progression-free survival) in patients who fall within the broad response category of stable disease via RECIST in early-phase clinical trials. Specific Aim 3: To identify the median time prior to which rising ctDNA levels presages eventual radiologic progression in patients who initially benefit from targeted or immunomodulatory therapy (i.e., complete/partial response or stable disease as best overall response) in early-phase clinical trials. Impact: The insights from this study will lay the groundwork for integrating advanced imaging and ctDNA-based biomarkers in the future that may be used by regulatory agencies around the globe for the purpose of assessing and approving novel precision therapies and ultimately allow the possibility for personalized precision medicine.