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

项目总结 新疗法的开发是改善全球癌症结果的核心。不过，目前 用于获取这些新疗法的临床益处的指标可能并不总是获取治疗成功或 失败了。拟议研究的首要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指标相结合，如血浆循环肿瘤DNA的变化 (CtDNA)在接受新疗法的患者中。拟议的研究建立在临床原则证明的基础上，通过 研究小组使用减少变异等位基因的下一代ctDNA测序(NGS) 可在常规放射学反应之前观察所选改变的频率(VAF)，并且 VAF的增加通常发生在放射进展前几周到几个月。在基础上建设 在NGS中，MSK-ACCESS是一种高度敏感的深度测序液体活组织检查方法，最近由 调查小组基于FDA授权的对应物MSK-Impact对肿瘤组织进行的研究，这 能够识别可作为药物靶点的可操作的基因改变。此外， 研究建立在调查团队的丰富经验基础上，对#年的活动进行“篮子试验”评估。 精确的基因组驱动和免疫调节疗法，其入选标准是假定的 与癌症类型无关的生物标记物，这使得连续收集共同临床试验ctDNA变得更加重要 样本和MSK对肿瘤组织的影响测试，提供了一个基线基因组图谱来指导 基于ctDNA的疾病监测。预期收集的ctDNA样本的多样性和广泛性 在这些试验中提供的时间点可以与监管级别的治疗前、治疗中、 以及通过计算机断层扫描(CT)和/或磁共振成像进行后处理成像评估 (MRI)和正电子发射断层扫描(PET)。具体目标1：评估早期和早期的相关性 对常规和高级治疗反应最好的ctDNA变异等位基因频率(VAF)的变化 早期靶向或免疫调节性临床试验中的影像评估。具体目标2：确定是否 血浆ctDNA趋势可以更准确地预测纵向临床益处(以无进展衡量 存活)在早期阶段通过RECIST进行的稳定型疾病的广泛反应类别的患者 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数时间 最初受益于靶向或免疫调节治疗的患者的放射进展(即， 在早期临床试验中，完全/部分反应或稳定的疾病为最佳总体反应)。影响： 这项研究的见解将为集成先进的成像和基于ctDNA的生物标记物奠定基础。 在未来，全球各地的监管机构可能会使用这些信息来评估和 批准新的精准疗法，并最终使个性化精准医学成为可能。

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.