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

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.