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.
