Changes in circulating tumor DNA (ctDNA) and outcomes in solid tumors treated with immune checkpoint inhibitors (ICIs).

Abstract

2544 Background: Quantification of ctDNA levels can be a reliable prognostic tool in several malignancies. More recently, detection of genomic alterations in ctDNA have been validated as a predictive biomarker to guide treatment planning. Dynamic changes in ctDNA levels over time and in response to treatment may also provide prognostic information. However, less is known about the value of changes to ctDNA levels in response to immune checkpoint inhibitors (ICIs). Methods: We searched MEDLINE (host:PubMed) and reviewed trials exploring outcomes of patients with advanced solid tumors receiving ICIs in which outcomes were reported based on changes to ctDNA levels. ctDNA clearance was defined as reported in individual trials. Typically, this was defined as either >50% reduction or a reduction to undetectable levels. We extracted progression free survival (PFS) and/or overall survival (OS) values, related 95% Confidence intervals (CI) and/or p-values. Data were then included in a meta-analysis utilizing the generic inverse variance and random effects model. Variation in effect size was examined using random effects meta-regression analysis. Results: A total of 17 trials were included in the meta-analysis; ctDNA levels were detectable in all participants in all studies prior to initiation of ICIs. Method of detection included next generation sequencing and/or droplet digital polymerase chain reaction assays. Overall, low to undetectable ctDNA levels, measured 6-16 weeks after starting treatment was associated with significantly better PFS, (HR 0.20 95% CI, 0.14-0.28; p<0.001). Similarly, OS was superior in patients with substantially reduced or undetectable ctDNA levels after receiving ICIs, (HR 0.18, 95% CI, 0.12-0.26; p<0.001. The results were consistent across all disease sites, lines of treatment, level of change (undetectable vs. >50% reduction) and whether treatment exposure comprised single or multiple ICIs (see Table). Conclusions: In unselected advanced solid tumors, a substantial fall in ctDNA levels in response to ICIs is associated with substantial improvements in both PFS and OS. ctDNA change is an early response biomarker which may allow for de-escalation of cross-sectional imaging in patients receiving ICIs, or support treatment de-escalation strategies. Further research is needed to quantify variations in sensitivity between the available NGS assays, as well as differences discovery range between assay platforms. [Table: see text]