Abstract 6558: Ultra-sensitive ctDNA detection predicts response to immune checkpoint inhibition in advanced melanoma patients
Authors: Gebhardt Christoffer , Keller Laura , Heidrich Isabel , Koett Julian , Geidel Glenn , Smit Daniel J. , Simon Ronald , Schneider Stefan W. , Pugh Jason , Abbott Charles W. , Boyle Sean , Chen Richard O. , Pantel Klaus 
Published: March 2024

Abstract
Immune checkpoint inhibition (ICI) provides clinical benefit to a subset of cancer patients. Monitoring circulating tumor DNA (ctDNA) in peripheral blood may allow clinicians to predict ICI response or resistance earlier than imaging and track response more frequently. In this study, melanoma patients receiving ICI were profiled using an ultra-sensitive, tumor-informed ctDNA detection platform, and the findings were correlated with clinical outcome. In this retrospective study, 188 plasma samples were collected from 23 advanced melanoma patients receiving immune checkpoint inhibitor (ICI) treatment, spanning a period of up to 40 months. Levels of ctDNA were then profiled using the NeXT Personal® assay. NeXT Personal is a liquid biopsy platform that utilizes whole-genome sequencing of tumor and normal samples to create a customized panel for each patient, encompassing up to 1,800 genetic somatic variants. This enables the detection of molecular residual disease (MRD) down to a limit of detection (LOD) of 1-3 parts per million (PPM). We subsequently compared the results obtained through NeXT Personal with RECIST-defined measurements and clinical outcomes. Ultra-sensitive ctDNA detection was achieved across a wide dynamic range, spanning from 2.3 PPM to over 130,000 PPM (median LOD = 2 PPM). A significant number of detections were attained at low PPM levels, with 30% (31/105) occurring below 100 PPM and 25% (26/105) occurring below 50 PPM. 94% (17/18) of baseline samples were ctDNA+ among patients without recent second-line therapy, including all patients who progressed. All ctDNA+ detections aligned with imaging results that indicated the presence of tumor. Likewise, all plasma timepoints corresponding to complete responses (CR) assessed via RECIST were ctDNA-. Early increase in ctDNA from baseline to treatment cycle 3 significantly predicted PFS (log-rank 0.003; Wald p=0.01, HR=8.35, 95% CI 1.62-43.15). Survival was predicted by both imaging CR (log-rank p=0.018) and ctDNA clearance (log-rank p=0.003). Molecular progression, defined as a 20% increase in ctDNA, significantly predicted OS (log-rank p=0.023), whereas imaging PD status did not predict OS (log-rank p=0.09). We achieved detection of ctDNA with an LOD down to 1.3 PPM in this cohort, with nearly a third of detections occurring below 100 PPM, suggesting the importance of an ultra-sensitive ctDNA approach even in late stage patients. Our findings suggest that ctDNA changes arepredictive of ICI response in late stage melanoma. These results highlight the potential for patient-specific ctDNA monitoring to inform patient management and for clincal trial design.
Citation Format: Christoffer Gebhardt, Laura Keller, Isabel Heidrich, Julian Koett, Glenn Geidel, Daniel J. Smit, Ronald Simon, Stefan W. Schneider, Jason Pugh, Charles W. Abbott, Sean Boyle, Richard O. Chen, Klaus Pantel. Ultra-sensitive ctDNA detection predicts response to immune checkpoint inhibition in advanced melanoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6558.