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Longitudinal methylated ctDNA increases predict immunotherapy progression across solid tumors
Journal article   Open access   Peer reviewed

Longitudinal methylated ctDNA increases predict immunotherapy progression across solid tumors

Muhammad Anees, Patrick L. Wagner, Ashten Omstead, Erin Grayhack, Christopher Sherry, Lee D. McDaniel, Matthew G. Varga, Seyed Mohammad Hossein Hosseiny, William Laframboise, John Nakayama, …
Journal of Liquid Biopsy, v 13, 100477
01 Sep 2026
DOI: https://doi.org/10.1016/j.jlb.2026.100477
PMID: 42395173
Featured in Collection :   Drexel's Newest Publications
url
https://doi.org/10.1016/j.jlb.2026.100477View
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Abstract

ctDNA DNA methylation Immune checkpoint inhibitors Liquid biopsy Northstar Pan-cancer Response monitoring Tumor-naive assay
Timely identification of treatment failure during immune checkpoint blockade remains a critical unmet need in oncology. We evaluated a tissue-free, methylation-based circulating tumor DNA (ctDNA) assay applied serially across 142 patients with advanced solid tumors receiving immune checkpoint inhibitor monotherapy or chemo-immunotherapy in two independent prospective cohorts. Blood was collected pre-treatment, C2D1, and C3D1. Molecular progression, mPD, was defined as an increase in ctDNA while on therapy. mPD stratified progression-free and overall survival across both cohorts (PFS HR 5.8 95% CI 3.4-9.9; OS HR 4.1 95%CI 2.3-7.0). Notably, incorporating ctDNA at C2 identified more molecular rebounders, and mPD was significant for OS in RECIST 6-month BOR stable disease subgroup where imaging is least informative (HR 8.4, 95% CI 1.4 to 48.7). Monitoring with ctDNA continued to predict progression after C3 and identified progression with median lead time of 62 days. These findings confirm prior studies that have shown that ctDNA is predictive for immunotherapy response and furthermore demonstrate the utility of a clinically practical molecular progression rule across the multiple cancer types treated by immune checkpoint inhibitors.

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