Methylation-Based ctDNA Tumor Fraction Changes Predict Long-Term Clinical Benefit From Immune Checkpoint Inhibitors in RADIOHEAD, a Real-World Pan-Cancer Study.

Current response evaluation methods have accuracy limitations. Monitoring with a ctDNA methylation-based tumor fraction (TF) may provide a more accurate assessment of tumor burden across solid tumors. In this study, we evaluate a tissue-free, methylation-based TF and explore the association with treatment outcomes in RADIOHEAD, a cohort of 1,070 patients with solid tumors receiving standard-of-care immune checkpoint inhibition (ICI) regimens, with blood samples collected prospectively for retrospective analysis. A total of 1,997 baseline and serial on-treatment plasma samples from 627 patients with stage IV cancer were analyzed with an analytically validated next-generation sequencing methylation-based ctDNA assay (Guardant Reveal). The primary outcome measure was real-world progression-free survival (rwPFS). Secondary outcomes included real-world overall survival (rwOS) and the lead time between nonmolecular response (nMR) to rwPFS event. Patients with any decrease in TF while receiving ICI had superior outcomes. Patients with ≥80% decrease in TF at two timepoints or TF below the limit of quantification had longer rwPFS and rwOS than those with <80% decrease [nMR; rwPFS HR, 0.24 (95% confidence interval, 0.19-0.32) P < 0.005; rwOS HR, 0.28 (95% confidence interval, 0.21-0.38) P < 0.005]. nMR was detected prior to clinical progression in 209 patients with a median lead time of 3.03 months. Among 627 patients with stage IV cancer receiving standard-of-care ICI, monitoring with methylation-based TF identified patients who have significantly longer rwPFS and rwOS. Changes in TF on ICI can provide additional response data earlier than imaging alone and support the potential of serial monitoring to inform treatment decisions.

Significance: This study found that early decreases in tumor DNA levels in the blood are linked to longer survival in patients with cancer treated with immunotherapy. These findings support the use of blood-based monitoring to help predict treatment response and improve decision-making in real-world cancer care.