Circulating cell free tumor DNA (ctDNA) in patients with immune checkpoint inhibitor associated inflammatory arthritis (ICI-IA): developing a biomarker to assess immunosuppressive drug safety

PROJECT SUMMARY Immune checkpoint inhibitors (ICI) are monoclonal antibodies that block regulators of T cell activation, activating anti-cancer immunity and greatly improving overall survival in patients with advanced cancer. However, ICI commonly cause immune related adverse events (irAE), including inflammatory arthritis (ICI-IA). It is estimated that as many as 14,000 ICI-treated patients will develop ICI-IA each year. ICI-IA can i. be destructive to the joint, ii. persist for months to years, and iii. require treatment with glucocorticoids and immunosuppressive disease modifying antirheumatic drugs (DMARDs). However, immunosuppression may worsen cancer survival in this setting. Identifying the safest approach to ICI-IA management (with regard to tumor control) is a critical unmet need. However, cancer recurrence is measured on radiographic imaging which is often performed months after ICI-IA treatment is initiated and this makes it difficult to disentangle which medication or intervention may have been responsible. In this study, we use MRD-EDGE, a new ultra- sensitive approach to measure circulating cell free tumor DNA (ctDNA) and identify patients with cancer recurrence long before it is demonstrated on standard of care radiographic imaging. MRD-EDGE couples whole genome sequencing with deep learning approaches to provide a tumor fraction detection sensitivity as low as 10-5 and allow tracking of cancer ctDNA over time, even in patients with a low tumor burden. Even more critically, this approach does not require reference to matched tumor tissue. This is important because simultaneous tumor sampling is impractical in most clinical settings (e.g., rheumatology clinic). This study takes advantage of plasma samples from patients enrolled in one of two large prospective ICI-IA registries, the Hospital for Special Surgery rheumatic irAE Registry (2018-2022), and the multicenter Rheumatology Adverse Events Due to Immunotherapy Observational Study (RADIOS) registry (first enrollment 1/2023). In Aim 1, we measure ctDNA levels in patients with melanoma or non-small cell lung cancer (NSCLC) at their first visit for ICI-IA to quantify the association between ctDNA and subsequent cancer progression. In Aim 2, we measure changes in ctDNA from baseline to weeks 4, 8 and 12 after institution of glucocorticoids in ICI-IA patients, to assess the sensitivity of this biomarker to the effects of immunosuppression, and the kinetics of change. Our overarching hypothesis is that ctDNA can be detected in patients with ICI-IA long before cancer progression is demonstrated on imaging, and that any rise in ctDNA will be detectable within 4 weeks of initiating glucocorticoids. This study will provide preliminary data and optimal plasma sampling times for a future interventional study (e.g., comparing up-front glucocorticoids to up-front IL6R inhibition for high-grade irAE). If effect sizes are small, we will plan a much larger multicenter observational study powered to assess ctDNA levels before and after steroid-sparing immunosuppressive agents including IL6 and TNF inhibitors.