Frequent monitoring of NSCLC immunotherapy using an mDETECT liquid biopsy to identify therapy response and progression compared to CT scans.

Abstract

e14532 Background: Response to immunotherapy in metastatic non-small cell lung cancer (NSCLC) is heterogeneous, and early identification of non-responders remains a clinical challenge. The methylation DETEction of Circulating Tumour DNA (mDETECT) assays are targeted DNA methylation-based Next Generation Sequencing liquid biopsies. We have developed a version of our mDETECT assay that sensitively and quantitatively monitors NSCLC. The mDETECT NSCLC assay has a 95% sensitivity at 95% specificity with an AUC of 0.95. With only 2 million reads required per sample, multiple samples can be sequenced at the same time allowing for more frequent testing. Methods: We conducted a pilot observational study to frequently measure tumour dynamics in patients undergoing first-line pembrolizumab monotherapy for metastatic NSCLC. 19 participants were recruited prior to the initiation of immunotherapy with blood being collected pretreatment then weekly or biweekly after treatment initiation with some patients being followed for up to 2.3 years. In total we collected 226 samples (median 11.8 timepoints per patient). Radiological assessment was performed approximately every three months as per the standard of care. Results: The primary aim of the study was to determine if overall survival (OS) could be predicted with the mDETECT assay within the first 6 weeks of treatment. Patients were divided by short ( < 1 year), medium (1-4 years), and long term ( > 4 years) OS. Patients with short OS showed constant or increasing mDETECT levels and never dropped below 80% of their pre-treatment mDETECT level. Patients with long OS showed an immediate decrease within the first 6 weeks of treatment and generally reached undetectable levels. Patients with medium OS showed a slower decline and a higher steady state level than the long OS patients. Continued monitoring revealed progression in some initially responding patients, with increasing mDETECT levels detected 4-6 months in advance of radiological progression. Eight patients had CT imaging available for analysis. Five of eight patients had concordance between ctDNA kinetics and radiological response to immunotherapy. Conclusions: These patterns, while derived from a small pilot cohort, suggest the mDETECT assay can determine within weeks of treatment initiation if a patient is responding to immunotherapy. Frequent assessment of tumour burden by a liquid biopsy such as mDETECT offers the opportunity to modify treatments earlier than radiology alone and to do so on an ongoing basis. These findings support the feasibility and potential clinical utility of integrating frequent methylation-based ctDNA monitoring into immunotherapy management workflows and justify further prospective validation in a larger study.