Using a Pharmacokinetic Model to Design and Evaluate an Early ctDNA Biomarker for Response to Targeted Therapy

Early prediction of response to therapy or lack thereof can help physicians plan treatment more efficiently. Biomarkers based on circulating tumor DNA (ctDNA) are promising. However, biomarkers beyond direct comparison to baseline have not been thoroughly explored. We develop a model for ctDNA shedding under targeted therapy that incorporates pharmacokinetics. Using a simulated cohort of virtual patients with varied parameters, we define and analyze a biomarker based on ctDNA samples at baseline, 12 hours, and 24 hours after initiation of treatment. The biomarker identified patients who would achieve partial or complete response with high sensitivity and specificity and was able to match the performance of a neural network classifier. Our result highlights the potential of ctDNA as a biomarker and underlines the importance of early ctDNA data collection.