Although circulating tumor DNA (ctDNA) dynamics have been widely explored for therapeutic response assessment, standardized methodologies remain elusive. Here, we developed MinerVa-Delta, a novel approach to quantify ctDNA dynamics by calculating weighted mutation changes in samples with multiple tracked variants.MinerVa-Delta was developed and analytically validated using serially diluted reference samples. The optimal cutoff was determined in a discovery cohort of 227 patients with advanced lung squamous cell carcinoma (LUSC) receiving programmed cell death protein 1 blockade plus chemotherapy or chemotherapy alone and further validated in an independent cohort of 97 patients with LUSC treated with chemotherapy alone. Variants were de novo called in pretreatment samples using a 769-gene next-generation sequencing panel, serving as a basis for personalized variant tracking in posttreatment plasma after two cycles of treatment. We applied MinerVa-Delta to evaluate prognosis and therapeutic response in advanced LUSC.Patients classified as molecular responders (MinerVa-Delta <30%) exhibited significantly improved outcomes compared with nonresponders (MinerVa-Delta ≥30%), with superior progression-free survival (hazard ratio = 0.19, p < 0.001) and overall survival (hazard ratio = 0.24, p < 0.001). MinerVa-Delta displayed consistent prediction performance in the validation cohort. Furthermore, MinerVa-Delta accurately identified radiologic stable disease patients, a clinically heterogeneous population, who could benefit from initial treatment.Our findings suggest MinerVa-Delta is feasible for evaluating treatment response in patients with advanced LUSC. Integrating ctDNA profiling with conventional imaging could enhance response assessment, particularly in radiologic stable disease patients, enabling more precise therapeutic decision-making.Copyright © 2025 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.