Cone-beam computed tomography (CBCT) images acquired during radiotherapy may allow early response assessment. Previous studies have reported inconsistent findings on an association of CBCT-measured tumor volume changes with clinical outcomes. The purpose of this pilot study was twofold: (1) to characterize changes in CBCT-based radiomics features during treatment; and (2) to quantify the potential association of CBCT-based delta-radiomics features with overall survival in locally advanced lung cancer. We retrospectively identified 23 patients and calculated 658 radiomics features from each of 11 CBCT images per patient. Feature selection was performed based on repeatability, robustness against contouring uncertainties, and non-redundancy. We calculated the coefficient of determination (R 2) for the relationship between the actual feature value at the end of treatment and predicted value based on linear models fitted using features between the first and kth fractions. We also quantified the predictive ability for survival with two methods by: (1) comparing delta-radiomics features (defined as the mean change between the first and kth fractions) between two groups of patients divided by a cutoff survival time of 18 months using the t-test or Wilcoxon rank-sum test; and (2) quantifying univariate discrimination of two groups divided by the median of delta-radiomics feature. All selected seven radiomics features during treatment (as early as the 10th fraction) were predictive of those at the end of treatment (R 2 > 0.64). Three delta-radiomics features demonstrated significant differences (q < 0.05, as early as the 10th fraction) between the two groups of patients divided by the cutoff survival time. Two of those three features were also predictive of survival according to the log-rank statistics. We provided the first demonstration of a potential association of CBCT-based delta-radiomics features early during treatment with overall survival in locally advanced lung cancer. Our preliminary findings should be validated for a larger cohort of patients.