Abstract: Objective To evaluate the prognostic significance of C-PLAN index, comprising C-reactive protein (CRP), performance status (PS), lactate dehydrogenase (LDH), albumin (ALB), and derived neutrophil-to-lymphocyte ratio (dNLR), in patients with advanced non-small cell lung cancer (NSCLC) after first-line immunotherapy.Methods A total of 411 patients who were initially diagnosed with advanced NSCLC and received immunotherapy at the Affiliated Hospital of Xuzhou Medical University between January 2019 and January 2024. The patients were randomly divided into a training cohort (n=288) and a validation cohort (n=123) in a 7:3 ratio. The C-PLAN index was calculated within pre-treatment 7 days and at week 6 post-treatment. Progression-free survival (PFS) and overall survival (OS) were recorded during follow-up. Both cohorts were compared for clinical and pathological characteristics, and the association between C-PLAN index and treatment efficacy was analyzed. Kaplan-Meier survival curves were plotted, and the log-rank test was used to assess survival differences. Univariate and multivariate Cox regression analyses were performed on the training cohort to construct prediction models, and receiver operating characteristic (ROC) curves and calibration curves were plotted to evaluate prediction performance.Results In the training cohort, the objective response rate (ORR) and disease control rate (DCR) were 30.6% and 41.0%, respectively; in the validation cohort, ORR and DCR were 34.1% and 44.7%. Both pre-treatment and week 6 post-treatment, both high and low C-PLAN indexes were significantly associated with ORR and DCR (P<0.05), with lower C-PLAN indexes correlating with prolonged PFS and OS. In the prediction models, the pre-treatment C-PLAN index contributed most to PFS prediction, while the post-treatment C-PLAN index was most influential for OS prediction, indicating its potential as a robust prognostic indicator.Conclusions The C-PLAN index can serve as an effective prognostic factor for advanced NSCLC patients undergoing immunotherapy.