Clinical trials on icotinib, a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), have shown promising results as targeted therapy for non-small cell lung cancer (NSCLC). This study aimed to establish an effective scoring system to predict the one-year progression-free survival (PFS) of advanced NSCLC patients with EGFR mutations treated with icotinib as targeted therapy. A total of 208 consecutive patients with advanced EGFR-positive NSCLC treated with icotinib were enrolled in this study. Baseline characteristics were collected within 30 days before icotinib treatment. PFS was taken as the primary endpoint and the response rate as the secondary endpoint. Least absolute shrinkage and selection operator (LASSO) regression analysis and Cox proportional hazards regression analysis were used to select the optimal predictors. We evaluated the scoring system using a five-fold cross-validation. PFS events occurred in 175 patients, with a median PFS of 9.9 months (interquartile range, 6.8-14.5). The objective response rate (ORR) was 36.1%, and the disease control rate (DCR) was 67.3%. The final ABC-Score consisted of three predictors: age, bone metastases and carbohydrate antigen 19-9 (CA19-9). Upon comparison of all three factors, the combined ABC-score (area under the curve (AUC)= 0.660) showed a better predictive accuracy than age (AUC = 0.573), bone metastases (AUC = 0.615), and CA19-9 (AUC = 0.608) individually. A five-fold cross-validation showed good discrimination with AUC = 0.623. The ABC-score developed in this study was significantly effective as a prognostic tool for icotinib in advanced NSCLC patients with EGFR mutations.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10637-023-01329-8.