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ObjectiveTo explore prognostic indicators of lung adenocarcinoma with leptomeningeal metastases (LM) and provide an updated graded prognostic assessment model integrated with molecular alterations (molGPA).MethodsA cohort of 162 patients was enrolled from 202 patients with lung adenocarcinoma and LM. By randomly splitting data into the training (80%) and validation (20%) sets, the Cox regression and random survival forest methods were used on the training set to identify statistically significant variables and construct a prognostic model. The C-index of the model was calculated and compared with that of previous molGPA models.ResultsThe Cox regression and random forest models both identified four variables, which included KPS, LANO neurological assessment, TKI therapy line, and controlled primary tumor, as statistically significant predictors. A novel targeted-therapy-assisted molGPA model (2022) using the above four prognostic factors was developed to predict LM of lung adenocarcinoma. The C-indices of this prognostic model in the training and validation sets were higher than those of the lung-molGPA (2017) and molGPA (2019) models.ConclusionsThe 2022 molGPA model, a substantial update of previous molGPA models with better prediction performance, may be useful in clinical decision making and stratification of future clinical trials.