Immune-related adverse event profiles and survival outcomes in non–small cell lung cancer: a cluster analysis from a long-term real-world study

BACKGROUND: Immune-related adverse events (irAEs) are heterogeneous in patients with non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICIs). This study aimed to characterize post-treatment irAE phenotypes and explore their temporal and survival associations. METHODS: We retrospectively analyzed 202 patients with pathologically confirmed NSCLC who received at least two cycles of ICI therapy. Mixed irAE features were integrated using factor analysis of mixed data (FAMD) and clustered by K-means. Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier and landmark analyses. Time-dependent Cox models were used to account for delayed irAE-cluster formation, and Fine-Gray models evaluated baseline predictors of irAE occurrence with death treated as a competing event. RESULTS: FAMD-based clustering identified five descriptive post-treatment irAE phenotypes: multiorgan non-hepatic/gastrointestinal, hepatic/gastrointestinal-enriched multiorgan, irAE-negative, other/atypical, and thyroid-dominant endocrine phenotypes. Conventional Kaplan-Meier analysis showed longer observed OS in patients with any irAE than in those without irAEs (median OS, 30.5 vs. 20.0 months; hazard ratio, 0.68; 95% CI, 0.47-0.99). However, survival patterns differed across irAE phenotypes, and PFS did not differ significantly by irAE occurrence or across clusters. In time-dependent Cox analyses, the hepatic/gastrointestinal-enriched multiorgan phenotype was consistently associated with poorer subsequent OS, highlighting heterogeneity beyond overall irAE occurrence. Fine-Gray analyses identified radiotherapy and older age as baseline factors associated with a higher cumulative incidence of irAEs. Cluster stability analyses showed acceptable overall reproducibility, although smaller clusters required cautious interpretation. CONCLUSIONS: Data-driven irAE phenotypes captured heterogeneity in the timing and organ distribution of immune toxicity among ICI-treated NSCLC patients. Integrating irAE organ distribution and timing may provide exploratory prognostic information beyond overall irAE occurrence, but these findings should be interpreted cautiously because irAE clusters were post-treatment phenotypes and may be influenced by treatment exposure and survivorship.