Association of Immune‐Related Adverse Events and the Efficacy of Immune Checkpoint Inhibitors in Non‐Small Cell Lung Cancer: Adjusting for Immortal Time Bias

ABSTRACT Background Associations between immune‐related adverse events (irAEs) and survival outcomes in non‐small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) remain controversial, partly due to inconsistencies in dealing with immortal time bias (ITB). To address this, we adjusted for ITB in this single‐center retrospective study. Methods We included 129 patients with advanced NSCLC receiving ICIs as first‐line therapy and assessed associations between irAE development and progression‐free survival (PFS) and overall survival (OS). To mitigate ITB, we performed landmark analyses at 30, 42, and 75 days and used multivariable Cox models with irAEs as a time‐dependent covariate. Results During a median follow‐up of 9.7 months, 58 (45.0%) patients developed irAEs. Unadjusted analyses showed a significant association between irAEs and longer PFS (hazard ratio HR 0.55; p < 0.01) and OS (HR 0.42; p < 0.01), but this was no longer evident after adjusting for ITB. Specifically, landmark analyses revealed no significant survival differences, except for PFS at the 42‐day landmark. The time‐dependent Cox model confirmed no significant association between irAE occurrence and PFS (HR 1.16) or OS (HR 0.93). In contrast, good Eastern Cooperative Oncology Group performance status at baseline was an independent predictor of improved survival. Conclusion After appropriate adjustment for ITB, irAE development was not associated with improved survival in NSCLC patients treated with ICIs. Baseline performance status, rather than irAE occurrence, remains a more critical prognostic factor for these patients. The relationship between irAE development and clinical outcome should be evaluated with consideration of ITB.