Immune-related Adverse Event Phenotypes Differentially Associate with Survival in Immune Checkpoint Inhibitor-treated Mucosal HNSCC

Introduction: Immune-related adverse events (irAEs) are common during immune checkpoint inhibitor (ICI) therapy and are often interpreted as a favorable sign. However, irAEs are clinically heterogeneous and may carry different prognostic implications. In mucosal head and neck squamous cell carcinoma (mHNSCC), real-world evidence linking specific irAE subtypes to overall survival remains limited.

Methods: We performed a retrospective multi-institutional cohort study using Epic COSMOS (January 2015-October 2024). Adults with mHNSCC initiating pembrolizumab or nivolumab were included. irAEs within 12 months of ICI start were identified using diagnosis-code definitions for dermatologic, endocrine, gastrointestinal, hepatic, pulmonary, renal, neurologic, and pancreatic events; irAE diagnosis code history in the year prior to ICI start was collected to capture new-onset events. Overall survival (OS) was measured from ICI initiation and evaluated using Cox survival models adjusted for demographic, comorbidity, tumor, and treatment factors. Sensitivity analyses reclassified irAE exposure to new-onset events only. A planned 90-day landmark, classifying irAE exposure by events occurring in the first 90 days, will mitigate immortal-time bias.

Results: Among 21,476 patients, 63.7% developed ≥1 irAE within 12 months of ICI initiation, among those patients 72.7% had no corresponding irAE diagnosis code in the year prior. Any irAE was associated with longer OS in adjusted models (aHR 0.77; 95% CI 0.74-0.79) with directionally consistent results in new-onset only models. In subtype models, notably dermatologic (0.74, 0.71-0.77) and endocrine (0.84, 0.81-0.87) irAEs were associated with longer OS, whereas hepatic (1.33, 1.20-1.47) and pulmonary (1.42, 1.21-1.66) irAEs were associated with shorter OS.

Conclusions: In this large real-world cohort of ICI-treated mHNSCC, irAE occurrence was associated with longer OS, possibly reflecting treatment response, but associations varied substantially by irAE phenotype. These findings support interpreting irAEs by subtype rather than as a uniform prognostic signal.