Heterogeneous survival impact of immune-related adverse events in US veterans

Immune-related adverse events (irAEs) have been associated with improved overall survival (OS) in patients with cancer treated with immune checkpoint inhibitors (ICIs), as irAEs are thought to signify a potentially robust antitumor immune response. The interplay between irAE subtypes, irAE severity, and oncological outcomes remains understudied.

We conducted a retrospective study of patients with cancer in the US Veteran Health Administration who received first-line or second-line ICI therapy (programmed cell death protein 1, programmed death-ligand 1, cytotoxic T-lymphocyte-associated protein 4, or lymphocyte activation gene 3 inhibitors)±chemotherapy from 2010 to 2023. Manual chart review was performed on a random sample to ascertain irAEs. The primary outcome was OS, analyzed by irAE status (no irAE vs irAE), severity (steroid-requiring vs non-steroid-requiring), and subtype (thyroid/cutaneous vs other). To account for immortal time bias, OS was analyzed with multivariable time-dependent Cox regression and 180-day landmark analysis.

Among 1707 patients, 465 (27.2%) experienced at least one irAE (median onset: 108 days; unadjusted 2-year rate: 38.2% (35%-41%)). The occurrence of any-grade irAE was not associated with improved OS (adjusted HR (aHR) 0.87; 95% CI 0.75 to 1.01). Analysis stratified by steroid requirement (n=222/465 events, 47.7%) showed improved survival with non-steroid-requiring irAE (aHR 0.69, 95% CI 0.57 to 0.84), whereas steroid-requiring irAEs were associated with a trend toward worse survival (aHR 1.13, 95% CI 0.92 to 1.38). The non-steroid-requiring irAE subset was enriched for thyroid (45% vs 8%) and cutaneous (27% vs 16%) toxicities compared with the steroid-requiring group. Exploration of the impact of irAE subtype on OS showed significant survival benefit in patients with thyroid/cutaneous irAEs (aHR 0.57, 95% CI 0.46 to 0.71) but not other irAE subtypes.

irAEs are not uniformly associated with improved survival. Favorable outcomes are driven by thyroid-related and skin-related, non-steroid-requiring irAEs, suggesting shared biological mechanisms underlying organ-specific autoimmunity and antitumor immune response.