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Cutaneous immune-related adverse events independently predict overall survival with a grade-dependent association in ICI-treated advanced NSCLC: a time-dependent analysis
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DOI：10.3389/fonc.2026.1860717.png)
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Abstract
En 中文
IntroductionCutaneous immune-related adverse events (cirAE) affect up to 34% of patients receiving immune checkpoint inhibitor (ICI) therapy; yet their prognostic significance in advanced non-small cell lung cancer (NSCLC) remains disputed. A key methodological flaw in the existing literature is immortal time bias; which inflates the apparent benefit of cirAE in conventional analyses.MethodsWe conducted a retrospective cohort study of 262 advanced NSCLC patients treated with ICIs at a single institution between January 2021 and January 2025. Patients were classified into cirAE (n=80) and no cirAE (n=182) groups. Time-dependent Cox regression was the primary analysis to address immortal time bias; landmark analysis at 2.2 months (the median cirAE onset) served as a supportive analysis. The primary endpoint was overall survival (OS); progression-free survival (PFS) was secondary.ResultsIn multivariable time-dependent Cox analysis; cirAE was independently associated with improved OS (HR = 0.52; 95% CI: 0.35–0.78; P = 0.002). No time-invariant PFS association was observed (HR = 0.91; P = 0.586); a complementary time-varying analysis revealed an early PFS hazard reduction that attenuated over follow-up; consistent with detection bias from more intensive surveillance in cirAE patients. The OS association was consistent across all prespecified subgroups (all P for interaction >0.05); and was confirmed in a sensitivity analysis re-including patients with concurrent non-cutaneous irAE (HR = 0.56; P = 0.002).An exploratory grade-stratified analysis suggested a severity-associated trend: grade 1–2 (HR = 0.51; P = 0.001) and grade 3+ cirAE (HR = 0.33; P = 0.003) showed progressively lower OS hazard estimates (P for trend <0.001; median OS: 18.8; 36.1; and 47.7 months for no cirAE; grade 1–2; and grade 3+ groups; respectively).DiscussionGiven the small grade 3+ subgroup (n=21); these findings should be considered hypothesis-generating. cirAE may serve as an early; accessible signal of ICI efficacy in NSCLC. The exploratory severity-outcome gradient suggests that high-grade cirAE may identify patients deriving the greatest benefit from continued ICI therapy under appropriate dermatologic management; pending prospective validation.
Keywords:
non-small cell lung cancer
overall survival
immune checkpoint inhibitors
dose-response
landmark analysis
cutaneous immune-related adverse events
immortal time bias
time-dependent Cox regression
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