Cutaneous immune-related adverse events independently predict overall survival with a grade-dependent association in ICI-treated advanced NSCLC: a time-dependent analysis.

INTRODUCTION: Cutaneous 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. METHODS: We 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. RESULTS: In 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). DISCUSSION: Given 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.