{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T05:27:56Z","timestamp":1786512476250,"version":"build-2736575974"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In multivariable time-dependent Cox analysis, cirAE was independently associated with improved OS (HR = 0.52; 95% CI: 0.35\u20130.78; 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 &amp;gt;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\u20132 (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 &amp;lt;0.001; median OS: 18.8, 36.1, and 47.7 months for no cirAE, grade 1\u20132, and grade 3+ groups, respectively).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1860717","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T04:40:39Z","timestamp":1786509639000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cutaneous immune-related adverse events independently predict overall survival with a grade-dependent association in ICI-treated advanced NSCLC: a time-dependent analysis"],"prefix":"10.3389","volume":"16","author":[{"given":"Tao","family":"Xu","sequence":"first","affiliation":[{"name":"Graduate School, Beijing University of Chinese Medicine","place":["Beijing, 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