{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T16:54:59Z","timestamp":1789750499307,"version":"4.0.1"},"reference-count":39,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>In metastatic NSCLC with high PD-L1 expression (TPS \u2265 50%), pembrolizumab monotherapy yields durable benefit in a subset of patients. Immune-related thyroid dysfunction (irTD) is common during PD-1\/PD-L1 blockade, but its predictive value remains uncertain. We conducted a retrospective, single-center study including 363 patients with metastatic NSCLC, PD-L1 TPS \u2265 50%, and no actionable oncogenic drivers treated with first-line pembrolizumab. Thyroid function tests were performed at baseline and every six weeks. irTD was defined based on laboratory abnormalities with or without clinical symptoms and classified as early onset (\u226490 days) or late onset (&gt;90 days). Progression-free survival (PFS) was estimated using Kaplan\u2013Meier methods and compared using log-rank tests. Cox proportional hazards models included irTD as a time-varying covariate. Landmark analyses at 3 and 6 months reduced immortal-time bias. Events were graded according to CTCAE v5.0. Among 363 eligible patients, irTD occurred in 110 (30.3%); median onset was 114 days (range 21\u2013550). Median cohort PFS was 9.8 months (95% CI 7.26\u201312.34). Patients with irTD had significantly longer PFS than those without irTD: 26.33 (95% CI 19.09\u201333.57) vs. 6.16 months (95% CI 4.70\u20137.63), with an HR of 0.378 (95% CI 0.280\u20130.511; p &lt; 0.001). Landmark analyses confirmed benefit at 3 months (28.4 vs. 13.7 months; HR 0.490, p &lt; 0.001) and 6 months (29.0 vs. 20.5 months; HR 0.587, p &lt; 0.001). PFS did not differ by irTD timing (early vs. late; HR 0.926, p = 0.682). Poor ECOG PS (\u22652) was associated with worse outcomes and a lower incidence of irTD. We found that irTD is common, clinically manageable, and strongly associated with improved PFS in PD-L1-high metastatic NSCLC treated with pembrolizumab. Thyroid dysfunction may serve as a feasible on-treatment biomarker of effective immune activation, warranting further prospective validation.<\/jats:p>","DOI":"10.3390\/curroncol33020109","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T09:48:34Z","timestamp":1770889714000},"page":"109","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Immune-Related Thyroid Dysfunction in PD-L1 High Non-Oncogene-Addicted NSCLC Treated with First-Line Pembrolizumab: Incidence, Timing, and Predictive Impact"],"prefix":"10.3390","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7992-7279","authenticated-orcid":false,"given":"Filip","family":"Markovi\u0107","sequence":"first","affiliation":[{"name":"Clinic for Pulmonology, University Clinical Centre of Serbia, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1787-1438","authenticated-orcid":false,"given":"Mihailo","family":"Stjepanovi\u0107","sequence":"additional","affiliation":[{"name":"Clinic for Pulmonology, University Clinical Centre of Serbia, 11000 Belgrade, Serbia"},{"name":"Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milica","family":"Konti\u0107","sequence":"additional","affiliation":[{"name":"Clinic for Pulmonology, University Clinical Centre of Serbia, 11000 Belgrade, Serbia"},{"name":"Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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