| Sumario: | Simple Summary: In metastatic NSCLC with high PD-L1 expression, about one-third of patients treated with pembrolizumab develop immune-related thyroid dysfunction (irTD). Our study of 363 patients shows that those who experience irTD have significantly longer progression-free survival compared to those who do not. The timing of thyroid dysfunction (early or late) did not affect outcomes. Importantly, irTD was manageable and occurred more often in patients with good performance status. These results suggest that irTD may serve as a useful marker of effective immune response during pembrolizumab therapy and could help identify patients likely to derive long-term benefit. In metastatic NSCLC with high PD-L1 expression (TPS ≥ 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 ≥ 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 (≤90 days) or late onset (>90 days). Progression-free survival (PFS) was estimated using Kaplan–Meier 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 21–550). Median cohort PFS was 9.8 months (95% CI 7.26–12.34). Patients with irTD had significantly longer PFS than those without irTD: 26.33 (95% CI 19.09–33.57) vs. 6.16 months (95% CI 4.70–7.63), with an HR of 0.378 (95% CI 0.280–0.511; p < 0.001). Landmark analyses confirmed benefit at 3 months (28.4 vs. 13.7 months; HR 0.490, p < 0.001) and 6 months (29.0 vs. 20.5 months; HR 0.587, p < 0.001). PFS did not differ by irTD timing (early vs. late; HR 0.926, p = 0.682). Poor ECOG PS (≥2) 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.
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