Incidence and Predictors of Immune-Related Hypothyroidism Under Pembrolizumab Across Gynecologic Malignancies and Melanoma: A Real-World Cohort Study.

Abstract

Immune checkpoint inhibitors (ICIs) frequently cause thyroid immune-related adverse events (irAEs). Permanent hypothyroidism, the clinically most relevant phenotype, requires lifelong hormone replacement. We investigated its incidence, course, risk factors, and prognostic relevance under pembrolizumab. This retrospective single-center study included patients from the Departments of Gynecology and Dermatology who received ≥ 3 cycles of pembrolizumab between 2018 and 2024. Permanent hypothyroidism occurred in 30/188 patients (16.0%). Thyrotoxicosis was observed in 46/188 (24.5%) and de novo hypothyroidism in 33/188 (17.6%). Overt thyrotoxicosis progressed to permanent hypothyroidism in 71% of cases. Nearly all permanent cases were overt at first detection (29/30), and most patients were asymptomatic. Permanent hypothyroidism developed earlier than transient courses (median 15 vs. 26 weeks), and no new permanent events occurred beyond 50 weeks. Prior chemotherapy was strongly associated with permanent hypothyroidism (33% vs. 11%; p = 0.001), whereas age, sex, tumor stage, treatment setting, and other systemic therapies were not. Permanent hypothyroidism was not associated with progression-free survival, recurrence-free survival, or overall survival. Permanent hypothyroidism is a common pembrolizumab-related irAE, typically occurring within the first 6 months but occasionally up to 12 months after treatment initiation. Prior chemotherapy emerged as an independent predictor of permanent hypothyroidism. Most cases were mild and manageable with oral levothyroxine. These findings suggest that cycle-based thyroid monitoring may warrant continuation through the first 12 months of ICI therapy, with heightened attention to patients with prior chemotherapy exposure.