Immune-related thyroid dysfunction and overall survival in metastatic colorectal cancer treated with pembrolizumab: A real-world TriNetX analysis.

Abstract

e15558 Background: Immune checkpoint inhibitors (ICIs) are standard therapy for MSI-H/dMMR metastatic colorectal cancer (CRC), yet reliable on-treatment biomarkers of benefit are lacking. Thyroid dysfunction is a common immune-related adverse event (irAE) associated with ICIs and has been linked to improved outcomes in non-gastrointestinal cancers; however, it remains unclear whether this association holds in metastatic CRC. Methods: Using the TriNetX Research Network, we conducted a retrospective cohort study of adults with metastatic colorectal cancer treated with pembrolizumab from 2014–2024. Patients were divided into two groups based on whether they developed new-onset thyroid dysfunction after starting pembrolizumab. Thyroid dysfunction was defined by new thyroid ICD-10 diagnoses, thyroid medication initiation, or elevated TSH within 16 weeks of treatment initiation, excluding patients with pre-existing thyroid disease. Propensity score matching (1:1) was performed to balance baseline clinical differences between groups. Overall survival (OS) was assessed using Kaplan–Meier and Cox models. A 12-week landmark analysis was performed to reduce potential immortal time bias. Results: Among 2,477 eligible patients, 190 (7.7%) developed thyroid dysfunction after pembrolizumab initiation. After propensity score matching, 380 patients were included (190 per cohort). The matched cohort had a mean age of 64 years, was predominantly female (57%) and White (82%), with colon primaries in 67%. Baseline comorbidities were balanced between groups (Table 1). When comparing survival between patients who did versus did not develop thyroid dysfunction, those who developed thyroid dysfunction had significantly improved OS in the primary matched analysis (median OS 780 vs 513 days; 5-year OS 44% vs 29%; log-rank p = 0.017), corresponding to a lower risk of death (HR 0.71; 95% CI 0.54–0.94). In the 12-week landmark analysis, survival remained numerically higher in the thyroid dysfunction group (5-year OS 47% vs 36%), although the difference was no longer statistically significant (HR 0.87; 95% CI 0.63–1.19; p = 0.37). Conclusions: In this large real-world cohort of metastatic CRC patients treated with pembrolizumab, patients who developed immune-related thyroid dysfunction experienced longer overall survival than those who did not. These findings support thyroid irAEs as a potential on-treatment biomarker of benefit in MSI-H/dMMR CRC and warrant further validation. Baseline characteristics in matched cohort. Variable Thyroid Dysfunction (n=190) No Thyroid Dysfunction (n=190) Demographics Age, mean (SD) 64 (13) 64 (12) Female sex, % 60 57 White race, % 81 84 Primary tumor site, % Colon 69 66 Rectum/rectosigmoid 31 34 Comorbidities, % Diabetes mellitus 20 20 Chronic kidney disease 13 15 Coronary artery disease 15 15 Heart failure 7 10 COPD 10 10