Characterizing Thyroid Hormone Replacement, Baseline Thyrotropin, and Survival in Immune Checkpoint Inhibitor–Associated Thyroid Dysfunction

Background: Thyroid dysfunction (TD) occurs commonly from immune checkpoint inhibitors (ICI) cancer therapy, but questions remain regarding its predicting factors, appropriate dosing for thyroid hormone replacement, and the strength of association with overall survival (OS). We aim to address these three questions in our study. Methods: We performed a retrospective cohort study of adult patients with cancer who received ICIs from December 1, 2012, to December 31, 2019. After excluding 28 patients with preexisting primary hypothyroidism, 811 patients were evaluated for the development of new-onset ICI-TD. Kaplan-Meier survival and log-rank tests were used to compare OS distributions between ICI-TD status groups, following which Cox regression models addressed immortal time bias (ITB). Results: Of the 811 included patients with a median follow-up of 19.2 months, 122 (15.0%) patients developed ICI-TD. The median age at initiation of ICIs was 64.8 years; women comprised 42.8% of the cohort. There were no significant differences in age, sex, race, malignancy type, or personal history of autoimmunity in patients who developed ICI-TD versus those who did not. ICI-TD occurred most frequently after combination ICI therapy (32%) compared with CTLA-4 ICI and PD-1/PD-L1 ICI monotherapy (p = 0.002). The median levothyroxine dose was the highest, being 1.41 mcg/kg/day in the overt hypothyroidism group. Patients with ICI-TD had a higher median pre-treatment log2(thyrotropin or TSH) level (1.2, corresponding to TSH 2.3 mIU/L) versus those without (0.79, corresponding to TSH 1.7 mIU/L; p = 0.008); however, the area under the curve was <0.6, hence lacking predictive ability. The survival benefit of ICI-TD was not apparent after addressing ITB and adjusting for other variables affecting patient outcomes. Conclusions: The levothyroxine dose needed for overt hypothyroidism from ICI-TD is similar to athyreotic hypothyroidism. While baseline TSH in the upper normal range is associated with an increased risk of ICI-TD, there is no absolute baseline TSH value that accurately predicts ICI-TD in the clinical setting. The link between ICI-TD and OS needs further validation after accounting for ITB.