Thyroid Immune-Related Adverse Events Are Associated With Improved Survival in Cancer Patients

Abstract

Abstract Introduction: Thyroid immune-related adverse events (irAEs) occur frequently after immune checkpoint inhibitor (ICI) cancer therapy, but their risk factors and potential influence on survival need further investigation. Methods: We performed a retrospective single-center cohort study of adult cancer patients who received ICIs including CTLA-4, PD-1, PD-L1 inhibitors from 12/1/2012- 12/31/2019. Patients who developed thyroid irAEs after excluding surgical or ablative hypothyroidism were included. Survival analysis was performed by Kaplan-Meier curves and Cox-proportional hazards model. Results: Thyroid irAEs occurred in 145 (17.4%) of 834 ICI-treated patients (median age 64.9 y, 43.4% females) during a median follow-up of 11.6 mo. New-onset thyroid dysfunction occurred in 118 (14.2%), of which 55 presented with thyrotoxicosis (32 progressed to hypothyroidism, 22 returned to euthyroid state, 1 had Graves’ disease). Worsening of pre-existing autoimmune hypothyroidism (≥50% increase in levothyroxine dose) occurred in 27 (3.2%). Of those with new-onset thyroid dysfunction, 79 (67%) required levothyroxine eventually. Patients with thyroid irAE had similar age, sex and cancer type as compared to those without but had higher median pre-treatment TSH [2.4 vs. 1.7 mIU/L (p<0.0001); multivariable OR for TSH ≥2.4 mIU/L of 2 (95% CI 1.3, 3.2; p=0.004)] and higher frequency of autoimmune disease history [26.9% vs. 14.8% (p=0.0009); multivariable OR of 2 (95% CI 1.2, 3.5; p=0.013)]. Thyroid irAEs occurred after a median of 2.4 mo from ICI, most frequently with PD-1/PD-L1 inhibitor. Thyroid irAEs were associated with better median overall survival [38.8 mo (95% CI 26.6, not reached) vs. 18.9 (95% CI 14.2, 24.8); p<0.0001] which persisted on restricting to patients with new-onset thyroid dysfunction [40.1 mo (95% CI 26.6, not reached) vs. 18.8 (95% CI 13.6, 24.8); p<0.0001]. On multivariable analysis, thyroid irAEs had HR for mortality of 0.51 (95% CI 0.37, 0.71; p<0.0001), which persisted on restricting to new-onset thyroid dysfunction [HR 0.48 (95% CI 0.34, 0.69; p<0.0001)]. Conclusions: Thyroid irAEs frequently occur after PD-1/PD-L1 inhibitor therapy, presenting as hypothyroidism or thyrotoxicosis usually progressing to hypothyroidism. Higher TSH even within normal range and autoimmune disease history may be risk factors for thyroid irAE. Improved survival with thyroid irAEs suggests these could be a marker for anti-tumor activity.