Thyroid Immune-related Adverse Events Following Immune Checkpoint Inhibitor Treatment

Abstract

Background Thyroid dysfunction occurs commonly following immune checkpoint inhibition. The etiology of thyroid immune-related adverse events (irAEs) remains unclear and clinical presentation can be variable. This study sought to define thyroid irAEs following immune checkpoint inhibitor (ICI) treatment and describe their clinical and biochemical associations. Methods We performed a retrospective cohort study of thyroid dysfunction in patients with melanoma undergoing CTLA-4 and/or PD-1 based ICI treatment from Nov 1, 2009 to Dec 31, 2019. Thyroid function was measured at baseline and at regular intervals following the start of ICI-treatment. Clinical and biochemical features were evaluated for associations with ICI-associated thyroid irAEs. The prevalence of thyroid autoantibodies and the effect of thyroid irAEs on survival were analysed. Results A total of 1246 patients were included with a median follow-up of 11.3 months. 518 (42%) patients developed an ICI-associated thyroid irAE. Subclinical thyrotoxicosis (n=234) was the most common thyroid irAE, followed by overt thyrotoxicosis (n=154), subclinical hypothyroidism (n=61), and overt hypothyroidism (n=39). Onset of overt thyrotoxicosis occurred a median of 5 weeks (IQR 2-8) after receipt of first dose of ICI. Combination immunotherapy was strongly associated with development of overt thyrotoxicosis (OR 10.8, 95% CI 4.51-25.6 vs. CTLA-4 monotherapy; p<0.001), as was female sex (OR 2.02, 95% CI 1.37-2.95; p<0.001) and younger age (OR 0.83 per 10-years, 95% CI 0.72-0.95; p=0.007). By comparison, median onset of overt hypothyroidism was 14 weeks (IQR 8-25). The frequency of overt hypothyroidism did not differ between different ICI-types. The strongest associations for hypothyroidism were higher baseline TSH (OR 2.33 per mIU/L, 95% CI 1.61-3.33; p<0.001) and female sex (OR 3.31, 95% CI 1.67-6.56; p=0.01). Overt thyrotoxicosis was associated with longer progression free survival (HR 0.68, 95% CI 0.49-0.94; p=0.02) and overall survival (HR 0.57, 95% CI 0.39-0.84; p=0.005). There was no association between hypothyroidism and cancer outcomes. Conclusions Thyroid irAEs are common and there are multiple distinct phenotypes. Different thyroid irAE subtypes have unique clinical and biochemical associations, suggesting potentially distinct etiologies for thyrotoxicosis and hypothyroidism arising in this context.

Immune-Related Thyroiditis as a Predictor for Survival in Metastatic Renal Cell Carcinoma

“…Previously, it was suggested that treatment with VEGFi is an inducer of thyroid injury, increasing the risk for irT with CPI exposure [ 12 ]. While the rate of irT is higher in our cohort than the commonly reported 20–30% [ 7 , 8 , 10 , 12 , 18 , 19 , 20 ], the incidence rate did not differ between patients who were treated with immunotherapy in the first-line treatment or after previous treatment with VEGFi. For patients with previous thyroid dysfunction on VEGFi we found a non-significant trend of increased irT risk (HR = 2.14, p = 0.08).…”

“…The relationship between these phenomena and treatment-related thyroid dysfunction in RCC patients requires further research. The timing of thyroid dysfunction was similar to that reported in previous studies [ 12 , 19 ].…”

“…To our knowledge, this is the largest cohort studied to evaluate irT in mRCC patients to date. Several studies have evaluated the prognostic value of irT in several cancer types with indeterminate findings [ 7 , 8 , 10 , 12 , 18 , 19 , 20 ]. We found a strong and significant association with survival in poor risk/High risk patients.…”

“…In contrast, another study found no such association in RCC with the limitation that other urologic malignancies were grouped together, despite the significant variability in clinical, molecular, and pathological characteristics [ 18 ]. Several studies in melanoma demonstrated that irT is predictive for survival [ 19 ], while others did not find any association [ 11 ].…”

Immune-checkpoint inhibitors: long-term implications of toxicity

“…Hypothyroidism is the most common endocrine irAE, occurring in around 10% of patients receiving anti-PD-1–PD-L1 antibodies as monotherapy and in up to 20% receiving ipilimumab plus nivolumab. Prior to hypothyroidism, approximately half of all patients have destructive thyroiditis resulting in excessive thyroid hormone secretions (thyrotoxicosis), which is often asymptomatic 77 . The median time to onset is approximately 6 weeks after commencing therapy, although hypothyroidism can arise at any time on therapy 78 .…”