To our knowledge, this is the first study to report on the clinical timeline and associated factors for developing irTAEs in patients with resected stage III/IV melanoma treated with adjuvant PD-1 inhibitors.

Previous research has demonstrated a wide range in the incidence of irTAEs among cancer patients treated with ICIs, probably given the variable assessment methods in detecting the irTAEs [12,13,14,15, 20]. We found that the development of irTAEs in patients with stage III/IV melanoma treated with adjuvant PD-1 inhibitors was common during the first 3 months, which is comparable to other studies in a metastatic setting [13, 15, 20]. Our findings are in line with the current understanding of the development of irTAE, starting with a hyperthyroid phase, which either recovers or progresses to persistent hypothyroidism [2, 12]. The current study detected 22 patients with an irTAE with a hypothyroid phase without a prior hyperthyroid phase. This could be explained by the fact that TSH values were measured every 4 weeks, and a potential hyperthyroid phase could have been missed, but factors such as degree/burden of thyroid inflammation and presence of underlying thyroid autoimmunity may also play a role. Among the transient irTAEs, 29 patients had no detected hypothyroid phase, which is similar to what others have reported [15, 20]. Overall, this suggests different degrees of severity of the irTAEs according to reversibility [15, 20]. However, mechanisms involved in developing irTAEs have not been fully elucidated [14].

The present study identified female sex and younger age as predictors of developing an irTAE, which is in accordance with the result of Muir et al., although both monotherapy and combination therapy with ICIs were included in their study [15]. The higher risk of irTAEs for females is likely to be due to a preponderance of autoimmune diseases in females compared to males [15] and the borderline significance of younger age as an independent risk factor for irTAE in unknown, but it has been suggested that it could at least partly be explained by relationship between thyroid diseases and younger women [15].

Two large systematic reviews and meta-analyses concluded that the occurrence of ICI-induced irAEs overall was significantly associated with longer progression-free survival (PFS) and OS in the metastatic setting [1, 5]. However, Sun et al. clarify in the summary analysis that specifically irTAEs were not associated with a favorable PFS and OS outcome [1]. This is consistent with the results of the current study and other research [23]. Eggermont et al. found that occurrence of an irAE was associated with a longer RFS in patients receiving pembrolizumab in the adjuvant setting (HR, 0.61; 95% CI, 0.39–0.95; p = 0.03) in both men and women, and comparable results were found when only endocrine irAEs were considered [24]. Additionally, other studies have reported better OS among patients with melanoma who developed an irTAE [13,14,15]. Furthermore, Muir et al. showed that overt thyrotoxicosis was associated with longer PFS [15]. In the current study, the time to recurrence of melanoma, albeit not statistically significant, was shorter in transient compared to persistent irTAEs. More studies are needed to investigate whether persistent irTAEs could be a surrogate marker of a more robust immune response to ICIs. Furthermore, patients with irTAEs were not more likely to discontinue treatment due to toxicity, thus indicating that irTAEs are not correlated with a higher toxicity profile.

A strength of this multicenter study was the use of a national sample size with blood samples collected prospectively. This allowed us to characterize a clinical timeline of the irTAE. The detection of the irTAE was based on abnormal TSH values since the development of irTAE in many cases does not result in clinical symptoms or signs of thyroid dysfunction [2, 4, 10].

Measurement of TSH values was analyzed with different assays. Despite this, the study managed to investigate the specific TSH RefR at the different hospitals during the given study period. This increases the precision in the detection of abnormal TSH values and, therefore, the accuracy of detected irTAEs.

To prevent misclassification and a possible overestimation in the number of detected irTAEs in the cohort, patients with known thyroid risk factors and ir-hypophysitis were excluded. Furthermore, patients excluded due to missing TSH values were not demographically or clinically different from patients included, which reduces the risk of selection bias.

Importantly, the present study controlled for time-dependent variables by taking immortality bias into account.

The current study has limitations inherent to the retrospective design. Follow-up data was inconsistent between the outcome groups. Patients with irTAEs were followed with blood samples more frequently, most likely due to the need for close monitoring of patients with irTAEs.

Relevant risk factors such as thyroid peroxidase antibodies (TPOAb), TSH receptor antibodies (TRAb), thyroglobulin antibodies (TgAb), and pre-existing autoimmune diseases were not collected. Studies have reported a positive association between TPOAb and/or TgAb and the incidence of irTAEs [15, 18]. Other studies have hypothesized that patients with pre-existing autoimmune diseases have a different immune response and consequently an enhanced risk of developing irAEs [6, 7, 25]. Overall, this limits the external validity of the study. Furthermore, information on the corresponding serum levels of the thyroid hormones FT3/FT4 could have provided a greater insight into the clinical impact of the irTAE.