Best practices in the management of thyroid dysfunction induced by immune checkpoint inhibitors

in European Thyroid Journal
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Ichiro Yamauchi Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan

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https://orcid.org/0000-0002-4236-502X
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Daisuke Yabe Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan

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Correspondence should be addressed to I Yamauchi: ichiroy@kuhp.kyoto-u.ac.jp
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Immune checkpoint inhibitors (ICIs) frequently cause immune-related adverse events (irAEs), with thyroid irAEs being the most common endocrine-related irAEs. The incidence of overt thyroid irAEs was in the range of 8.9–22.2% in real-world settings, typically triggered by antibodies against PD-1 and PD-L1 and rarely by anti-CTLA-4 antibodies alone. The representative clinical course involves biphasic changes in thyroid function: transient thyrotoxicosis and subsequent persistent hypothyroidism. The identified risk factors for thyroid irAEs include the presence of thyroid autoantibodies, thyroid uptake on 18F-FDG-PET, prior use of tyrosine kinase inhibitors (TKIs), high BMI and high thyroid-stimulating hormone levels. There is evidence that overt thyroid irAEs are associated with good prognosis, at least in non-small cell lung cancer. Although the clinical features have been well clarified, the management strategies require further refinement. Routine monitoring of thyroid function every 4–6 weeks during ICI therapy is recommended for early detection of thyroid irAEs. While thyrotoxicosis generally requires observation only, hypothyroidism should be promptly treated with levothyroxine replacement. Continuation of ICI therapy is typically feasible in patients with thyroid irAEs, provided their overall health remains stable. However, these strategies were largely based on clinical experience with monotherapy. As combination ICI therapies have been developed as first-line treatments, antitumor agents may modify the clinical features of thyroid irAEs. For example, cytotoxic agents can delay the onset of thyroid irAEs, while TKIs are often linked to early-onset hypothyroidism, independent of ICI use. Given the increasing diversity and complexity of cancer immunotherapy, it is essential to vigilantly screen for thyroid irAEs.

Abstract

Immune checkpoint inhibitors (ICIs) frequently cause immune-related adverse events (irAEs), with thyroid irAEs being the most common endocrine-related irAEs. The incidence of overt thyroid irAEs was in the range of 8.9–22.2% in real-world settings, typically triggered by antibodies against PD-1 and PD-L1 and rarely by anti-CTLA-4 antibodies alone. The representative clinical course involves biphasic changes in thyroid function: transient thyrotoxicosis and subsequent persistent hypothyroidism. The identified risk factors for thyroid irAEs include the presence of thyroid autoantibodies, thyroid uptake on 18F-FDG-PET, prior use of tyrosine kinase inhibitors (TKIs), high BMI and high thyroid-stimulating hormone levels. There is evidence that overt thyroid irAEs are associated with good prognosis, at least in non-small cell lung cancer. Although the clinical features have been well clarified, the management strategies require further refinement. Routine monitoring of thyroid function every 4–6 weeks during ICI therapy is recommended for early detection of thyroid irAEs. While thyrotoxicosis generally requires observation only, hypothyroidism should be promptly treated with levothyroxine replacement. Continuation of ICI therapy is typically feasible in patients with thyroid irAEs, provided their overall health remains stable. However, these strategies were largely based on clinical experience with monotherapy. As combination ICI therapies have been developed as first-line treatments, antitumor agents may modify the clinical features of thyroid irAEs. For example, cytotoxic agents can delay the onset of thyroid irAEs, while TKIs are often linked to early-onset hypothyroidism, independent of ICI use. Given the increasing diversity and complexity of cancer immunotherapy, it is essential to vigilantly screen for thyroid irAEs.

Introduction

Immune checkpoint inhibitors (ICIs) have been approved for a wide range of malignancies across various stages. Among ICIs, antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) are commonly used in clinical practice. ICI therapy is frequently associated with immune-related adverse events (irAEs) that can resemble autoimmune disorders. Organs commonly affected include the skin, gastrointestinal tract, liver, lungs and endocrine organs. Endocrinologists play a crucial role in the management of cancer patients undergoing immunotherapy with ICIs.

Endocrine-related irAEs include thyroid irAEs, pituitary irAEs, adrenal insufficiency, diabetes mellitus and other rare conditions. Thyroid irAEs have been recognized in several case series (1, 2, 3). Thyroid irAEs are frequently caused by antibodies against PD-1 and PD-L1 and are rarely caused by anti-CTLA-4 antibodies alone. Therefore, thyroid irAEs should be carefully managed during PD-1 pathway blockade. The pathophysiology of thyroid irAEs has been progressively clarified. In patients with thyroid irAEs, intrathyroidal lymphocyte accumulation is observed, similar to Hashimoto’s thyroiditis, as determined through analyses of thyroid fine-needle aspiration specimens (4, 5). Lechner et al. identified a clonal population of effector CD8+ T cells predominantly present in the thyroid glands of patients with thyroid irAEs, in contrast to Hashimoto’s thyroiditis (5). A genetic analysis highlighted the involvement of several genes in thyroid irAEs, including CTLA-4, CBLB, PTPN22 and CD69, which are implicated in immune regulation and autoimmunity (6). Murine models revealed the pathogenic role of thyroidal infiltration by cytotoxic CD4+ T cells (7) and IL-17-producing CD4+ T cells (8).

Here, we aimed to provide a comprehensive review of thyroid irAEs with a focus on clinical management. By incorporating published reports, we offer an updated understanding of the clinical characteristics and management strategies for thyroid irAEs. In addition, we discuss the impact of combination therapies involving ICIs and other antitumor agents on thyroid function. We hope that this review serves as a bridge between endocrinologists and oncologists by fostering a common understanding of thyroid irAEs.

Clinical features of thyroid irAEs

Incidence

Thyroid irAEs were frequently observed in clinical trials, with a systematic review reporting the incidence of hypothyroidism at 6.6% and hyperthyroidism at 2.9% (9). However, real-world data from thyroid disease specialists who carefully monitor and diagnose thyroid irAEs have revealed a higher incidence than that observed in clinical trials. We believe the findings from real-world studies are highly valuable and summarize them in Table 1 (2, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27).

Table 1

Incidence of thyroid irAEs in the real-world cohorts. Data are presented as number of patients (n). The overt thyroid irAEs are presented in bold.

Reference Patients, n ICIs used: n Primary sites: n Incidence of thyroid irAEs
de Filette et al. (2) 99 Pembrolizumab: 99 MM: 99 17.2%
Delivanis et al. (10) 93 Pembrolizumab: 93 MM: ND; NSCLC: ND 14.0%
Osorio et al. (11) 48 Pembrolizumab: 48 NSCLC: 48 20.8%
Kobayashi et al. (12) 66 Nivolumab: 66 NSCLC: 39; MM: 19 6.1%
Yano et al. (13) 24 Nivolumab: 24 MM: 24 29.2%
Kim et al. (14) 58 Nivolumab: 52; pembrolizumab: 6 NSCLC: 58 32.8%
Yamauchi et al. (15) 200 Nivolumab: 200 NSCLC: 118; MM: 42 SC: 20.0%; O vert: 13.5%
Sakakida et al. (16) 150 Nivolumab: 117; pembrolizumab: 33 NSCLC: 59; MM: 26 16.7%
Kotwal et al. (17) 91 Atezolizumab: 86; avelumab: 5 LC: 65; UC: 19 SC: 13.2%; O vert: 12.1%
Sbardella et al. (18) 126 Nivolumab: 107; pembrolizumab: 19 NSCLC: 92; RCC: 21 23.0%
Basak et al. (19) 168 Nivolumab: 118; pembrolizumab: 50 NSCLC: 93; MM: 63 SC: 20.2%; O vert; 11.9%
Pollack et al. (20) 185 PD-1: 165; PD-L1: 20 NSCLC: 97; others: 88 SC: 16.8%; O vert: 22.2%
Muir et al. (21) 1246 PD-1/PD-L1: 705; CTLA-4 combi : 376 MM: 1246 SC: 23.7%; O vert 15.5%
Zhou et al. (22) 241 PD-1/PD-L1: 186; CTLA-4 combi: 38 NSCLC: 241 11.2%
Baek et al. (23) 185 Pembrolizumab: 100; nivolumab: 66 LC: 112; MM: 22 31.3%
Kobayashi et al. (24) 148 Atezolizumab: 102; durvalumab: 46 NSCLC: 98; HCC: 27 10.1%
Ueba et al. (25) 291 Pembrolizumab: 207; atezolizumab: 84 NSCLC: 169; UC: 49 Overt: 8.9%
Wu et al. (26) 270 PD-1/PD-L1: 262; CTLA-4 combi: 7 LC: 220; others: 50 44.4%
Zhou et al. (27) 516 PD-1: 516 LC: 181; HNC: 82 9.9%

irAE, immune-related adverse event; ICI, immune checkpoint inhibitor; n, number of subjects; PD-1, anti-PD-1 antibody; PD-L1, anti-PD-L1 antibody; PD-1/PD-L1, anti-PD-1 antibody or anti-PD-L1 antibody; CTLA-4 combi, anti-CTLA-4 antibody and anti-PD-1 antibody or anti-PD-L1 antibody; ND, not described; MM, malignant melanoma; NSCLC, non-small cell lung cancer; LC, lung cancer; UC, urothelial cancer; RCC, renal cell carcinoma; HCC, hepatocellular carcinoma; HNC, head and neck cancer; SC, subclinical. ICIs used and primary sites are listed up to the second most frequent one.

The reported incidence rates of thyroid irAEs vary widely, ranging from 6.1 to 44.4%. This variability may stem from the differing definitions of thyroid irAEs across studies. To address this, we proposed distinguishing between overt and subclinical thyroid irAEs (15). Overt thyroid irAEs were diagnosed when both serum free T4 (fT4) and TSH levels were abnormal, excluding cases with abnormal values unrelated to thyroid irAEs, based on established criteria (15). Overt thyroid irAEs were found to be associated with risk factors and prognostic implications, as described in the following sections, whereas subclinical thyroid irAEs were not. Since subclinical thyroid irAEs generally do not require clinical intervention, overt thyroid irAEs represent more significant adverse events.

The incidence of overt thyroid irAEs has been reported to range from 8.9 to 22.2% (15, 17, 19, 20, 21, 25). Across these studies, the cumulative incidence was 14.6%, with 318 of 2181 patients affected. The cohort reported by Muir et al. included a substantial number of patients who received combination immunotherapy with anti-PD-1 and anti-CTLA-4 antibodies (21). For our analysis, we excluded this study to focus on patients treated with anti-PD-1 or anti-PD-L1 antibodies alone, resulting in an incidence rate of 13.4% (125 of 935 patients). These findings underscore that thyroid irAEs are frequent adverse events associated with ICIs targeting the PD-1 pathway.

Clinical course

Early studies have shown that thyroid irAEs caused by anti-PD-1 antibodies involve both thyrotoxicosis and hypothyroidism (1, 2, 3). Subsequent analyses of detailed clinical data from patients with overt thyroid irAEs revealed a typical pattern: transient thyrotoxicosis tends to occur within 2–6 weeks, followed by the onset of hypothyroidism around 12 weeks, often requiring long-term levothyroxine replacement (15). The clinical courses of thyroid irAEs induced by anti-PD-L1 antibodies mirror those observed with anti-PD-1 antibodies (24).

To illustrate the biphasic changes in thyroid function, we present a representative case of thyroid irAE (Fig. 1). A 51-year-old male with urothelial carcinoma was treated with pembrolizumab for peritoneal metastasis. He developed thyrotoxicosis 28 days after initial pembrolizumab administration, followed by hypothyroidism 70 days later. The patient required long-term levothyroxine (LT4) replacement therapy thereafter.

Figure 1
Figure 1

Representative clinical course of immune-related adverse events involving the thyroid gland (thyroid irAEs). Clinical information for this patient is available in the manuscript. Longitudinal values of free T3 (fT3, orange dotted line), free T4 (fT4, green solid line) and thyroid-stimulating hormone (TSH, gray dashed line) are shown; their reference ranges were 2.33–4.00 pg/mL, 0.880–1.620 ng/dL and 0.500–5.000 lIU/mL, respectively. The horizontal axis represents days since the first administration of pembrolizumab. LT4, levothyroxine.

Citation: European Thyroid Journal 14, 1; 10.1530/ETJ-24-0328

Predicting the development of hypothyroidism following thyrotoxicosis is crucial for its effective management. Analyses of 50 cases of thyroid irAEs demonstrated that rapid-onset severe thyrotoxicosis was strongly associated with a higher likelihood of subsequent hypothyroidism (28). In addition, the presence of anti-thyroglobulin antibodies (TgAbs) during the thyrotoxic phase is another predictive factor for the development of hypothyroidism (28). Thus, the clinical course of thyroid irAEs associated with PD-1 blockade therapy alone is well understood. For insights into thyroid irAEs arising from combination therapies involving anti-PD-1 antibodies, anti-PD-L1 antibodies and other agents, refer to the ‘Future perspectives’ section.

Risk factors

The first report identifying risk factors for thyroid irAEs highlighted the presence of thyroid autoantibodies, including TgAbs and anti-thyroperoxidase antibodies (TPOAbs) (12). Although this initial study included only four patients with thyroid irAEs, subsequent reports confirmed that positive thyroid autoantibodies, in particular for TgAbs, represent a significant risk factor for developing thyroid irAEs (24, 27, 29, 30, 31). The adjusted odds ratio (OR) for thyroid irAE development in patients with positive TgAbs was 11.927 (2.526–56.316) (24). Thyroid uptake of 18F-FDG-PET has been identified as another significant risk factor, with an adjusted OR of 14.48 (3.12–67.19) (15). It is important to note that this uptake was associated only with the development of overt thyroid irAEs and not with subclinical cases (15). Additional risk factors include prior use of tyrosine kinase inhibitors (TKIs), high BMI and elevated TSH levels, with adjusted ORs of 9.213 (1.417–59.921), 1.09 (1.02–1.16) and 1.53 (1.13–2.07), respectively (18, 20). Although adjusted ORs were not reported, heterogeneous patterns on thyroid ultrasonography and elevated levels of IL-1, IL-2 and GM-CSF have been identified as potential risk factors (30, 32). Human leukocyte antigens associated with the development of thyroid irAEs have also been identified: DPA1*01:03 and DPB1*02:01 (33).

Image findings

Representative imaging findings for thyroid irAEs are shown in Fig. 2. Ultrasonography typically revealed that the thyroid glands become hypoechoic and atrophic as the irAE progresses (Fig. 2A and B), consistent with the findings from previous reports (12, 25, 34). Given that thyroid irAEs are a form of thyroiditis, reduced iodine uptake in the thyroid is often observed on 99mTcO4 or 123I scintigraphy (Fig. 2C). Another notable imaging feature is increased thyroid uptake on 18F-FDG-PET (2, 15, 25). As mentioned earlier, pre-treatment thyroid uptake on 18F-FDG-PET is a known risk factor for the development of thyroid irAEs (Fig. 2D). In addition, thyroid uptake on 18F-FDG-PET can appear de novo or become more pronounced during the course of treatment (Fig. 2E).

Figure 2
Figure 2

Imaging findings of thyroid irAEs. (A, B and C) Imaging results from a 63-year-old female with urothelial carcinoma who developed thyroid irAEs during pembrolizumab therapy. (A) Thyroid ultrasonography performed before treatment. ICI, immune checkpoint inhibitor. (B) Thyroid ultrasonography performed 6 months after the first administration of pembrolizumab. (C) 99mTcO4 scintigraphy during thyrotoxicosis development. (D and E) Imaging results of a 66-year-old female with breast cancer who developed thyroid irAEs during nivolumab therapy. (D) 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) performed before treatment. (B) 18F-FDG-PET performed 6 months after the first administration of nivolumab.

Citation: European Thyroid Journal 14, 1; 10.1530/ETJ-24-0328

Prognosis

Two early studies suggested an association between the development of thyroid irAEs and improved prognosis (11, 14). Since then, several real-world studies have been conducted to further investigate this relationship, as summarized in Table 2 (11, 14, 15, 16, 17, 19, 21, 23, 35, 36, 37, 38). Prolonged overall survival (OS) and progression-free survival (PFS) were linked to thyroid irAE development in multiple studies. Our study found that thyroid irAEs were associated with better prognosis in non-small cell lung cancer (NSCLC), although the findings were inconclusive for malignant melanoma (15). Similar inconclusiveness has been reported in other studies (16, 35). Beyond lung cancer, the significance of this association has only been reported in high-risk renal cell carcinoma (38). Nonetheless, the development of thyroid-related irAEs is associated with a better prognosis in certain types of cancer, highlighting the importance of examining risk factors for thyroid irAEs. These factors suggest that patients with such characteristics are more likely to achieve an anticancer response.

Table 2

Associations between thyroid irAE development and prognosis. Statistically significant values are presented in bold.

Reference Patients, n ICIs used: n Primary site: n OS, HR (95% CI) PFS, HR (95% CI) Site-specific analysis Landmark analysis
Osorio et al. (11) 48 Pembrolizumab: 48 NSCLC: 48 0.29 (0.09–0.94) 0.58 (0.27–1.21) NSCLC significant Not performed
Kim et al. (14) 58 Nivolumab: 52; pembrolizumab: 6 NSCLC: 58 0.11 (0.01–0.92) 0.38 (0.17–0.85) NSCLC significant Not performed
Yamauchi et al. (15) 200 Nivolumab: 200 NSCLC: 118; MM: 42 0.61 (0.39–0.93) 0.66 (0.46–0.95) NSCLC significant

MM not significant
Performed
Sakakida et al. (16) 150 Nivolumab: 117; pembrolizumab: 33 NSCLC: 59; MM: 26 0.34 (0.13–0.75) 0.50 (0.26–0.89) NSCLC not significant

MM not significant
Not performed
Kotwal et al. (17) 91 Atezolizumab: 86; avelumab: 5 LC: 65; UC: 19 0.49 (0.25–0.99) Not performed Not performed
Basak et al. (19) 168 Nivolumab: 118; pembrolizumab: 50 NSCLC: 93; MM: 63 0.18 (0.04–0.76) 0.39 (0.15–1.00) Not performed Not performed
Kobayashi et al. (35) 174 Nivolumab: 91; pembrolizumab: 81 NSCLC: 108; MM: 66 NA NSCLC significant

MM not significant
Not performed
Muir et al. (21) 1246 PD-1/PD-L1: 705; CTLA-4 combi: 376 MM: 1246 0.95 (0.77–1.16) 0.97 (0.81–1.16) MM not significant Not performed
Luo et al. (36) 744 PD-1/PD-L1: 659; CTLA-4 combi: 85 NSCLC: 744 0.42 (0.33–0.54) NSCLC significant Performed
von Itzstein et al. (37) 1614 PD-1/PD-L1: 1301; CTLA-4 combi: 258 LC: 457; RCC: 326 NA Not performed Not performed
Sagie et al. (38) 123 CTLA-4 combi: 60; nivolumab: 35 RCC: 123 0.85 (0.50–1.45) High-risk RCC significant Not performed
Baek et al. (23) 185 Pembrolizumab: 100; nivolumab: 66 LC: 112; MM: 22 0.42 (0.24–0.73) Not performed Not performed

OS, overall survival; PFS, progression-free survival; HR, hazard ratio; irAE, immune-related adverse event.

The mechanisms underlying the differences in the prognostic effects of thyroid irAEs across primary sites remain unclear. The following reports may be informative in discussing this intriguing matter: pneumonitis is common in lung cancer, while skin irAEs are prevalent in malignant melanoma (39); patients with pneumonitis as an irAE have longer PFS in NSCLC (40); and patients with skin-related irAEs have longer OS in malignant melanoma (39). Based on these findings, a hypothesis has emerged that antigens common to both the primary sites and the thyroid gland may contribute to the prognostic effects of thyroid irAEs. A pilot study identified thyroid-specific autoantibodies, other than TgAbs and TPOAbs, in patients with thyroid irAEs receiving PD-1 blockade therapy (41), which suggested the potential presence of common antigens related to the immune response. Investigating these mechanisms could provide valuable insights into how to enhance immunotherapy from the perspective of thyroid irAEs.

Immortal time bias must be addressed, as thyroid irAEs often occur several weeks or even months after the initial ICI administration. This bias arises because patients must survive long enough to develop thyroid irAEs. Landmark analysis is commonly used to adjust for this bias. In our study, significantly longer OS in NSCLC was observed in 1-month and 2-month landmark analyses, although this was not the case for the 3-month and 6-month landmark analyses (15). Luo et al. similarly found that PFS was extended in patients with thyroid irAEs, even in their 90-day landmark analysis of an NSCLC cohort (36). Moreover, overt thyroid irAEs were significantly associated with better prognosis, while subclinical thyroid irAEs were not (15). As previously discussed, thyrotoxicosis due to overt thyroid irAEs typically has an early onset. In light of the landmark analysis results, overt thyroid irAEs occurring within the first 2 months of ICI administration seem to be particularly relevant to improved prognosis.

Management of thyroid irAEs

Monitoring

The American Society of Clinical Oncology (ASCO) guidelines recommend routine clinical monitoring of asymptomatic patients with thyroid irAEs, suggesting that ‘TSH, with the option of also including fT4, can be checked every 4–6 weeks’ (42). Both the European Society of Endocrinology (ESE) guideline and the European Society for Medical Oncology (ESMO) also recommend checking TSH and fT4 every 4–6 weeks (43, 44). As noted earlier, thyrotoxicosis typically occurs transiently between 2 and 6 weeks after ICI initiation, followed by hypothyroidism that tends to develop around 12 weeks (15). Monitoring at 4- or 6-week intervals allows for the timely detection of hypothyroidism, which may require intervention with levothyroxine replacement. However, since thyrotoxicosis can arise and resolve within the first 6 weeks after ICI administration, early detection is crucial. As thyrotoxicosis caused by thyroid irAEs is a prognostic factor and a predictor of subsequent hypothyroidism, we believe that measuring thyroid function at 4 weeks post-ICI initiation is essential to avoid missing this transient phase. Furthermore, both fT4 and TSH measurements are valuable for the following reasons: elevated fT4 levels during thyrotoxicosis are predictive of later development of hypothyroidism (28), and relying solely on TSH measurement may lead to pitfalls when anti-CTLA-4 antibodies are used concomitantly. Central hypothyroidism due to pituitary irAEs is common with anti-CTLA-4 antibodies and can present with low TSH values, mimicking thyrotoxicosis.

Monitoring thyroid function before initiating ICI therapy is also crucial. Pre-existing thyroid dysfunction can complicate the diagnosis of thyroid irAEs when relying on a single measurement. Identifying the underlying causes of thyroid dysfunction during ICI treatment is important, as it not only aids in predicting prognosis but also raises suspicion for other potential irAEs. The decision to discontinue thyroid function monitoring remains a challenge. In large cohorts, most thyroid irAEs manifest within the first 6 months of treatment (15, 21, 27). If no thyroid irAEs develop within this period, routine thyroid function monitoring may be considered. In fact, the ESE guideline advises that the monitoring interval can be extended to every 2–3 months after 6 months (43). However, thyroid function should always be assessed when patients exhibit symptoms indicative of thyroid dysfunction.

Treatment

A flow diagram outlining the management of thyroid irAEs, as proposed by the authors, is presented in Fig. 3. In most cases, thyrotoxicosis requires observation only. For moderate to severe symptoms, β-blockers may be administered to provide symptomatic relief. In contrast, hypothyroidism subsequent to thyrotoxicosis should be actively treated with levothyroxine replacement, as it frequently progresses to overt hypothyroidism and persists (3). A retrospective study found that rapid-onset severe thyrotoxicosis in patients with TgAbs was strongly associated with a high likelihood of subsequent hypothyroidism (28). On the other hand, since subclinical hypothyroidism may resolve (17), the ESE guideline suggests periodically considering the tapering and discontinuation of levothyroxine in patients with low-dose replacement (43).

Figure 3
Figure 3

Schematic diagram of thyroid irAE management.

Citation: European Thyroid Journal 14, 1; 10.1530/ETJ-24-0328

The levothyroxine replacement regimens recommended in the guidelines largely align with those for hypothyroidism not caused by thyroid irAEs. For example, the ESE guideline recommends a starting dose of 1.0 μg/kg/day for patients without risk factors and 25 μg/day for elderly patients or those with cardiovascular comorbidities (43). Regular thyroid function monitoring is then necessary to titrate the levothyroxine dosage.

ICI administration can be continued during thyroid dysfunction caused by thyroid irAEs, provided that the patient remains in good condition. It is important to emphasize that thyroid irAEs may occasionally coincide with irAEs affecting other organs. For instance, pneumonitis and liver injury are common and often necessitate pausing ICI therapy. Therefore, if thyroid irAEs are identified, continuing ICI administration should only be recommended after confirming the absence of irAEs in other organs.

Future perspectives

ICIs have traditionally been used as monotherapy in later-line treatments, indicating that much of the evidence discussed above is based on clinical experience with monotherapy. However, various combination ICI therapies have been developed as first-line treatments, and some antitumor agents may alter the clinical presentation of thyroid irAEs. Although reports specifically addressing thyroid irAEs in different regimens are limited, the following section presents the available findings along with our clinical experience.

Combination therapy with cytotoxic agents

Several regimens combining ICIs with chemotherapy have been approved (45). A retrospective cohort study determined that delayed-onset thyroid irAEs are commonly observed in patients who receive combination therapy with cytotoxic agents (25). We present two representative clinical cases to illustrate the typical clinical course. The first case, shown in Fig. 4A, involved a 72-year-old male with NSCLC treated with atezolizumab in combination with carboplatin (CBDCA) and nanoparticle albumin-bound paclitaxel (nab-PAC). For every CBDCA administration, 4.95 mg of dexamethasone was administered as a prophylactic glucocorticoid. After 93 days, maintenance therapy with atezolizumab alone was initiated. The patient developed thyrotoxicosis 135 days after the first administration, followed by hypothyroidism 177 days later. He required ongoing LT4 replacement therapy. The second case, shown in Fig. 4B, was a 63-year-old female with breast cancer treated with atezolizumab in combination with nab-PAC. Prophylactic glucocorticoids were not administered. She developed thyrotoxicosis 90 days after the first administration of atezolizumab and later developed subclinical hypothyroidism 146 days after the first dose. LT4 replacement therapy was not required in her case.

Figure 4
Figure 4

Representative clinical course of thyroid irAEs during combination therapy. (A and B) Case presentation of combination therapy with cytotoxic agents. Clinical courses of the patients who received atezolizumab plus chemotherapy are shown. Clinical information for this patient is available in the manuscript. CBDCA, carboplatin; nab-PAC, nanoparticle albumin-bound paclitaxel. (C, D and E) Case presentation of combination therapy with tyrosine kinase inhibitors. Clinical information for this patient is available in the manuscript. (C) Early phase of her clinical course. (D) Thyroid ultrasonography performed 18 days after the first administration of pembrolizumab when she developed hypothyroidism. (E) Overall clinical course.

Citation: European Thyroid Journal 14, 1; 10.1530/ETJ-24-0328

Prophylactic glucocorticoids were administered in the first case (Fig. 4A) but not in the second case (Fig. 4B). This suggests that the mechanisms of delayed-onset thyroid irAEs may involve immunosuppression induced by cytotoxic agents. When using combination therapy with cytotoxic agents, thyroid irAEs should be carefully monitored over an extended period to avoid being missed.

Combination therapy with CTLA-4 antibodies

Several studies have reported a higher frequency of endocrine irAEs during dual ICI therapy with anti-CTLA-4 and anti-PD-1 antibodies compared to PD-1 blockade monotherapy (21, 46, 47). However, data on the clinical features specific to dual ICI therapy remain limited. Hypothyroidism has been shown to occur earlier with the concomitant use of anti-CTLA-4 antibodies (47), while overt thyrotoxicosis is more frequent, although the incidence of overt hypothyroidism remains (21).

Conversely, anti-CTLA-4 antibody use is often associated with pituitary irAEs. In PD-1 blockade therapy without the use of anti-CTLA-4 antibodies, pituitary irAEs typically manifest as isolated ACTH deficiency without primary thyroid dysfunction (48, 49, 50), whereas combined pituitary irAEs with anti-CTLA-4 antibodies can result in secondary hypothyroidism (51, 52, 53). Thus, the etiology of hypothyroidism becomes more complex during dual ICI therapy, making it difficult to predict the clinical course. Since monitoring based solely on TSH levels may overlook secondary hypothyroidism, measuring both TSH and fT4 levels is recommended for patients undergoing dual ICI therapy.

Combination therapy with TKIs

During combination therapy with TKIs, several adverse events occur more frequently than during ICI monotherapy. Diarrhea, hypertension and increased transaminases are the most common adverse events associated with TKI combination therapy (54, 55, 56, 57). Since diarrhea and hypertension are also observed with TKI monotherapy (54, 55, 56), TKI-related adverse events occur in addition to irAEs. Furthermore, the incidence of thyroid dysfunction was also higher during combination therapy with TKIs compared to ICI monotherapy. In the KEYNOTE-426 study, which evaluated axitinib combined with pembrolizumab for renal cell carcinoma, hypothyroidism occurred in 35.4% of patients and hyperthyroidism occurred in 12.8% (54). Similarly, in the CLEAR trial, which examined lenvatinib combined with pembrolizumab for renal cell carcinoma, the incidence of hypothyroidism was 47.2% and that of hyperthyroidism was 8.0% (55). In the CheckMate 9ER study, which evaluated cabozantinib and nivolumab for renal cell carcinoma, hypothyroidism was observed in 34.1% of the patients and hyperthyroidism in 10.0% (56). In the KEYNOTE-775 study, which evaluated lenvatinib and pembrolizumab for endometrial cancer, hypothyroidism was observed in 57.4% of the patients and hyperthyroidism was observed in 11.6% (57).

However, much of the thyroid dysfunction observed in these studies appears to be attributable to TKIs themselves, as thyroid dysfunction was also common in the control groups receiving TKIs alone. For example, in the KEYNOTE-426 study, the incidence of hypothyroidism was 31.5% and hyperthyroidism was 3.8% with sunitinib monotherapy (54). Similarly, in the CLEAR trial, hypothyroidism occurred in 24.5% of patients receiving lenvatinib and everolimus and in 23.2% of those treated with sunitinib alone (55).

Thyroid dysfunction due to TKIs is well known and includes both hypothyroidism and thyrotoxicosis (58). Hypothyroidism is more prevalent than thyrotoxicosis; a review of various studies on TKIs revealed an incidence of 33.2% for hypothyroidism and 3.14% for hyperthyroidism (59). During combination therapy with TKIs, TKI-induced thyroid dysfunction may coexist with irAE-induced thyroid dysfunction. Although the clinical course of TKI-induced thyroid dysfunction is not fully understood, a retrospective study indicated that hypothyroidism typically develops early, with a median onset of 16 days after the first TKI administration (60).

Our patient, who received combination therapy of pembrolizumab and lenvatinib, experienced a similar clinical course (Fig. 4C, D, E). A 57-year-old female with renal cell carcinoma developed hypothyroidism 18 days after the first administration (Fig. 4C). Both TgAbs and TPOAbs were negative. Simultaneously, thyroid ultrasonography revealed no hypoechoic or atrophic changes in the thyroid gland (Fig. 4D). Hypothyroidism was initially managed with a small dose of levothyroxine, but the patient subsequently developed thyrotoxicosis, followed by worsened hypothyroidism (Fig. 4E). Thyrotoxicosis occurred 88 days after the first administration, and worsened hypothyroidism was observed 130 days post-treatment initiation.

The clinical course of TKI-induced thyroid dysfunction appears to differ from that of thyroid irAEs, which typically present as non-severe hypothyroidism initially. Identifying the underlying cause of thyroid dysfunction during combination therapy with TKIs is crucial, as TKI-induced thyroid dysfunction may not be associated with a favorable prognosis often associated with thyroid irAEs. At this point, distinguishing the etiology of thyroid dysfunction during combination therapy with TKIs is challenging. However, the negative results of thyroid autoantibodies, along with the absence of hypoechoic changes in thyroid ultrasonography, as seen in the presented case, may suggest TKI-induced thyroid dysfunction.

Conclusion

Thyroid irAEs are common adverse events associated with cancer immunotherapy. The real-world evidence reviewed here clarifies their clinical features and suggests the optimal management strategies, which help endocrinologists and oncologists develop a common understanding of thyroid irAEs. However, as cancer immunotherapy becomes increasingly diverse and complex, the management of thyroid irAEs must be adapted accordingly. ICIs are now used as first-line, adjuvant and even neoadjuvant therapies, further complicating treatment. Endocrine-related irAEs typically require lifelong replacement therapies, such as levothyroxine for thyroid irAEs and insulin for diabetes. Unlike later-line ICI therapies, early-line ICI treatments require a careful balance between their benefits and the risk of irAEs, particularly the potential for persistent hormone deficiencies. This review aims to support shared decision making and improve the clinical management of thyroid irAEs.

Declaration of interest

The authors declare that there are no conflicts of interest that could be perceived as prejudicing the impartiality of this study.

Funding

This work did not receive any specific grants from any funding agency in the public, commercial or not-for-profit sectors.

Author contribution statement

All authors were involved in drafting the manuscript and critically revising it for important intellectual content. All authors have read and approved the final version of the manuscript.

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  • Figure 1

    Representative clinical course of immune-related adverse events involving the thyroid gland (thyroid irAEs). Clinical information for this patient is available in the manuscript. Longitudinal values of free T3 (fT3, orange dotted line), free T4 (fT4, green solid line) and thyroid-stimulating hormone (TSH, gray dashed line) are shown; their reference ranges were 2.33–4.00 pg/mL, 0.880–1.620 ng/dL and 0.500–5.000 lIU/mL, respectively. The horizontal axis represents days since the first administration of pembrolizumab. LT4, levothyroxine.

  • Figure 2

    Imaging findings of thyroid irAEs. (A, B and C) Imaging results from a 63-year-old female with urothelial carcinoma who developed thyroid irAEs during pembrolizumab therapy. (A) Thyroid ultrasonography performed before treatment. ICI, immune checkpoint inhibitor. (B) Thyroid ultrasonography performed 6 months after the first administration of pembrolizumab. (C) 99mTcO4 scintigraphy during thyrotoxicosis development. (D and E) Imaging results of a 66-year-old female with breast cancer who developed thyroid irAEs during nivolumab therapy. (D) 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) performed before treatment. (B) 18F-FDG-PET performed 6 months after the first administration of nivolumab.

  • Figure 3

    Schematic diagram of thyroid irAE management.

  • Figure 4

    Representative clinical course of thyroid irAEs during combination therapy. (A and B) Case presentation of combination therapy with cytotoxic agents. Clinical courses of the patients who received atezolizumab plus chemotherapy are shown. Clinical information for this patient is available in the manuscript. CBDCA, carboplatin; nab-PAC, nanoparticle albumin-bound paclitaxel. (C, D and E) Case presentation of combination therapy with tyrosine kinase inhibitors. Clinical information for this patient is available in the manuscript. (C) Early phase of her clinical course. (D) Thyroid ultrasonography performed 18 days after the first administration of pembrolizumab when she developed hypothyroidism. (E) Overall clinical course.

  • 1

    Orlov S , Salari F , Kashat L , et al. Induction of painless thyroiditis in patients receiving programmed death 1 receptor immunotherapy for metastatic malignancies. J Clin Endocrinol Metab 2015 100 17381741. (https://doi.org/10.1210/jc.2014-4560)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    de Filette J , Jansen Y , Schreuer M , et al. Incidence of thyroid-related adverse events in melanoma patients treated with pembrolizumab. J Clin Endocrinol Metab 2016 101 44314439. (https://doi.org/10.1210/jc.2016-2300)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Yamauchi I , Sakane Y , Fukuda Y , et al. Clinical features of nivolumab-induced thyroiditis: a case series study. Thyroid 2017 27 894901. (https://doi.org/10.1089/thy.2016.0562)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Kotwal A , Gustafson MP , Bornschlegl S , et al. Immune checkpoint inhibitor-induced thyroiditis is associated with increased intrathyroidal T lymphocyte subpopulations. Thyroid 2020 30 14401450. (https://doi.org/10.1089/thy.2020.0075)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Lechner MG , Zhou Z , Hoang AT , et al. Clonally expanded, thyrotoxic effector CD8(+) T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis. Sci Transl Med 2023 15 eadg0675. (https://doi.org/10.1126/scitranslmed.adg0675)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Khan Z , Hammer C , Carroll J , et al. Genetic variation associated with thyroid autoimmunity shapes the systemic immune response to PD-1 checkpoint blockade. Nat Commun 2021 12 3355. (https://doi.org/10.1038/s41467-021-23661-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Yasuda Y , Iwama S , Sugiyama D , et al. CD4(+) T cells are essential for the development of destructive thyroiditis induced by anti-PD-1 antibody in thyroglobulin-immunized mice. Sci Transl Med 2021 13 eabb7495. (https://doi.org/10.1126/scitranslmed.abb7495)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Lechner MG , Cheng MI , Patel AY , et al. Inhibition of IL-17A protects against thyroid immune-related adverse events while preserving checkpoint inhibitor antitumor efficacy. J Immunol 2022 209 696709. (https://doi.org/10.4049/jimmunol.2200244)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Barroso-Sousa R , Barry WT , Garrido-Castro AC , et al. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncol 2018 4 173182. (https://doi.org/10.1001/jamaoncol.2017.3064)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Delivanis DA , Gustafson MP , Bornschlegl S , et al. Pembrolizumab-induced thyroiditis: comprehensive clinical review and insights into underlying involved mechanisms. J Clin Endocrinol Metab 2017 102 27702780. (https://doi.org/10.1210/jc.2017-00448)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Osorio JC , Ni A , Chaft JE , et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. Ann Oncol 2017 28 583589. (https://doi.org/10.1093/annonc/mdw640)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Kobayashi T , Iwama S , Yasuda Y , et al. Patients with antithyroid antibodies are prone to develop destructive thyroiditis by nivolumab: a prospective study. J Endocr Soc 2018 2 241251. (https://doi.org/10.1210/js.2017-00432)

    • PubMed
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