Endocrinol Metab.  2021 Apr;36(2):413-423. 10.3803/EnM.2020.906.

Characteristics of Immune-Related Thyroid Adverse Events in Patients Treated with PD-1/PD-L1 Inhibitors

• Yoon JH
• Hong AR
• Kim HK
• Kang HC

• KMID: 2515467
• DOI: http://doi.org/10.3803/EnM.2020.906

Abstract

Background
Thyroid immune-related adverse events (IRAEs) have been reported in patients treated with programmed cell death protein-1 (PD-1) and programmed cell death protein-ligand 1 (PD-L1) inhibitors. We investigated the incidence and clinical course of PD-1/PD-L1 inhibitor-induced thyroid IRAEs, and identified predictable clinical risk factors of thyroid IRAEs, in particular, overt hypothyroidism (OH).
Methods
We retrospectively reviewed the medical records of 325 cancer patients receiving PD-1/PD-L1 inhibitor in a tertiary referral center.
Results
A total of 50.5% (164/325) of patients experienced at least one abnormal thyroid function following PD-1/PD-L1 inhibitor. Eighty-four patients (51.2%) of them recovered to normal thyroid function during follow-up. In overall population, 25 patients (7.7%) required thyroid hormone replacement therapy due to PD-1/PD-L1 inhibitor-induced OH. Patients who progressed to OH showed significantly higher baseline thyroid stimulating hormone level and longer duration of PD-1/PD-L1 inhibitor therapy than those without thyroid dysfunction or OH (both P<0.001). Median time interval to the development of OH was 3 months after the therapy. OH was significantly associated with positive anti-thyroid peroxidase antibody at baseline and anti-thyroglobulin antibody during the therapy than those without thyroid dysfunction or OH (P=0.015 and P=0.005, respectively). We observed no patients with OH who were able to stop levothyroxine replacement after the cessation of PD-1/PD-L1 inhibitor therapy.
Conclusion
PD-1/PD-L1 inhibitor-induced thyroid dysfunctions are considerably reversible; however, OH is irreversible requiring levothyroxine replacement even after stopping the therapy. Positive thyroid autoantibodies may predict the progression to OH.

Keyword

Programmed cell death 1 receptor; Immune checkpoint inhibitors; Hypothyroidism; Adverse effects

Figure

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  Fig. 1 Flow diagram of investigated cohort of programmed cell death 1 (PD-1)/programmed cell death protein-ligand 1 (PD-L1) inhibitor-treated cancer patients to evaluate the occurrence of thyroid immune-related adverse events (IRAEs).

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  Fig. 2 Thyroid ultrasonographic findings in a 68-year-old male patient treated with programmed cell death 1 (PD-1) inhibitor pembrolizumab for renal cell carcinoma. He initiated to receive 125 μg/day of levothyroxine at 3 months after pembrolizumab. Thyroid ultrasonographic images (A) before therapy, (B) at 1 month after therapy, (C) at 15 months after therapy, and (D) at 40 months after therapy. TSH, thyroid stimulating hormone; T4, thyroxine; TPO, thyroid peroxidase; Tg, thyroglobulin. aOn levothyroxine replacement.

• 

  Fig. 3 Thyroid ultrasonographic features and clinical course of a 57-year-old male patient with lung cancer treated with programmed cell death 1 (PD-1) inhibitor nivolumab. He started to receive levothyroxine replacement at 4 months after nivolumab. Severe thyroid gland atrophy was revealed on thyroid ultrasonography at 2 months after stopping nivolumab. Pre-therapy thyroid ultrasonographic images in (A) transverse and (B) longitudinal view. Thyroid ultrasonographic images at 2 months after the last injection of nivolumab in (C) transverse and (D) longitudinal view. TSH, thyroid stimulating hormone; T4, thyroxine; TPO, thyroid peroxidase; Tg, thyroglobulin. aOn levothyroxine replacement.

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