Incidence, features, and prognosis of immune-related adverse events involving the thyroid gland induced by nivolumab

Background Blocking the PD-1 pathway induces immune-related adverse events (irAEs) which often involve the thyroid gland (thyroid irAEs). Clinical features of a thyroid irAE including its predictability and relationship to prognosis remain to be elucidated. Methods Two hundred consecutive patients treated with nivolumab at Kyoto University Hospital between September 1, 2014 and August 31, 2017 were included in a retrospective cohort study. We systematically determined and classified subclinical and overt thyroid irAEs based on data collected of serum free T4 and TSH levels. Baseline characteristics and detailed clinical data were analyzed, and analyses of overall survival (OS) excluded patients censored within 1 month from the first administration of nivolumab. Results Sixty-seven patients (33.5%) developed thyroid irAEs and these were divided into a subclinical thyroid irAE group (n = 40, 20.0%) and an overt thyroid irAE group (n = 27, 13.5%). Patients with thyroid uptake of FDG-PET before treatment showed high incidences of overt thyroid irAE (adjusted odds ratio 14.48; 95% confidence interval [CI] 3.12–67.19), while the same relationship was not seen with subclinical thyroid irAE. Regarding the total cohort, the thyroid irAE (+) group had a significantly longer median OS than the thyroid irAE (−) group (16.1 versus 13.6 months, hazard ratio [HR] 0.61; 95% CI 0.39–0.93). In 112 non-excluded patients with lung cancer, the thyroid irAE (+) group similarly had a longer median OS than the thyroid irAE (−) group (not reached versus 14.2 months, HR 0.51; 95% CI 0.27–0.92). However, this observation was not seen in 41 non-excluded patients with malignant melanoma (12.0 versus 18.3 months, HR 1.54; 95% CI 0.67–3.43). Conclusions By thyroid uptake of FDG-PET, overt thyroid irAEs could be predicted before nivolumab therapy. Thyroid irAEs related to good prognosis in lung cancer but might be inconclusive in malignant melanoma.

[1]  Xin Wang,et al.  Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-analysis. , 2019, JAMA oncology.

[2]  Young Hak Kim,et al.  Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study. , 2018, Lung cancer.

[3]  M. Akiyama,et al.  Patients With Antithyroid Antibodies Are Prone To Develop Destructive Thyroiditis by Nivolumab: A Prospective Study , 2018, Journal of the Endocrine Society.

[4]  Tae Yong Kim,et al.  Development of thyroid dysfunction is associated with clinical response to PD-1 blockade treatment in patients with advanced non-small cell lung cancer , 2018, Oncoimmunology.

[5]  E. Plimack,et al.  Immune-Related Adverse Events as a Biomarker in Non-Melanoma Patients Treated with Programmed Cell Death 1 Inhibitors. , 2017, The oncologist.

[6]  Kaoru Tanaka,et al.  Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non–Small-Cell Lung Cancer , 2017, JAMA oncology.

[7]  A. Dietz,et al.  Pembrolizumab-Induced Thyroiditis: Comprehensive Clinical Review and Insights Into Underlying Involved Mechanisms , 2017, The Journal of clinical endocrinology and metabolism.

[8]  D. Taura,et al.  Clinical Features of Nivolumab-Induced Thyroiditis: A Case Series Study. , 2017, Thyroid : official journal of the American Thyroid Association.

[9]  J. Wolchok,et al.  Cancer immunotherapy — immune checkpoint blockade and associated endocrinopathies , 2017, Nature Reviews Endocrinology.

[10]  C. Rudin,et al.  Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[11]  S. Moschos,et al.  Next steps in immuno-oncology: enhancing antitumor effects through appropriate patient selection and rationally designed combination strategies , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[12]  B. Neyns,et al.  Incidence of Thyroid-Related Adverse Events in Melanoma Patients Treated With Pembrolizumab , 2016, The Journal of clinical endocrinology and metabolism.

[13]  G. Gibney,et al.  Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes , 2015, Clinical Cancer Research.

[14]  S. Orlov,et al.  Induction of painless thyroiditis in patients receiving programmed death 1 receptor immunotherapy for metastatic malignancies. , 2015, The Journal of clinical endocrinology and metabolism.

[15]  Irwin Klein,et al.  Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. , 2012, Thyroid : official journal of the American Thyroid Association.

[16]  V. Lowe,et al.  Clinical Significance of Diffusely Increased 18F-FDG Uptake in the Thyroid Gland , 2007, Journal of Nuclear Medicine.

[17]  W Harry Hannon,et al.  Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). , 2002, The Journal of clinical endocrinology and metabolism.

[18]  J R Anderson,et al.  Analysis of survival by tumor response. , 1983, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  Pintong Huang,et al.  A CASE SERIES STUDY , 2020 .

[20]  Y. Koh,et al.  Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab. , 2018, Lung cancer.

[21]  L. Schwartz,et al.  New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). , 2009, European journal of cancer.