Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer
Open accessAbstract
Background Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described.Patient and methods Patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n = 51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated.Results Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P < 0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09-0.94; P = 0.04).Conclusions Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity.
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Positive TPOAb and/or thyroglobulin autoantibodies (TgAb) are associated with a 40 to 70% risk of hypothyroidism during immune checkpoint inhibitor (ICPi) treatment.
“Two retrospective and two prospective studies reported that positive TPOAb and/or thyroglobulin autoantibodies (TgAb) are associated with a 40 to 70% risk of hypothyroidism during treatment”
From Graves’ Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review) (2021) · cites this paper as [56]
The ‘TSH kinetics and association of thyroid dysfunction with anti-thyroid antibodies’ section reports a strong association during pembrolizumab treatment: antibodies were present in 8 of 10 patients who developed thyroid dysfunction, versus 3 of 38 who did not. But the paper does not report a 40–70% risk of hypothyroidism among antibody-positive patients. Its figures concern thyroid dysfunction in patients with non-small-cell lung cancer, and antibody positivity could arise during treatment rather than being present beforehand. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPatients who had ICPi-induced hypothyroidism had positive anti-thyroid autoantibodies in 75 to 100% of cases.
“and that patients who had ICPi-induced hypothyroidism had positive anti-thyroid autoantibodies in 75 to 100% of cases [54,55,56,57].”
From Graves’ Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review) (2021) · cites this paper as [56]
In the Osorio study, survival was better if patients developed ICPi-induced thyroid dysfunction.
“Note that in the Osorio study [56], survival was better if patients developed ICPi-induced thyroid dysfunction”
From Graves’ Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review) (2021) · cites this paper as [56]
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- Authors
- Osorio, J. C., Ni, A., Chaft, J. E., Pollina, R., Kasler, M. K., Stephens, D., Rodriguez, C., Cambridge, L., Rizvi, H., Wolchok, J. D., Merghoub, T., Rudin, C. M., Fish, S., & Hellmann, M. D.
- Affiliations
- Weill Cornell Medicine (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Hellmann, M.D.
- Venue
- Annals of Oncology
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 28
- Issue
- 3
- Pages
- 583-589
- ISSN
- 0923-7534 (ISSN-L)
- PMC
- PMC5834017
- OpenAlex
- W2561156916
- Cited by
- 659
- References
- 26
- Citations by year
- 2026: 23 · 2025: 50 · 2024: 70 · 2023: 75 · 2022: 102 · 2021: 95 · 2020: 98 · 2019: 77 · 2018: 51 · 2017: 17
- FWCI
- 26.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Annals of Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (P30 CA008748)
- Fiona and Stanley Druckenmiller Center for Lung Cancer Research
- KEYNOTE-001 (NCT01295827)
- Merck Sharp & Dohme, a subsidiary of Merck
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Neurology › Autoimmune Neurological Disorders and Treatments
- Keywords
- immune-related adverse events, anti-thyroid antibodies, pembrolizumab, anti-PD-1 therapy, non-small cell lung cancer, hypothyroidism, hyperthyroidism, humoral immunity, immune checkpoint inhibitors, progression-free survival, overall survival
- MeSH terms
- Adolescent, Adult, Aged, Antibodies, Monoclonal, Carcinoma, Non-Small-Cell Lung, Female, Humans, Hyperthyroidism, Male, Middle Aged, Neoplasm Staging, T-Lymphocytes, Thyroid Gland, Disease-Free Survival, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized, Drug-Related Side Effects and Adverse Reactions
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