The risk of thyroid immune-related adverse events (irAEs) was higher after anti-programmed cell death-1 antibodies (PD-1-Ab) and anti-cytotoxic T-lymphocyte antigen-4 antibody (CTLA-4-Ab) combination immunotherapy, compared with PD-1-Ab alone. This was shown even in patients with malignancies who were negative for antithyroid antibodies (ATAs) at baseline, investigators reported in the Journal of Clinical Endocrinology and Metabolism.

The prospective study analyzed irAEs in patients treated with immune checkpoint inhibitors (ICIs) from November 2, 2015, through January 12, 2021. The researchers assessed serum levels of free T3 (FT3), free T4 (FT4), and thyroid-stimulating hormone (TSH) at baseline and every 6 weeks for 24 weeks after the first treatment.

A total of 451 patients with various malignancies—including malignant melanoma (n = 126), non-small cell lung carcinoma (n = 164), and renal cell carcinoma (n = 61)—who were treated with PD-1-Ab (nivolumab or pembrolizumab, n = 416), CTLA-4-Ab (ipilimumab, n = 8), or PD-1/CTLA-4-Abs (nivolumab plus ipilimumab, n = 27) were included.

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In the observation period, 41 (9.9%) and 10 (37.0%) patients had thyroid irAEs after initiation of PD-1-Ab and PD-1/CTLA-4-Abs therapy, respectively, vs no patients with thyroid irAEs after initiation of CTLA-4-Ab treatment alone. The cumulative incidence of thyroid irAEs was significantly different among the 3 ICI treatment groups (log-rank test, P < .001) and was significantly increased after PD-1/CTLA-4-Abs vs PD-1-Ab treatment alone. (log-rank test, P < .001).

The cumulative incidence of thyroid irAEs was higher in patients who were positive for antithyroid antibodies (ATA) at baseline in the PD-1-Ab (Ab+) vs the PD-1-Ab (Ab-) group (28/87 [32.2%] vs 13/329 [4.0%], log-rank test, P < .001) and in the PD-1/CTLA-4-Abs (Ab+) vs the PD-1/CTLA-4-Abs (Ab-) group (6/10 [60.0%] vs 4/17 [23.5%], log-rank test, P < .05). Thyrotoxicosis was observed in 35 patients (28 patients treated with PD-1-Ab and 7 patients treated with PD-1/CTLA-4-Abs), of whom 25 (21 patients treated with PD-1-Ab and 4 patients treated with PD-1/CTLA-4-Abs) eventually developed hypothyroidism.

In patients who did not have ATAs at baseline, the cumulative incidence of thyroid irAEs was significantly higher in the PD-1/CTLA-4-Abs (Ab-) group than in the PD-1-Ab (Ab-) group (23.5% vs 4.0%, log-rank test, P < .001).

Study limitations include the small number of patients treated with CTLA-4-Ab and PD1/CTLA-4-Abs. In addition, the PD-1-Ab group included patients treated with PD-1-Ab alone as well as those treated with PD-1-Ab plus chemotherapy.

“Our prospective study demonstrated that the incidence of thyroid irAEs was high and not negligible after PD-1/CTLA-4-Abs treatment, even in patients negative for ATAs at baseline, indicating a requirement for closer monitoring of thyroid function in patients starting combination immunotherapy,” the researchers concluded.

Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Iwama S, Kobayashi T, Yasuda Y, et al. Increased risk of thyroid dysfunction by PD-1 and CTLA-4 blockade in patients without thyroid autoantibodies at baseline. J Clin Endocrinol Metab. Published online November 15, 2021. doi:10.1210/clinem/dgab829