PD-1/CTLA-4-Abs Linked to Risk of Thyroid Immune System Adverse Events

PD-1/CTLA-4-Abs Linked to Risk of Thyroid Immune System Adverse Events

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

The prospective study analyzed irAEs in patients treated with immune checkpoint inhibitors (ICI) from November 2, 2015 to 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) 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.

Continue Reading

During the observation period, 41 (9.9%) and 10 (37.0%) patients had thyroid AEs after starting treatment with PD-1-Ab and PD-1/CTLA-4- Abs, respectively, versus no patient with thyroid AEs after starting CTLA-4-Ab treatment alone. The cumulative incidence of thyroid AEs was significantly different between the 3 ICI treatment groups (log-rank test, P < 0.001) and increased significantly after PD-1/CTLA-4-Abs treatment vs. PD-1-Abs alone. (log-rank test, P < .001).

The cumulative incidence of thyroid AEs was higher in patients positive for antithyroid antibodies (ATA) at baseline in the Ac-PD-1 (Ac+) group compared to the Ac-PD-1 (Ac-) group ( 28/87 [32.2%] against 13/329 [4.0%]log rank test, P < 0.001) and in the PD-1/CTLA-4-Abs (Ab+) group vs the PD-1/CTLA-4-Abs (Ab-) group (6/10 [60.0%] against 4/17 [23.5%]log rank test, P < .05). Thyrotoxicosis was observed in 35 patients (28 patients treated with Ac-PD-1 and 7 patients treated with Ac-PD-1/CTLA-4), including 25 (21 patients treated with Ac-PD-1 and 4 patients treated with by PD-1/CTLA-4-Abs) eventually developed hypothyroidism.

In patients who did not have ATA at baseline, the cumulative incidence of thyroid AEs was significantly higher in the PD-1/CTLA-4-Abs (Ab-) group than in the PD-1-Ab group. (Ab-) (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. Additionally, 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 AEs was high and non-negligible after PD-1/CTLA-4-Abs treatment, even in ATA-negative patients at baseline, indicating the need for monitoring. tighter thyroid function in patients starting the combination. immunotherapy,” the researchers concluded.

Disclosure: Some of the study authors have disclosed affiliations with biotechnology, pharmaceutical and/or device companies. Please see the original citation for a full list of author disclosures.


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