BACKGROUND
New drugs that use the body’s immune system to attack cancer, called immunotherapy, have been a major breakthrough in treating non-thyroid cancer. Indeed, drugs called anti-programmed cell death ligand-1 antibody (PD- (L)1-Ab) do have a side effect of occasionally attacking the thyroid, causing autoimmune thyroiditis and hypothyroidism. Another class of cancer drugs, known as Tyrosine kinase inhibitors (TKIs) also have been shown to cause hypothyroidism. Both of these drugs can treat cancer alone or in combination.

This study examined the frequency, and clinical characteristics of thyroid problems caused by combination therapy with PD-(L)1-Ab and TKI cancer immunotherapy drugs.

THE FULL ARTICLE TITLE
Kobayashi T et al. Combined use of tyrosine kinase inhibitors with PD-(L)1 blockade increased the risk of thyroid dysfunction in PD-(L)1 blockade: a prospective study. Cancer Immunol Immunother 2024;73(8):146; doi: 10.1007/s00262-024-03733-2. PMID: 38833157.

SUMMARY OF THE STUDY
This study included patients treated with a PD-(L)1-Ab drug alone or in combination with TKI drugs between November 2, 2015, and July 12, 2023, at Nagoya University Hospital. Thyroid function tests and thyroid autoantibodies (TPO and thyroglobulin antibodies) were measured in all patients and TSH receptor antibody measured in patients who developed hyperthyroidism at baseline prior to starting the drugs and during follow-up.

The study included 757 patients: 734 (97%) were treated with PD-(L)1-Ab alone and 23 (3%) were treated with PD-(L)1-Ab and TKI together. The total number of patients with autoimmune thyroiditis were significantly higher in patients treated with PD-(L)1-Ab in combination with TKI than in those treated with PD-(L)1-Ab alone for autoimmune thyroiditis (4 of 23, 17.4% vs. 45 of 734, 6.1%), isolated hypothyroidism (10 of 23, 43.5% vs. 29 of 734, 4.0%) and all thyroid problems (14 of 23, 60.9% vs. 74 of 734, 10.1%). All patients with positive TPO or thyoglobulin antibodies at baseline developed thyroid problems after PD-(L)1-Ab in combination with TKI treatment, which was a significantly higher risk than in patients negative for these thyroid antibodies at baseline (4 of 4, 100% vs. 10 of 19, 52.6%). The average time to the development of thyroid problems did not differ significantly between the PD-(L)1-Ab alone group (48 days) and the PD-(L)1-Ab in combination with TKI group (58 days).

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
This study confirms that the use of cancer immunotherapy drugs for non-thyroid cancer frequently cause thyroid problems, including thyroiditis and hypothyroidism. This study also shows that the risk of developing thyroid problems is more common when using these drugs in combination as compared to using these drugs alone. Further, patients with positive thyroid antibodies are at a much higher risk of developing thyroid problems on these drugs. This is important in monitoring patients on these cancer drugs for the development of thyroid problems.

— Alan P. Farwell, MD

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