BACKGROUND
Recent advancements in cancer treatment include the introduction of immunotherapy and kinase inhibitors, which have significantly improved cancer prognosis among patients. However, these compounds are responsible for several adverse events that affect the endocrine glands. Endocrine-related adverse events, and specifically thyroid abnormalities, are now acknowledged as frequent side effects of classes of drugs known as immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs). Interestingly, thyroid abnormalities during treatment with ICIs has been shown to be a positive prognostic sign.

The favorable outcome achieved with ICI and TKI drugs individually have prompted clinical trials assessing combined ICI+TKI regimens. Initial reports indicate a potential increase in rates of thyroid abnormalities during combined ICI+TKI therapy. This study examines the effect of ICI+TKI therapy on thyroid function in cancer patients with normal thyroid function as determined by pretreatment TSH levels.

THE FULL ARTICLE TITLE
Tsai K et al. The combined effect of immune checkpoint inhibitors and tyrosine kinase inhibitors on thyroid function. Thyroid 2024;34(2):158-166; doi: 10.1089/ thy.2023.0542. PMID: 38069567.

SUMMARY OF THE STUDY
This study included adult patients treated with a combination of ICI and TKI therapy for solid cancers. ICIs used were pembrolizumab, nivolumab, and ipilimumab, and the TKIs used were lenvatinib, axitinib, sunitinib, pazopanib, cabozantinib, tivozanib, and imatinib. After receiving ICI+TKI, patients were identified as having no thyroid abnormalities if they had no changes in thyroid hormone levels. Thyroid disturbances were defined as follows: 1) hypothyroidism as elevated TSH and low FT4 levels; 2) subclinical hypothyroidism as elevated TSH with normal FT4 levels; 3) hyperthyroidism as a low TSH and elevated FT4 levels; and 4) subclinical hyperthyroidism as low TSH with normal FT4 levels. Patients who needed an increase in thyroid hormone therapy after initiation of ICI+TKI were defined as having worsening of hypothyroidism.

A total of 106 patients with previous notmal thyroid function were included. Most patients were female (70.8%), the average age was 63.5 years and the most common cancer was uterine cancer (43.4%). The most common ICI+TKI therapy was pembrolizumab plus lenvatinib (73 patients, 68.9%). Of these patients, 67 (63.2%) developed new thyroid abnormalities after receiving ICI+TKI. In particular, 14 (13.2%) developed hypothyroidism, 42 (39.6%) developed subclinical hypothyroidism and 11 (10.4%) developed hyperthyroidism. No patients had subclinical hyperthyroidism. The onset of thyroid abnormalities occurred during the early phase of treatment with ICI+TKI. The average time from initiation of ICI+TKI treatment to hyperthyroidism was 7 weeks, to hypothyroidism 8.1 weeks and to subclinical hypothyroidism 8 weeks. All cases of hyperthyroidism resolved to a normal thyroid state or hypothyroidism in 12 weeks without intervention. Females had a 2.72-fold increased risk of developing thyroid abnormalities, after adjusting for age.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
This study shows that changes in thyroid function are commonly observed during treatment with the combination ICI+TKI, typically starting within the initial weeks of therapy. Hypothyroidism is the most common result and is often long-term and requires treatment with levothyroxine. Hyperthyroidism is also common, but is short lived, resolving within 3 months and usually does not need to be treated. It is recommended to routinely monitor thyroid function from the initial stages of ICI+TKI therapy to promptly detect any abnormalities.

— Alan P. Farwell, MD

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