How Prevalent Is Checkpoint Inhibitor Thyroid Dysfunction, Really?

Thyroid dysfunction stemming from immune checkpoint inhibitor use in cancer may be more common than previously reported, according to a new study.

In an analysis of over 1,100 patients treated with checkpoint inhibitors, 19% developed thyroid immune related adverse events, reported Zoe Quandt, MD, of the University of California San Francisco.

Of these patients who developed immune checkpoint inhibitor induced thyroid dysfunction, hypothyroidism developed in 13.4% and hyperthyroidism in 9.5%, Quandt explained at the virtual ENDO 2020 meeting sponsored by the Endocrine Society.

These rates are considerably higher than were reported in clinical trials, as summarized in a previous meta-analysis. Pooled data from 38 trials showed rates of 6.6% for hypothyroidism and 2.9% for hyperthyroidism. Rates in the current analysis were consistent, however, with an earlier cohort study from the Mayo Clinic.

"I think some of the reason we're finding more cases than previous studies is that once we're actually using these drugs outside of clinical trials, the restrictions on giving them to patients with other autoimmune diseases have been lifted," Quandt explained during an online press conference on the findings. "My guess is that some of this is just that as we give it to a broader population, we're seeing more of these results."

Another likely aspect at play, she said, is that "in the initial trials, people weren't quite as aware of the possibility of certain side effects, and so we're now doing many more labs -- you basically get thyroid function tests with every infusion -- and so I think we're probably catching more patients who develop disease."

The risk for new onset thyroid dysfunction was also significantly tied to the type of cancer, even after adjustment for age, gender, and type of checkpoint inhibitor used. Calling this finding "surprising," Quandt said her group is currently looking into these differences.

A total of 40% of those on a checkpoint inhibitor for renal cell cancer developed thyroid dysfunction -- the highest rate out of all the cancers. On the other hand, only 10.2% of those on a checkpoint inhibitor for glioblastoma developed thyroid dysfunction.

"One possibility [for these differences] is the other treatments the patients are getting," Quandt suggested. "Particularly for renal cell cancer, some of these patients have gotten tyrosine kinase inhibitors, which can also cause thyroid dysfunction, and so perhaps those patients have already been exposed to that drug and then they get put on an immune checkpoint inhibitor, and so they're thyroids a little bit more susceptible."

Part of it may be the "shared antigen," she said -- that is, thyroid proteins resemble those in some cancer cells and are inadvertently targeted by the therapy.

Risk was also higher when checkpoint inhibitors were combined -- particularly with ipilimumab (Yervoy) and nivolumab (Opdivo) together, which showed a rate of 31%. Patients on pembrolizumab (Keytruda), nivolumab, or ipilimumab monotherapy developed thyroid abnormalities at rates of about half that.

Quandt's study drew upon electronic health records at a single U.S. academic center for patients treated from 2012 to 2018. Individuals with thyroid cancer or preexisting thyroid disease were excluded.

New onset thyroid dysfunction was defined as lab results showing abnormal thyroid stimulating hormone or free T4 levels, or the initiation of a thyroid medication such as hormone replacement, methimazole (Tapazole), or propylthiouracil.

The cancer most commonly treated with an immune checkpoint inhibitor was melanoma (32%), followed by non-small cell lung cancer (13%). Rates of treatment with checkpoint inhibitors were less than 10% for all other cancers.

Pembrolizumab was the most commonly used agent (45%), followed by nivolumab (20%). Less than 10% of patients received another type of checkpoint inhibitor, such as atezolizumab (Tecentriq), durvalumab (Imfinzi), ipilimumab monotherapy, or combinations.

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