Mayo Study Characterizes Pembrolizumab-Induced Thyroiditis

Danae Delivanis, MD

Abnormal thyroid function tests were reported in up to 15% of patients treated with the PD-1 inhibitor pembrolizumab, according to a comprehensive review from the Mayo Clinic presented by Danae Delivanis, MD, at the 2015 International Thyroid Congress.

"We found that the incidence of any thyroid abnormality was as high as 15%," Delivanis, Division of Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic, told OncLive. "We had from the 14 cases of abnormal thyroid tests, 7 cases of thyroiditis, 4 cases of new-onset, overt, or subclinical hypothyroidism, and 3 cases of recurrent hypothyroidism actually requiring adjustments of their levothyroxine dose more than 50%."

Pembrolizumab is FDA-approved to treat patients with metastatic melanoma and for those with metastatic non—small cell lung cancer (NSCLC). The therapy is known to cause immune-related adverse events (AEs), often of the thyroid. Other severe immune-mediated AEs associated with the drug include pneumonitis, colitis, hepatitis, hypophysitis, hyperthyroidism, hypothyroidism, type 1 diabetes mellitus, and nephritis.

For the study, researchers completed a comprehensive retrospective review of 93 patients with cancer who received pembrolizumab at the Mayo Clinic from March 2014 through January 2015. Most were male (61%). The goal of the study was to comprehensively characterize pembrolizumab-induced thyroid dysfunction and examine its potential pathophysiology, said Delivanis.

Overall, the study identified 14 cases of abnormal thyroid function tests, which were examined to determine etiology, incidence, and clinical presentation of the thyroid disorder. Given this high rate of occurrence, Delivanis said routine thyroid function testing should be recommended for patients on pembrolizumab.

For the study, thyroiditis was defined as suppressed thyroid stimulating hormone (TSH) with an elevated T3 and T4 that progressed or self-resolved. Overt hypothyroidism was defined as an increased TSH and low T4 or T3. Subclinical hypothyroidism was diagnosed when the TSH was increased but the thyroid hormone levels were normal.

Seven of the 57 patients treated with pembrolizumab who developed thyroid dysfunction were male (12%). The other 7 cases were seen in the 36 females enrolled in the study (19%). The median age across both groups was 58 years.

Thirteen of the patients were being treated for metastatic melanoma and one for NSCLC. Of those who developed an abnormal test, 73% had received ipilimumab prior to pembrolizumab (n = 11). These findings suggest that sequencing immune checkpoint inhibitors may enhance the incidence of thyroiditis/hypothyroidism.

The median time to onset of thyroid dysfunction was 6 weeks, after the second cycle of pembrolizumab. Four patients (29%) had a recovery of thyroid function, whereas 8 did not (57%). Recovery data were not available for the remaining two cases. Four of the patients developed additional immune-related AEs.

Thirteen patients had their thyroid peroxidase (TPO) antibodies measured at the time of thyroiditis. Of these patients, 5 had an elevated titer, with a mean titer of 85 IU/mL. At baseline anti-TPO ranged from 0.5 IU/mL to more than 800 IU/mL. Following treatment with pembrolizumab, anti-TPO ranged from 0.7 IU/mL to greater than 800 IU/mL.

A patient with new onset thyroiditis had the lowest levels, 0.5 IU/mL and 0.7 IU/mL and a patient with recurrent hypothyroidism had the highest level, at >800 IU/mL, both before and after treatment with pembrolizumab. One patient with subclinical hypothyroidism showed a decrease in anti-TPO following treatment, from 211 IU/mL before treatment to 125 IU/mL after treatment with pembrolizumab.

“Patients with an underlying autoimmune profile are at high risk once started on therapy with pembrolizumab,” said Delivanis. “Checking baseline antibodies may help identify patients at high risk.”

On PET/CT, new thyroid fluorodeoxyglucose (FDG) uptake after pembrolizumab was identified in seven cases. The median time to increased FDG uptake was 12 weeks. A correlation between FDG uptake and anti-TPO antibodies was not observed.

According to Delivanis, the investigators assume a T-cell—mediated destructive pattern is involved in pembrolizumab-induced thyroid dysfunction. Studies comparing healthy volunteers with patients with autoimmune disease may help in understanding the underlying pathophysiology involved. Further studies will continue to assess the immune-related AEs associated with the immune checkpoint inhibitors, specifically as they continue to gain new FDA approvals.

Delivanis D, Merten MM, Kottschade L, et al. Immune therapies targeting the thyroid: new insights from a comprehensive review of pembrolizumab-induced thyroiditis cases at Mayo Clinic. Presented at: International Thyroid Congress; October 18-23, 2015; Orlando, FL. Abstract 88.

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