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 

. "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 ï¬‚uorodeoxyglucose (FDG) uptake after pembrolizumab was identiï¬ed 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.

View more from the 2015 International Thyroid Congress

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Abnormal thyroid function tests were reported in up to 15% of patients treated with the PD-1 inhibitor pembrolizumab.

Mayo Study Characterizes Pembrolizumab-Induced Thyroiditis

The oral multikinase inhibitor cabozantinib (Cometriq) showed promise as a second- or third-line therapy in patients with advanced radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) following prior treatment with a VEGFR inhibitor, according to data from a phase II trial presented by Manisha H. Shah, MD, at the 2015 International Thyroid Congress.

In the 25-patient analysis, the confirmed partial response rate with cabozantinib was 36%. Additionally, 2 patients had an unconfirmed partial response. The median progression-free survival was 12.9 months. At the time of the analysis, median overall survival had not yet been reached.

“Cabozantinib is effective in inducing a durable partial response. It has statistically and clinically significant activity,” said Shah, a professor at The Ohio State University Comprehensive Cancer Center in Columbus. “We have a critical need for [treatment of] cancer that progresses after the first- or second-line therapy.”

The FDA approved cabozantinib, which targets MET and VEGFR, in 2012 for patients with progressive medullary thyroid cancer. Two multikinase inhibitors targeting VEGFR, sorafenib and lenvatinib, are approved as therapies for RAI-refractory advanced DTC.

In the open-label phase II study, 25 patients were enrolled who had received a standard of care: surgery, RAI, or external-beam radiation. The median age was 64 years and 64% were men.

One prior VEGFR-targeted therapy was administered to 80% of trial participants and 20% had received 2 prior therapies. The most common prior VEGFR-targeted therapies were sorafenib (52%) and pazopanib (28%), even though it is not FDA-approved for this indication.

Cabozantinib was administered at a starting dose of 60 mg per day orally, which could be increased to 80 mg if the patient failed to achieve a response within the first 4 months of therapy. Nine patients had no dose change, four had an increase to 80 mg, seven had a decrease to 40 mg, and five had a decrease to 40 mg and then 20 mg.

The primary endpoint of the study was an objective response within the first 6 months of treatment. The study was ruled a success, if cabozantinib elicited a response in at least 5 patients. 

Overall, 9 of the 25 patients enrolled experienced a confirmed partial response (36%). Additionally, 2 patients had responses that could not be confirmed during the regular 8-week scan, Shah noted. Twelve patients had stable disease with cabozantinib, representing a disease control rate (response plus stable disease) of 92%.

“We saw a 30% or more response in the tumor in those with a partial response,” Shah said. "We exceeded the five patient expectation of success. We are happy to say that, 'yes,' cabozantinib is effective as a second- or third-line therapy for these patients."

Cabozantinib was well tolerated, Shah noted. The most common treatment-related adverse events (AEs) were fatigue, hand-foot skin reaction, anorexia, nausea, mucositis, weight loss, diarrhea, and hypertension. “There were no surprises,” Shah said. “We have learned over the decades and were able to decrease the grade of events.”

Grade >3 AEs were experienced by just 8% of patients treated with cabozantinib. There were no grade 4 events. Three patients experienced grade 3 infections. One patient each experienced grade 3 left ventricular dysfunction, grade 3 skin ulceration, and grade 3 osteonecrosis of the jaw.

Overall, 5 patients discontinued cabozantinib due to AEs. Additionally, there was one death in the trial, which may have been related to the drug. In this incidence, the patient experienced a sudden onset of seizure-like activity possibly related to bleeding.

The prospective, phase II trial was sponsored by the National Cancer Institute and International Thyroid Oncology Group in collaboration with the Cancer Therapy Evaluation Program, the Academic and Community Cancer Research United, and eight participating centers.

“This study was the first of its kind in terms of collaboration,” Shah said. “It was truly teamwork.”

	Shah MH, De Souza J, Wirth L, et al. Cabozantinib in patients with radioiodine-refractory differentiated thyroid cancer who progressed on prior VEGFR-targeted therapy: results of NCI- and ITOG-sponsored multicenter phase II clinical trial. Presented at: 2015 International Thyroid Congress; October 18-23, 2015; Orlando, FL. Abstract 73.

The oral multikinase inhibitor cabozantinib showed promise as a second- or third-line therapy in patients with advanced radioactive iodine-refractory differentiated thyroid cancer.

Debra Wood

Articles

Mayo Study Characterizes Pembrolizumab-Induced Thyroiditis

Second-Line Cabozantinib Effective in RAI-Refractory DTC