Incidence of Thyroid-Related Adverse Events in Melanoma Patients Treated With Pembrolizumab

Abstract

Context: Immune checkpoint blockade is associated with endocrine-related adverse events. Thyroid dysfunction during pembrolizumab therapy, an anti-programmed cell death 1 (PD-1) receptor monoclonal antibody, remains to be fully characterized.

Objective: To assess the incidence and characteristics of pembrolizumab-associated thyroid dysfunction.

Design and setting: Thyroid function was monitored prospectively in melanoma patients who initiated pembrolizumab within an expanded access program at a referral oncology center. ¹⁸Fluorodeoxyglucose uptake on positron emission tomography/computed tomography (¹⁸FDG-PET/CT) was reviewed in cases compatible with inflammatory thyroiditis.

Patients: Ninety-nine patients with advanced melanoma (age, 26.3-93.6 years; 63.6% females) who received at least one administration of pembrolizumab.

Main outcome measures: Patient characteristics, thyroid function (TSH, free T₄), thyroid autoantibodies, and ¹⁸FDG-PET/CT.

Results: Eighteen adverse events of thyroid dysfunction were observed in 17 patients. Thyrotoxicosis occurred in 12 patients, of which nine evolved to hypothyroidism. Isolated hypothyroidism was present in six patients. Levothyroxine therapy was required in 10 of 15 hypothyroid patients. Thyroid autoantibodies were elevated during thyroid dysfunction in four of 10 cases. Diffuse increased ¹⁸FDG uptake by the thyroid gland was observed in all seven thyrotoxic patients who progressed to hypothyroidism.

Conclusions: Thyroid dysfunction is common in melanoma patients treated with pembrolizumab. Hypothyroidism and thyrotoxicosis related to inflammatory thyroiditis are the most frequent presentations. Serial measurements of thyroid function tests are indicated during anti-PD-1 monoclonal antibody therapy. Thyrotoxicosis compatible with inflammatory thyroiditis was associated with diffuse increased ¹⁸FDG uptake by the thyroid gland. The prospective role of thyroid autoantibodies should be further investigated, together with the histopathological correlates.

Trial registration: ClinicalTrials.gov NCT02673970.

Figure 1.

Overview of the investigated cohort of pembrolizumab-treated melanoma patients, displaying inclusion criteria and overall thyroid dysfunction.

Figure 2.

Overview of thyroid-related AEs in pembrolizumab-treated melanoma patients. A total of 18 events of abnormal thyroid function tests were observed in 17 patients. Hypothyroidism and thyrotoxicosis due to suspected inflammatory thyroiditis (spontaneous evolution of thyrotoxicosis to hypothyroidism) were the most frequent types of thyroid dysfunction.

Figure 3.

Graphic representation of fT4 values in patients with suspected inflammatory thyroiditis on pembrolizumab. The evolution of fT4 levels is plotted against the time (in days) after the introduction of pembrolizumab. Early transient thyrotoxicosis develops, followed by spontaneous progression to hypothyroidism.