Two distinct clinical trajectories of inflammatory thyroiditis evoked by checkpoint blockade in malignant melanoma.

Abstract

131 Background: Oncological immune checkpoint inhibitors (CPI) commonly cause immune related adverse events (irAEs). Thyroid irAEs have a significant clinical impact requiring therapeutic intervention and clinical coordination whilst often causing treatment delays. Methods: Retrospective review of all patients treated with CPIs (pembrolizumab, nivolumab +/- ipilimumab) for metastatic melanoma at the Clatterbridge Cancer Centre, UK identified patients experiencing thyroid irAEs. Clinical/biochemical course (T4 and thyroid stimulating hormone (TSH) levels) and autoantibody titers were evaluated to identify characterisable trajectories. Results: From February 2016 to May 2017, 103 patients received anti-PD1 therapy; 90 receiving monotherapy and 13 combination. Thyroid irAEs were seen in 13(14.4%) and 3(23%) patients respectively. Two distinct trajectories were identified: a hyperthyroid phase with subsequent hypothyroidism (HH) and de novo hypothyroidism (DN). There were no outliers. HH was the predominant pattern (75%) and the sole manifestation in combination therapy. In the HH cohort 69% of patients were female. The peak T4 was 39.3pmol/L occurring, on average, 7.5 weeks after CPI initiation. T4 levels declined within 6-21 days and hypothyroidism occurred within 8 weeks. The DN cohort was exclusively female. Thyroid irAE occurred 12 weeks after CPI initiation. Baseline TSH in HH (2.49mU/l) was significantly lower than DN (5.77mU/l); p = 0.0092. Positive thyroid autoantibodies were detected in 5 patients across both groups. One patient (HH) had symptomatic thyroid dysfunction. Corticosteroids conveyed no benefit. All patients had permanent dysfunction requiring long term levothyroxine replacement. All continued with immunotherapy treatment; however notable irAE-related treatment hiatuses occurred. Conclusions: Retrospective review revealed two distinct thyroid irAE trajectories, HH and DN. The trajectories may have biochemical predictors, are rarely associated with symptoms and appear unrelated to thyroid autoantibodies. Trajectory identification will optimise patient outcomes, reduce ineffective steroid use and promote early hormone replacement.