Immune-Related Thyroid Adverse Events Predict Response to PD-1 Blockade in Patients with Melanoma

Abstract

Antibodies against programmed cell death protein-1 or its ligand (PD-(L)1) are a standard of care in melanoma; however, this treatment may cause immune-related adverse events. The aim of this study was to evaluate the immune-related thyroid adverse events (irTAEs) during anti-PD-1 therapy and analyze their influence on the overall survival rates in melanoma. We included 249 patients with metastatic melanoma treated in our institution between 2014 and 2021; the median age was 62 years (range: 17–90); 58% were males, and 37% of patients had the BRAF mutation. We included patients with a normal TSH at baseline and followed up with measurement of TSH levels during immunotherapy. In our group, 95 patients had a TSH outside the normal range: 63 not clinically significant and 32 with clinical symptoms of hypothyroidism. The 3-year overall survival rate was related to the irTAEs of clinical hypothyroidism, abnormal clinically not significant TSH, and euthyreosis at 56%, 43%, and 32%, respectively (p = 0.002). After adjusting the Cox model for potential confounding variables, clinically significant hypothyroidism was an independent prognostic factor with HR 0.51 (95% CI 0.29–0.87). In conclusion, the patients who developed clinically significant hypothyroidism requiring replacement therapy with L-thyroxin were the group who benefitted most from anti-PD-1 treatment.

Low skeletal muscle mass predicts melanoma-specific survival in melanoma patients treated with adjuvant immune checkpoint blockade

“…At the same time, patients with LSMM less frequently experienced adverse events such as hypothyroidism under ICB. Since hypothyroidism and other immune-related adverse events have been described as favorable prognostic factors (Dawidowska et al 2022 ), this further substantiates a potential immunosuppressive impact of LSMM. Previous reports have linked the presence of LSMM with poor prognosis also in stage III melanoma without adjuvant therapy (Sabel et al 2011 ; Youn et al 2022 ), suggesting a broader applicability of LSMM as a risk factor in melanoma.…”

Window of opportunity with PD1 blockade before chemoradiotherapy for an advanced stage clear cell carcinoma of the cervix

“…Our patient presented after one dose of Nivolumab thyroid dysfunction, the most prevalent anti-PD1 related endocrinopathies with an estimated rate of 7 % ( Dawidowska et al, 2022 Feb 28 ). Most cases of hypothyroidism appear within the first one to three months of treatment and are managed with thyroid hormone replacement.…”

Is Melanoma Progression Affected by Thyroid Diseases?

“…Treatment with ICI greatly improved OS rates in unresectable and completely resected advanced-stage melanomas, as well as in adjuvant settings [ 76 , 77 ]. At present, antibodies targeting the cell surface programmed cell death 1 (PD-1) receptor (nivolumab or pembrolizumab), either in monotherapy or in combination with an antibody against the cytotoxic T-lymphocyte antigen-4 (CTLA-4) (ipilimumab), are the standard of care for melanoma patients [ 78 ]. In 2015, a systematic review and meta-analysis was performed on a total of 1265 patients from 22 clinical trials employing anti-CTLA-4 antibodies to assess the incidence of immunotherapy related adverse events (irAE) [ 79 ].…”

“…The results obtained evidenced that hyperthyroidism, hypothyroidism, hypophysitis, and thyroiditis were the most frequent endocrine irAE. A very recent work examined the influence of thyroid dysfunctions consequent to anti-PD-1 therapy on OS rates of 249 melanoma patients [ 78 ]. Interestingly, clinically significant hypothyroidism was found to be an independent prognostic factor, with Hazard Ratio (HR) 0.51 (95% CI 0.29–0.87).…”