Immune Checkpoint Inhibitor-induced Thyroid Dysfunction Is Associated with Higher Body Mass Index.

Obesity is a proinflammatory metabolic state that may play a role in the development of immune-related adverse events (irAEs) associated with immune checkpoint inhibitor therapy. To characterize the association between body mass index (BMI) and thyroid irAEs. We performed a single-center, retrospective analysis of 185 cancer patients treated with anti-PD-1/L1 from January 2014 to December 2018. Patients with normal thyroid function at baseline and available BMI were included. The primary endpoint was difference in BMI in patients who developed overt thyroid dysfunction versus those who remained euthyroid following anti-PD-1/L1 initiation. Additional endpoints included any (overt or subclinical) thyroid dysfunction, overt thyrotoxicosis or overt hypothyroidism, and time to development of dysfunction according to BMI. Any thyroid dysfunction developed in 72 (38.9%) patients and 41 (22.1%) developed overt thyroid dysfunction. Mean BMI was higher in those with overt thyroid dysfunction versus euthyroid (27.3 ± 6.0 vs 24.9 ± 4.5, P = .03). Development of overt thyrotoxicosis versus remaining euthyroid was associated with higher BMI (28.9 ± 5.9 vs 24.9 ± 4.5; P < .01), whereas overt hypothyroidism was not (26.7 ± 5.5 vs 24.9 ± 4.5, P = .10). Overt thyrotoxicosis developed within 57.5 (interquartile range [IQR] 31.8-78.8) days of treatment in the low-normal BMI group, 38.0 (IQR 26.8-40.5) days in the overweight group, and 23.0 (IQR 21.0-28.0) days in the obese group (P = .02). Patients treated with PD-1/L1 inhibitors were more likely to develop thyroid irAEs, specifically overt thyrotoxicosis, with increasing BMI. Overt thyrotoxicosis occurred earlier in obese versus leaner patients. These data highlight the complex interplay between obesity and immune response in immune checkpoint inhibitor-treated patients.

Pollack R ，Ashash A ，Cahn A ，Rottenberg Y ，Stern H ，Dresner-Pollak R ... -  《-》

Thyroid Immune-related Adverse Events Following Immune Checkpoint Inhibitor Treatment.

Thyroid dysfunction occurs commonly following immune checkpoint inhibition. The etiology of thyroid immune-related adverse events (irAEs) remains unclear and clinical presentation can be variable. This study sought to define thyroid irAEs following immune checkpoint inhibitor (ICI) treatment and describe their clinical and biochemical associations. We performed a retrospective cohort study of thyroid dysfunction in patients with melanoma undergoing cytotoxic T-lymphocyte antigen-4 (CTLA-4) and/or programmed cell death protein-1 (PD-1) based ICI treatment from November 1, 2009, to December 31, 2019. Thyroid function was measured at baseline and at regular intervals following the start of ICI treatment. Clinical and biochemical features were evaluated for associations with ICI-associated thyroid irAEs. The prevalence of thyroid autoantibodies and the effect of thyroid irAEs on survival were analyzed. A total of 1246 patients were included with a median follow-up of 11.3 months. Five hundred and eighteen (42%) patients developed an ICI-associated thyroid irAE. Subclinical thyrotoxicosis (n = 234) was the most common thyroid irAE, followed by overt thyrotoxicosis (n = 154), subclinical hypothyroidism (n = 61), and overt hypothyroidism (n = 39). Onset of overt thyrotoxicosis occurred a median of 5 weeks (interquartile range [IQR] 2-8) after receipt of a first dose of ICI. Combination immunotherapy was strongly associated with development of overt thyrotoxicosis (odds ratio [OR] 10.8, 95% CI 4.51-25.6 vs CTLA-4 monotherapy; P < .001), as was female sex (OR 2.02, 95% CI 1.37-2.95; P < .001) and younger age (OR 0.83 per 10 years, 95% CI 0.72-0.95; P = .007). By comparison, median onset of overt hypothyroidism was 14 weeks (IQR 8-25). The frequency of overt hypothyroidism did not differ between different ICI types. The strongest associations for hypothyroidism were higher baseline thyroid-stimulating hormone (OR 2.33 per mIU/L, 95% CI 1.61-3.33; P < .001) and female sex (OR 3.31, 95% CI 1.67-6.56; P = .01). Overt thyrotoxicosis was associated with longer progression free survival (hazard ratio [HR] 0.68, 95% CI 0.49-0.94; P = .02) and overall survival (HR 0.57, 95% CI 0.39-0.84; P = .005). There was no association between hypothyroidism and cancer outcomes. Thyroid irAEs are common and there are multiple distinct phenotypes. Different thyroid irAE subtypes have unique clinical and biochemical associations, suggesting potentially distinct etiologies for thyrotoxicosis and hypothyroidism arising in this context.

Muir CA ，Clifton-Bligh RJ ，Long GV ，Scolyer RA ，Lo SN ，Carlino MS ，Tsang VHM ，Menzies AM ... -  《-》

Another side of the association between body mass index (BMI) and clinical outcomes of cancer patients receiving programmed cell death protein-1 (PD-1)/ Programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors: A multicentre analysis of immune-related

Several studies have found an association between higher body mass index (BMI) and improved clinical outcomes in cancer patients receiving programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors. In a previous study, we found that overweight/obese patients were significantly more likely to experience any grade immune-related adverse events (irAEs) compared to non-overweight patients. We conducted a 'real-life', multi centre, retrospective observational study aimed at comparing the incidence of irAEs among cancer patients treated with PD-1/PD-L1 inhibitors according to baseline BMI. One thousand and seventy advanced cancer patients were evaluated. The median age was 68 years (range: 21-92), male/female ratio was 724/346. Primary tumours were: non-small-cell lung carcinoma (NSCLC) (653 patients), melanoma (233 patients), renal cell carcinoma (RCC) (152 patients) and others (29 patients). Median BMI was 25 (13.6-46.6); according to World Health Organisation (WHO) classification, 44 patients (4.1%) were defined as underweight, 480 patients (44.9%) as having a normal weight, 416 patients (38.9%) as overweight and 130 patients (12.1%) as obese. Higher BMI was significantly related to higher occurrence of any grade immune-related adverse events [irAEs] (p < 0.0001), G3/G4 irAEs (p < 0.0001) and irAEs leading to discontinuation (LTD) (p < 0.0001). Overweight and obesity were confirmed predictors for irAEs of any grade at both univariate and multivariate analysis. The adjusted odds ratios (ORs) (compared to normal-weight) were 10.6; 95% confidence interval (95%CI): 7.5-14.9 for overweight, and 16.6 (95%CI: 10.3-26.7) for obese patients. Obesity was the only factor significantly related to a higher incidence of G3/G4 irAEs (OR = 11.9 [95%CI: 6.4-22.3], p < 0.0001) and LTD irAEs (OR = 8.8 [95%CI: 4.3-18.2], p < 0.0001). Overweight and obese patients experienced a significantly higher occurrence of cutaneous, endocrine, gastro-intestinal (GI), hepatic and 'others' irAEs, compared to normal-weight patients. Only obese patients experienced a significantly higher occurrence of pulmonary and rheumatic irAEs, compared to normal-weight patients. Considering the previously evidenced association between higher BMI and better outcome, the current finding about the relationship between BMI and irAEs occurrence can contribute to consideration of these findings as the upside of the downside, which underlies an 'immunogenic phenotype'.

Cortellini A ，Bersanelli M ，Santini D ，Buti S ，Tiseo M ，Cannita K ，Perrone F ，Giusti R ，De Tursi M ，Zoratto F ，Marconcini R ，Russano M ，Zeppola T ，Anesi C ，Filetti M ，Marchetti P ，Botticelli A ，Gelibter A ，De Galitiis F ，Vitale MG ，Rastelli F ，Tudini M ，Silva RR ，Atzori F ，Chiari R ，Ricciuti B ，De Giglio A ，Migliorino MR ，Mallardo D ，Vanella V ，Mosillo C ，Bracarda S ，Rinaldi S ，Berardi R ，Natoli C ，Ficorella C ，Porzio G ，Ascierto PA ... -  《-》

PD-L1 Inhibitor-Induced Thyroiditis Is Associated with Better Overall Survival in Cancer Patients.

Kotwal A ，Kottschade L ，Ryder M 《-》

Tumor PD-L1 expression and molecular profiling are not associated with immune checkpoint inhibitor-induced thyroid dysfunction in advanced NSCLC patients.

Background: Immune-checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC), however are frequently associated with thyroid immune-related adverse events (IRAEs). We investigated the association between patient characteristics, tumor PD-L1 expression and molecular profile with the development of thyroid IRAEs in NSCLC patients. Methods: Single center, retrospective study including 107 NSCLC patients treated with PD-1/PD-L1 inhibitors from April 2016 to July 2020. All patients were euthyroid at baseline with at least two TSH measurements post-treatment initiation. The primary outcome was the difference in tumor PD-L1 expression in patients who developed any thyroid IRAEs versus those who remained euthyroid. Additional outcomes included development of overt thyroid dysfunction, the association of specific molecular alterations with thyroid IRAEs, and onset of thyroid IRAEs as a function of tumor PD-L1 expression. Results: Overall, 37 (34.6%) patients developed any thyroid dysfunction and 18 (16.8%) developed overt thyroid dysfunction. Tumor PD-L1 staining intensity was not associated with thyroid IRAEs. TP53 mutation was less likely to be associated with any thyroid dysfunction (p < 0.05) and no association was found between EGFR, ROS, ALK or KRAS mutations. There was no association between PD-L1 expression and time to develop thyroid IRAEs. Conclusion: PD-L1 expression is not associated with the development of thyroid dysfunction in advanced NSCLC patients treated with ICIs, suggesting that thyroid IRAEs are unrelated to tumor PD-L1 expression.

Horesh A ，Pollack R ，Nechushtan H ，Dresner-Pollak R ，Neuman T ... -  《-》