Gambale contributed equally to this work. Contributor Information C. 62?years (27C87)], thyroid irAEs occurred in 36 (37.5%), 16 (16.7%) a transient thyrotoxicosis, and 20 (20.8%) an hypothyroidism (in nine subjects hypothyroidism was ISX-9 preceded by a transient thyrotoxicosis). Only baseline TSH levels above 1.67?mIU/L and positive anti-thyroid antibodies (Ab-T) were associated with a higher risk of hypothyroidism. Patients with hypothyroidism during ICI treatment showed an improved 2-year PFS (HR?=?0.82 CI 0.47C1.43; test and Students test for unpaired data to compare values and average of continuous variables, Kaplan Meier curves (Gehan-Breslow-Wilcoxon test) for the calculation of OS and PFS. A value? ?0.05 was assumed as statistical significance. The statistical analysis was performed using the Graphpad software 8. Results Patient characteristics A total of 96 patients satisfied the inclusion criteria (Fig.?1), 69% were males and 72% were previously submitted to other systemic treatments. Their median age at the initiation of ICI treatment was 61?years (27C87); 43 (45%) had a non-small cell lung cancer (NSCLC), 31 (32%) a melanoma, 16 (17%) a renal cell ISX-9 carcinoma, and 6 (6%) another cancer type. Eighty-five patients (89%) were treated with an anti-PD 1 antibody (nivolumab 70% and pembrolizumab 19%). Nine patients (9%) who were affected by melanoma received ipilimumab. One patient was treated with ipilimumab combined with nivolumab and another patient with pembrolizumab in association with chemotherapy (pemetrexed plus cisplatin). All subjects with RCC were treated with nivolumab. Thyroid hormone levels were tested at baseline and after treatment initiation at a median of once a month during the first 5?months of treatment and later at a median of every 2 months (Table ?(Table22 and Fig.?2d). All patients had at least one serum thyroid hormone measurement between month 6 and month 12. Baseline anti-thyroid antibody status (anti-thyroglobulin and anti-thyroperoxidase) was available only for 43 patients, 8 (19%) of whom were positive (Table ?(Table22). Open in a separate window Fig. 2 Baseline TSH levels are associated with thyroid irAEs. a Baseline TSH levels in subjects who remained euthyroid (circle) during the ICI treatment or became hypothyroid (square); the dot lines indicate the TSH cutoffs associated with an increased risk of hypothyroid irAEs b Percentages of subjects that had a TSH higher than 1.67?mIU/L (black) and lower 1.67?mIU/L (white) and who remained euthyroid or became and hypothyroid. c Timing of appearance of hypothyroid irAEs; white boxes indicate subjects with a baseline TSH lower than 1.67?mIU/L, black boxes indicate subjects with a baseline TSH higher than 1.67?mIU/L. d Percentage of blood ISX-9 sampling for thyroid Snap23 hormones and TSH levels performed during the first 10?months of treatment; with open boxes, percentage of patients who have not been tested, black boxes percentage ISX-9 of subjects who have been tested Table 2 Thyroid status at baseline valuevalue /th /thead Number of Subjects96 (100%)7620Gender?Female30 (31.2%)21 (27.6%)9 (45%)0.50.1651?Male66 (68.8%)55 (72.4%)11 (55%)Age?Diagnosis59 (25C83)59 (25C83)62 (42C82)0.98671.0000?Immunotherapy61 (27C87)61 (27C84)63 (47C87)1.0520.8012Primary tumor?Squamous/NSCLC43 (45.3%)37 (48.7%)6 (30%)2.1450.2376b?Melanoma31 (32%)23(30.3%)8 (40%)?RCC16 (16.5%)12 (15.8%)4 (20%)?Other6 (6.2%)4 (5.3%)2 (10%)Immunotherapy agent?Nivolumab67 (69.1%)49 (69.8%)18 (90%)0.34030.2187c?Pembrolizumab18 (18.5%)16 (18.8%)2 (10%)?Ipilimumab9 (9.3%)9 (9.4%)0?Other2 (3.1%)2 (2.1%)0 Open in a separate window aAbT status was available only for 43 subjectecs bStatistical analysis has been performed on Squamous/NSCLC and Melanoma groups cStatistical analysis has been performed on Nivolumab and Pembrolizumab Six of the eight subjects with positive anti-thyroid antibodies (AbT) at baseline developed hypothyroidism, whereas only ISX-9 3 of the 35 subjects with negative baseline AbT became hypothyroid ( em p /em ? ?0.0001; Table ?Table2).2). Five of six patients with positive AbT who became hypothyroid had a baseline TSH higher than 1.67?mIU/mL (Table ?(Table22). Progression-free survival and overall survival After a median follow-up after initiation of ICI treatment of 11?months (1C69), the median PFS was 7?months and the median OS was 25?months. In subjects with hypothyroidism irAEs, the median PFS 13?months compared with 6?months for patients who remained euthyroid (HR?=?0.82 CI 0.47C1.43; em p /em ?=?0.0132; Fig.?3a). In the hypothyroid.
