Endocrine Immune-related Adverse Events Research Articles

Predictors of endocrine immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICI) in routine clinical practice.

e14713 Background: Endocrine irAEs have been reported in association with various ICI and are characterized by their correlation with improved survival outcomes. A growing clinical comprehension of endocrine irAEs has facilitated the development of effective treatment strategies involving hormone replacement, which has been shown to enhance patients' quality of life. This study aims to evaluate outcomes in patients (pts) experiencing endocrine irAEs and identify predictive factors for their occurrence. Methods: This retrospective cohort study comprised 214 adult pts with solid malignant tumors who underwent ICI, either as monotherapy or in combination with other chemotherapeutic agents, at the SBIH Moscow Clinical Scientific and Practical Center named after A.S. Loginov of DHM. Results: Between June 2016 and January 2023, 214 pts were included in the study (46.3% female, 53.7% male). The median age was 62.6 years (range 32–91). At the data cut-off (1 February 2024) the median overall survival (OS) for the analyzed population was 34,5 months (95%CI 21,15-43,91). No significant difference in median OS was observed between pts with overall endocrine irAEs and those exhibiting specific manifestations, such as hypocortisolism and destructive diabetes mellitus. However, thyroid irAEs were associated with improved median OS: 27.5 months compared to 22.6 months in those without (p=0.037); RR=1.39 (95%CI 1.025-1.89; p=0.036). The grade of endocrine irAEs did not impact the survival benefit. A significant association was observed between age group and endocrine irAEs (Pearson’s χ2=9.92, p=0.019), with a left-skewed age distribution due to a higher proportion of participants aged 32–44 years among those developing endocrine irAEs. Pts with nodular goiter had a 2.91 times higher risk of developing thyroiditis (95%CI 1.03–8.25), although this did not reach statistical significance (p=0.067). Calcium channel blockers were associated with an increased risk of developing thyroid irAEs (RR=1.54, 95%CI 1.09–2.19; p=0.036). Antihistamine use was a robust predictor of hypothyroidism with a RR=1.68 (95%CI 1.05–2.7, p=0.04). Initial derived neutrophil-to-lymphocyte ratio (dNLR) ≥3 predict the development of endocrine irAEs (Pearson χ2=4.02; p=0.045) as well as dNLR>2.2 (Pearson χ2=4.22, p=0.04). Conclusions: Thyroid irAEs are correlated with improved OS. Predictors of endocrine irAEs may include young age (32-44 years), calcium channel blocker or antihistamine use, dNLR ≥3, or dNLR >2.2. Prospective trials are warranted to validate these findings.

Endocrine Immune-Related Adverse Events Are Independent Predictors of Survival in Patients with Lung Cancer.

Lung cancer (LC) is a serious health problem worldwide. Survival outcomes have improved over time due to the widespread use of novel therapeutic agents, including immune checkpoint inhibitors (ICIs). Endocrine immune-related adverse events (e-irAEs) are common in LC patients treated with ICIs. We performed a retrospective study of patients with LC who received treatment with ICIs at a tertiary referral center between January 2014 and October 2023. In total, 983 LC patients were included in the study. E-irAEs presented at a median time of 4.1 months and included hypothyroidism (15.6%), hyperthyroidism (4.3%), adrenal insufficiency (0.4%), hypophysitis (0.4%), and diabetes mellitus (0.2%). These toxicities were not related to the duration of treatment or the type of ICIs. Most (97.6%) e-irAEs were mild (grade 1-2). Median overall survival (OS) was higher in LC patients who experienced e-irAEs (31.6 months) compared to those who did not (10.8 months). The difference remained statistically significant in the 3-month (HR: 0.42) and 6-month landmark analysis (HR: 0.51). The OS advantage was observed in both patients with NSCLC (HR: 0.36) and SCLC (HR: 0.27). Additional research is needed to validate the role of e-irAEs as an independent predictor of survival outcomes in patients with LC.

THU092 Characterizing Immune Checkpoint Inhibitor Induced Hypophysitis In A Large Urban Health Care System

Abstract Disclosure: M. Gogerly-Moragoda: None. U. Sharif Khawaja: None. K.C. Cheesman: None. A. Leiter: None. E.J. Gallagher: Consulting Fee; Self; Novartis Pharmaceuticals, Flare Therapeutics, Seagen, SynDevRx. INTRODUCTION Over the past decade, immune checkpoint inhibitors (ICIs) have transformed cancer therapy in multiple tumor types and improved outcomes. Endocrine immune related adverse events are well recognized side effects of ICIs. ICI induced hypophysitis is potentially life-threatening if not identified and treated. The present study examines the incidence and presentation characteristics of hypophysitis in a real-world cohort including a multitude of ICIs and tumor types. METHODS We conducted a retrospective analysis of all patients treated with ICIs at a large health system from 2011-2020. Patient demographics, type of cancer, type of ICI, endocrine symptoms and laboratory values were collected to characterize hypophysitis within the cohort. RESULTS A total of 1703 patients were treated with ICIs from 2011-2020 of whom 32 (1.9%) developed clinically apparent hypophysitis. Of the 32 patients, 26 patients were confirmed to have secondary adrenal insufficiency (AI), with 6 possible secondary AI. A majority were diagnosed in the outpatient setting (n=21, 66%). For those with hypophysitis, the most common tumor type was melanoma (n=12, 38%), followed by lung cancer (n=9, 28%) and genitourinary cancers (n=8, 25%). Combination cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, ipilimumab and programmed cell death protein 1 (PD-1) inhibitor, nivolumab (n=9, 28%) was the most common regimen, followed by monotherapies ipilimumab (n=6, 19%), nivolumab (n=6, 19%), pembrolizumab (n=6, 19%), the programmed cell death ligand 1 (PD-L1) inhibitor atezolizumab (n=3, 9%), with the remainder on durvalumab or combination durvalumab and tremelimumab. The most common presenting symptom was fatigue (n=21, 66%) with headache (n=8, 25%) and vision changes (n=2, 6%) being less common. The median time to presentation was 5 months with most presenting within 12 months of starting ICI (n=24, 75%). However, a subset of patients presented after 18 months on treatment (n=6, 19%), none of whom received ipilimumab. Seven patients underwent cosyntropin stimulation tests and six had muted responses, despite having low or inappropriately normal ACTH levels. DISCUSSION In this real-world dataset, we found a low percentage of hypophysitis across multiple tumor and ICI types. Secondary AI was most commonly seen with ipilimumab treatment. Notably, the subset of patients who presented after 18 months were all on PD-1 / PD-L1 inhibitors, which potentially indicates a distinct mechanism of hypophysitis with these agents compared with CTLA-4 inhibitors, and the new need to monitor these patients with labs and symptom review beyond the initial few months from ICI start. The muted cortisol response to cosyntropin was surprising in the setting of acute hypophysitis and warrants further investigation in these patients. Presentation: Thursday, June 15, 2023

FRI539 Vitamin D and Endocrine Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitors

Abstract Disclosure: Z. He: None. A. Leiter: None. E. Carroll: None. G. Santiago Pichardo: None. I. Khanna: None. E. Gutowski: None. E.J. Gallagher: Research Investigator; Self; Novartis Pharmaceuticals, Flare Therapeutics, Seagen. Background: Low vitamin D levels have been previously associated with the development of thyroid dysfunction in non-cancer populations. Thyroid dysfunction is one of the most common immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs). Currently, the effect of vitamin D deficiency or vitamin D supplementation on the development of ICI-induced thyroid dysfunction is unknown. This study was design to examine the association between baseline vitamin D levels and vitamin D supplementation, and the development of ICI-induced thyroid dysfunction. Methods: In this IRB-approved, retrospective cohort study, we collected demographic and clinical characteristics in addition to TSH, free T4, and vitamin D levels from patients with melanoma, multiple myeloma (MM), and transitional cell carcinoma (TCC) treated with ICIs between 2011 and 2020, in a large urban hospital system. The primary outcome was the occurrence of thyroid dysfunction defined by abnormal TSH or free T4 level after ICI initiation. Vitamin D deficiency / insufficiency was defined as serum 25-hydroxy-vitamin D level <30ng/mL. Patients were followed until the first occurrence of the primary outcome or the date of the most recent normal TSH level. Descriptive data are presented as n(%) and median±SD. Univariate and multivariate analysis were performed to examine the association between the primary outcome and vitamin D deficiency/ insufficiency or supplementation. Results: 288 patients with melanoma (n=111), MM (n=86) or TCC (n=91) were identified, with a median age of 65±13 years, and 64% were male. 110 (38%) patients experienced thyroid dysfunction. Among the TCC subgroup, the mean baseline TSH levels for patients who experienced the outcome was significantly higher than that for patients who did not (p = 0.0066). No statistical significance was found for the melanoma (p=0.42) or MM subgroups (p=0.30). Amongst patients with baseline vitamin D levels measured, we found no statistically significant association between thyroid dysfunction and baseline vitamin D deficiency (OR = 0.62, p = 0.34). In the entire cohort, the 1-year outcome-free rates for patients taking and not taking vitamin D supplementation were 68% and 61%, respectively (p=0.07). Vitamin D supplementation was found to reduce the risk of ICI-induced thyroid abnormality by approximately 40% (RR = 0.606, p=0.03) in the multivariate analysis. No difference in mortality was found between those who developed thyroid dysfunction and those who did not. Conclusions: In individuals with melanoma, MM and TCC, vitamin D supplementation may have a protective effect against ICI-induced thyroid dysfunction. Whether vitamin D supplementation impacts cancer response to ICIs is unknown at this time. Presentation: Friday, June 16, 2023

Endocrine immune-related adverse events in patients with metastatic renal and urothelial cancer treated with immune checkpoint-inhibitors

PurposeTo evaluate the incidence, diagnosis and treatment of immune-related adverse events (e-irAE) of checkpoint inhibition (ICI) in metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma (mRCC).MethodsA retrospective, single-center study was conducted to identify a cohort that received ICI for mUC or mRCC. e-irAE were classified according to the CTCAE V.5.0. Patients received ICI for mUC or mCC between 01/2017 and 03/2021. A retrospective chart review was performed. T-Test, the chi-squared test, and Fisher's exact test were performed.Results102 Patients received ICI [mUC: 40 (39%), mRCC: 62 (61%)]. 64 (63%) received an ICI monotherapy, 27 (27%) a dual ICI therapy, 11 (11%) a combination with VEGFi. e-irAE occurred in 19 (19%) patients [grade 1–2: 17 (84%), grade 3: 3 (16%)]. The median time until e-irAE was 42 days (range 11–211 days). 14 Patients developed thyroidism (14%), 4 (4%) a hypophysitis, 1 (1%) an adrenal insufficiency (AI). 7 patients (7%) had to discontinue ICI therapy [hypophysitis (100%), AI (100%), thyroidism (14%)]. 6 (86%) received cortisone. After a median range of 34 days 5 patients (71%) restarted ICI therapy. All patients (n = 4) with hypophysitis continued ICI [4 (100%) prednisone, 3 (75%) levothyroxine]. 11 (79%) presented with hyperthyroidism. 4 (37%) needed therapy (1 (7%) prednisone, 3 (21%) thiamazole, 2 (14%) beta blocker). The 9 (64%) patients with hypothyroidism received levothyroxine. Hypophysitis appears only on dual ICI (CTLA-4/PD-1) inhibition (p 0.007).ConclusionThis study shows the importance of adequate diagnosis and therapy of e-irAEs.

Challenges and Limitations of Endocrine Toxicity Evaluation in Non-Small Cell Lung Cancer Patients Treated with Immunotherapy-Retrospective Study from a Tertiary-Level Hospital in Romania.

(1) Background: The endocrine system has become a prominent target to autoimmune damage during treatment with immune checkpoint inhibitors (ICIs) in cancer patients. Real-world data regarding endocrine immune-related adverse events (irAEs) are needed to explore their impact in cancer patients. An analysis was conducted to evaluate endocrine irAEs caused by ICIs, besides the challenges and limitations of daily medical practice in oncology in Romania. (2) Methods: This was a retrospective cohort study of lung cancer patients treated with ICIs at Coltea Clinical Hospital, Bucharest, Romania, from 1 November 2017 to 30 November 2022. Endocrine irAEs were identified through endocrinological assessment and were distinguished as any occurring endocrinopathy during treatment with ICIs and related to immunotherapy. Descriptive analyses were performed. (3) Results: Of 310 cancer patients treated with ICIs, we identified 151 with lung cancer. From this cohort, 109 NSCLC patients qualified for baseline endocrine estimation and 13 patients (11.9%) developed endocrine irAEs, such as hypophysitis (4.5%), thyroid disorder (5.5%) and primary adrenal insufficiency (1.8%), with one or more endocrine glands being affected. There might be a correlation between endocrine irAEs and duration of ICI treatment. (4) Conclusions: Early diagnosis and adequate management of endocrine irAEs may be challenging in lung cancer patients. A high incidence of endocrine irAEs is expected with the growing use of ICIs, and because not all endocrine events are immune-related, cooperation between oncologists and endocrinologists is crucial in the management of these patients. More data are needed to confirm the correlation between endocrine irAEs and the efficacy of ICIs.

The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events.

Immune checkpoint inhibitors (ICIs) have been approved for the treatment of many cancers, either in adjuvant or metastatic settings. Regarding safety, endocrine adverse events (AEs) are some of the most common AEs in ICI-treated patients, with thyroid dysfunction and hypophysitis being the most frequent disorders. However, there are also some rare and very rare immune-related (ir) endocrine complications (incidence between ≥1/10,000 to <1/1000 and <1/10,000, respectively, according to the established classification) that have been reported in isolated case reports, with limited data about their management. In this systematic review, we summarize all published cases with primary adrenal insufficiency, central diabetes insipidus, primary hypoparathyroidism, lipodystrophy, osteoporosis, hypergonadotrophic hypogonadism, or Cushing disease and discuss their diagnostic and therapeutic approaches as well as the current knowledge on their pathophysiology. In these ICI-treated cancer patients, the presentation of symptoms unrelated to their underlying malignancy has led to further diagnostic tests, including hormonal profile and functional assays which subsequently confirmed endocrinopathy, while the assessment of autoantibodies was rarely available. In most of these cases, the exact pathogenesis remained unknown, and the endocrine dysfunction was permanent, requiring lifelong supplementation. Although endrocine irAEs are rare, physicians must be aware of these irAEs to recognize them on time and treat them appropriately.

Pituitary and adrenal disorders induced by immune checkpoint inhibitors

Over the past decade, the development of ICI (immune checkpoint inhibitors) has constituted a revolution in the treatment of many cancers, but with a specific toxicity profile including endocrine IRAEs (immune-related adverse events). As the indications for these molecules are constantly increasing due to their efficacy, it is important that endocrinologists and oncologists know how to detect, manage and monitor this type of toxicity. Many guidelines and recommendations have been proposed in the last few years for the management of endocrinopathies. French guidelines on immunotherapy-related endocrine IRAEs were published in 2018, with a specific algorithm for hypophysitis and primary adrenal insufficiency (PAI), based on clinical suspicion followed by biochemical and imaging evaluation, and are still relevant today. Here we present the general pathophysiological mechanisms of these toxicities, and discuss the incidence, diagnosis, treatment, progression, management and monitoring of pituitary and adrenal disorders in patients treated by immunotherapy, with emphasis on hypophysitis, which is much more frequent than PAI with this type of molecule. We also highlight several key points, such as the need for emergency treatment by hydrocortisone with the possibility of continuing immunotherapy in these endocrinopathies, and the long-term persistence of corticotropin or adrenal deficiency in most cases, requiring specific “hydrocortisone education”. These points should be kept in mind by oncologists and endocrinologists who treat and monitor patients treated by immunotherapy.

ODP068 A Case Report of Nivolumab Associated Hypercalcemia

Abstract Introduction Nivolumab is a human immunoglobulin G4 (IgG4) antibody which binds to programmed cell death receptor-1 (PD-1) and blocks the binding of PD-1 to either the PD-ligand 1 (PD-L1) or PD-L2 expressed on the surface of cancer cells. It has been approved for the treatment of melanoma, non-small cell lung cancer, renal cell carcinoma etc. Various endocrine immune-related adverse events including thyroiditis, hyper- and hypothyroidism, hypophysitis and type 1 diabetes has been described. We report a case of Nivolumab associated hypercalcemia. Case presentation 67-year-old female with history of CKD stage 3 with secondary hyperparathyroidism, melanoma of right ankle was admitted after one month of receiving the first dose of Nivolumab for her melanoma. She had altered mentation with elevated corrected calcium of 15.94(8.4-10.2) mg/dl. Prior calcium levels were in low to normal range, eGFR was 13, creatinine elevated at 3.4 (0.57-1.11) mg/dl, PTH 84 (10-65) pg/ml, 25 OH vitamin D 54 (30-74) ng/ml, Phosphorus normal, Magnesium normal, 1,25-OH vitamin D was elevated at 103(18-72) pg/ml, PTHrp normal, normal SPEP, normal TSH, no history of fractures, normal DXA, no history of kidney stones, not on any calcium supplements, not on thiazide or lithium. Chest x ray and NM full body PET CT did not show any evidence of granulomatous disease except for recurrence and metastasis of melanoma in right thigh, calf, and ankle. No family history of kidney stones or hypercalcemia. Patient was treated with IV fluids and Calcitonin. Her calcium quickly improved to 9.9 within 48 hours. Within 3 weeks of discharge, she was readmitted for elevated calcium of 14.4 mg/dl, creatinine 2.29 mg/dl, eGFR 21, PTH 96 pg/ml, Mg 1.8 (1.6-2.6) mg/dl. She was treated with IV fluids and calcitonin and calcium normalized within 48 hours. Parathyroid scan did not show any parathyroid adenoma. She was started on prednisone for possible Nivolumab associated immune adverse reaction. She was also briefly treated with cinacalcet which was discontinued. Prednisone was tapered and then stopped over the course of 6 weeks. Calcium remains normal. PTH remains slightly elevated which is thought to be due to secondary hyperparathyroidism from CKD. Normal cortisol level. Discussion This is likely a case of Nivolumab associated hypercalcemia given the onset soon after immunotherapy initiation and improvement with glucocorticoid therapy. Immunotherapy was not resumed after the first dose due to recurrent severe hypercalcemia. The patient is currently under surveillance for melanoma. Calcium level remains normal. Although it is rare, a few cases of Nivolumab associated hypercalcemia have been reported previously. Exact mechanism is not known but it has been speculated that macrophage activation by Nivolumab can cause increased level of 25(OH) D-hydroxylase with increased conversion of 25-OH vitamin D to 1,25-OH vitamin D resulting in calcitriol mediated hypercalcemia. Presentation: No date and time listed

SIADH &amp; Diabetes insipidus: Neues zu Diagnosestellung und Therapie

Dysnatremia is a common occurrence in patients with COVID-19 and is associated with higher mortality and risk for septic conditions. The pathomechanisms are probably multifaceted, but severe hyponatremia may also occur as a result of underlying SIADH or hypocortisolism. Patients with preexisting AVP dysfunction, like SIADH or diabetes insipidus, are at high risk for severe electrolyte imbalances in the event of a COVID-19 infection.The recently growing use of immune checkpoint inhibitors in oncology is associated with a spectrum of endocrine immune-related adverse events (endocrine irAEs). These AEs usually occur unpredictably and may even manifest after discontinuation of the anticancer therapy. Hyponatremia is a common factor of several endocrine irAEs and may serve as a red flag biomarker for possibly underlying endocrine irAEs such as hypophysitis or adrenalitis. New-onset hyponatremia should always prompt a comprehensive diagnostic workup and exclusion of endocrine irAEs before the diagnosis of SIADH is made.Hyponatremia with severe symptoms should be treated with hypertonic (3 %) saline solution to resolve the cerebral edema and prevent from detrimental neurological sequelae. Both rapid intermittent bolus (RIB) therapy and continuous infusion therapy have now been reported to be safe and equally effective. The RIB therapy limits the risk of overcorrection and requires less often re-lowering treatment than continuous infusion therapy.Fluid restriction has long been considered as first-line treatment of chronic hyponatremia due to SIADH. Additional treatment with Furosemid and/or oral NaCl tablets does not improve efficacy but reduces tolerance to therapy.Copeptin-based dynamic tests show higher diagnostic accuracy in the differential diagnosis of patients with hypotonic polyuria polydipsia syndrome than the indirect water deprivation test.

Long-term outcomes of adrenal insufficiency (AI) due to anti–PD(L)-1 immune checkpoint inhibitors (ICI) among patients with cancer.

12092 Background: Endocrine immune-related adverse events (irAEs) to anti-PD-(L)1 ICI, including hypophysitis, autoimmune insulin-dependent diabetes mellites (ICI-DM), and primary adrenal insufficiency (AI), are rare but often associated with long term co-morbidities. AI from anti-PD-(L)1 ICI without CTLA-4 blockade is not well characterized in the literature. Long term outcomes for AI including need for replacement steroids and cortisol levels are unknown. Methods: We performed a single center retrospective analysis of patients treated with ICI including anti-programmed cell death protein-1 (Anti-PD-1: nivolumab or pembrolizumab), anti-programmed death-ligand-1 (anti-PD-L1: atezolizumab or cemiplimab) and diagnosed with ICI induced AI by a board-certified endocrinologist from 1/1/2011 to 12/31/2021. Patients treated with anti-CTLA-4 based therapy were not included. Patient baseline characteristics, presenting symptoms at the time of AI diagnosis, and treatment with corticosteroids were obtained by chart review. Baseline labs were collected at the time of AI and during routine patient follow-up. Descriptive statistics are reported for the cohort. Results: Twenty-nine patients were identified, 27 diagnosed with secondary and 2 diagnosed with primary AI. The median age was 63 (range 39-84), 18 (62%) males and 11 (38%) females, 14 (48%) receiving anti-PD(L)-1 monotherapy and 22 receiving anti-PD(L)-1 combination therapy either with chemotherapy (7, 24%), targeted therapy (6, 21%) or other/investigational therapy (2, 7%). The common tumor types were 6 renal cell carcinoma, 4 urothelial carcinoma, 4 melanoma, 15 others. The common presenting symptoms were 26 (90%) with fatigue,16 (55%) weakness, 11 (38%) nausea/vomiting, 4 (14%) headaches and 2 (7%) arthralgias. The common concomitant irAEs were 16 (55%) hypothyroidism, 8 (28%) acute kidney injury, 7 (24%) colitis, 6 (21%) joint pain, 3 (10%) pneumonitis &amp; dermatitis. Eleven (38%) patients were treated with high dose steroids. Median follow-up time for survivors in the cohort was 24 months (range 7-68). Median cortisol level at time of AI diagnosis was 1.1 (IQR 0.9, 2.7; n = 27) and 1.8 (IQR 0.6, 6.4; n = 10) at last follow-up (median lab follow-up 39 months, range 29-58); 7 of 10 patients with available data had cortisol &lt; 5.0 at last follow-up. For secondary AI patients, median ACTH at time of diagnosis was 2.3 (IQR 2.0, 5.0; n = 21) and 2.0 (IQR 2.0, 7.2; n = 7) at last follow-up. Twenty-two of 23 patients with available data continued replacement steroids at last follow-up. Conclusions: AI associated with anti-PD(L)-1 ICI is primarily secondary. Cortisol and ACTH levels remain low even during long-term follow-up. Most patients need long-term replacement steroids. Systemic and comprehensive follow-up for patients who develop AI due to anti-PD(L)-1 ICI is needed to confirm these findings.

Clinical Presentation of Immune-Related Endocrine Adverse Events during Immune Checkpoint Inhibitor Treatment

Simple SummaryWith the growing use of immune checkpoint inhibitors (ICIs), clinicians are increasingly encountering a unique set of adverse events called immune-related adverse events (irAEs) associated with ICIs. In this retrospective study, we tried to analyse the clinical course of endocrine irAEs and determine the factors associated with persistent endocrine dysfunction. We also performed survival analysis of patients with endocrine irAEs compared to those without any irAEs. The clinical course of endocrine irAEs was found to be highly variable. The presentation of some endocrine irAEs could be nonspecific, and sometimes life-threatening if not detected early, e.g., hypocortisolism and diabetic ketoacidosis. Therefore, frequent clinical assessment and laboratory monitoring are recommended. Measuring thyroid antibodies at the start of thyroid dysfunction could be helpful as it was found to be associated with persistent thyroid dysfunction in our study. The presence of endocrine irAEs was found to have survival benefits in our patient population.The exact clinical course and factors associated with persistent endocrine immune-related adverse events (irAEs) are not well-established. Elucidation of these information will aid irAEs screening and follow-up planning for patients on immunotherapy. We analysed the clinical course of endocrine irAEs including thyroid and pituitary dysfunction and insulin-dependent diabetes mellitus (IDDM), identified factors associated with persistent thyroid dysfunction, and determined the association between endocrine irAEs and survival parameters. This retrospective observational study enrolled patients with metastatic cancer who underwent anti-PD-1, anti-PD-L1, and/or anti-CTLA-4 treatment and developed endocrine irAE at the National University Cancer Institute, Singapore, between June 2015 and December 2020. Sixty-six patients with endocrine irAE were evaluated, with a median follow-up time of 15.7 months. The median time to onset of thyroid dysfunction, pituitary dysfunction, and IDDM was 1.8 months (range: 0.3–15.8 months), 6.8 months (range: 1.5–27.3 months), and 7.8 months (range: 1.4–9.1 months), respectively. Positive thyroperoxidase antibodies (TPOAb) and/ or thyroglobulin antibodies (TgAb) status at the time of thyroid dysfunction was associated with persistent thyroid dysfunction (OR 11.6, 95% CI 1.3–570.8, p = 0.02; OR 8.8, 95% CI 1.3–106.9, p = 0.01, respectively). All patients with pituitary irAE had central hypocortisolism. All patients with IDDM had grade 4 irAE. Patients with endocrine irAE had longer median survival times. Endocrine irAEs were associated with non-progressive disease. The screening and follow-up approach for endocrine irAEs should be tailored according to each endocrinopathy’s clinical course. Early screening is imperative given its wide median time to onset.

T170 Three cases of endocrine immune-related adverse events caused by immune checkpoint inhibitor therapy

T170 Three cases of endocrine immune-related adverse events caused by immune checkpoint inhibitor therapy

Optimal Thyroid Hormone Replacement Dose in Immune Checkpoint Inhibitor-Associated Hypothyroidism Is Distinct from Hashimoto's Thyroiditis.

Background: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many advanced cancers but are recognized to cause treatment-limiting immune-related adverse events (IrAE). ICI-associated thyroiditis is the most common endocrine IrAE and usually resolves to permanent hypothyroidism. Optimal thyroid hormone replacement in these patients remains unclear. We report the levothyroxine (LT4) dose needed to achieve stable euthyroid state in patients with hypothyroidism from ICI-associated thyroiditis, with comparison to patients with Hashimoto's thyroiditis (HT) and athyreotic state. Methods: We conducted a retrospective study of adults with ICI-associated hypothyroidism treated with LT4 at an academic medical center. Patient data were collected from the electronic medical record. Cases had ICI exposure followed first by hyperthyroidism and then subsequent hypothyroidism. Controls were HT (positive thyroid autoantibodies, requiring LT4) and athyreotic (total thyroidectomy or radioiodine ablation, requiring LT4) patients. Patients with central hypothyroidism, thyroid cancer, pregnancy, gastrointestinal stromal tumors, and use of L-triiodothyronine were excluded. Our primary outcome compared LT4 dose needed to achieve euthyroid state (thyrotropin 0.3-4.7 mIU/L over >6 consecutive weeks) for ICI-associated hypothyroidism, HT, and athyreotic patients, considering the impact of age and possible interfering medications by linear regression modeling. Secondary analysis considered the impact of endocrine specialty care on the time to euthyroid state. Results: One hundred three patients with ICI-associated thyroiditis were identified. Sixty-six of the 103 patients achieved euthyroid state; 2 with intrinsic thyroid gland function recovery and 64 on LT4. The mean LT4 dose achieving stable euthyroid state was 1.45 ± standard deviation (SD) 0.47 mcg/[kg·day] in ICI-associated hypothyroidism, 1.25 ± SD 0.49 mcg/[kg·day] in HT, and 1.54 ± SD 0.38 mcg/[kg·day] in athyreotic patients, using actual body weight. The difference in dose between ICI-associated hypothyroidism and HT was statistically significant (p = 0.0093). Dosing differences were not explained by age or use of interfering medications. Conclusions: ICI-associated thyroiditis represents an increasingly recognized cause of hypothyroidism. Our study demonstrates that patients with ICI-associated hypothyroidism have different thyroid hormone dosing requirements than patients with HT. Based on our findings and prior reports, we recommend that in patients with ICI-associated thyroiditis LT4 therapy be started at an initial weight-based dose of 1.45 mcg/[kg·day] once serum free thyroxine levels fall below the reference range.

Eosinophil counts can be a predictive marker of immune checkpoint inhibitor-induced secondary adrenal insufficiency: a retrospective cohort study

Immune checkpoint inhibitors (ICIs) treatment can result in endocrine immune-related adverse events (irAEs), including pituitary dysfunction. Quick diagnosis of secondary adrenal insufficiency (AI) is challenging because no universal definition of ICI-induced secondary AI has been agreed. The aim of this study was to clarify the clinical features of ICI-induced secondary AI that can be used for screening in standard clinical practice. This retrospective study was performed using the medical records of patients who received ICIs at Hirosaki University Hospital between 1 September 2014 and 31 January 2021. Longitudinal clinical data of patients who developed AI were analyzed and compared with the data of thyroid irAEs. Regression analysis showed a significant correlation between ICI-induced secondary AI and absolute or relative eosinophil counts at pre-onset of AI, as well as differences or rate of increase in eosinophil counts at baseline and at pre-onset. Absolute eosinophil counts > 198.36/µL or relative eosinophil counts > 5.6% at pre-onset, and a difference of 65.25/µL or a rate of eosinophil count increase of 1.97 between the baseline and at pre-onset showed the best sensitivity and specificity. This is the first report to demonstrate that eosinophil counts can be a predictor of ICI-induced secondary AI.

New onset autoimmune diabetes mellitus and hypothyroidism secondary to pembrolizumab in a patient with metastatic lung cancer.

SummaryImmunotherapy has become an important pillar for the management of advanced cancer. Immune-related adverse events including endocrinopathies have been well described with programmed cell death 1 inhibitors such as pembrolizumab. While thyroid dysfunction is the most common endocrinopathy associated with pembrolizumab, new-onset autoimmune diabetes mellitus (DM) is extremely rare. The authors report a case of pembrolizumab-induced primary hypothyroidism and type 1 diabetes mellitus presenting with diabetic ketoacidosis (DKA). A 59-year-old female patient was treated with pembrolizumab for a stage 4 lung adenocarcinoma. She presented to the emergency department with hyperglycaemia-related signs and symptoms, such as polyuria, polydipsia, weight loss, vomiting, asthenia and dehydration, 3 weeks after her first dose of pembrolizumab. Laboratory evaluation revealed hyperglycaemia, hyperketonaemia and high anion gap metabolic acidaemia consistent with DKA. After prompt and adequate treatment of DKA, she transitioned to s.c. basal-bolus insulin. The diagnose of autoimmune DM was established based on the undetectable C-peptide levels and seropositivity for antiglutamic acid decarboxylase antibodies. Additional hormonal parameters revealed overt hypothyroidism and levothyroxine therapy was initiated. This case highlights the importance of blood glucose and thyroid function monitoring as an integral part of cancer treatment protocols for pembrolizumab and other immune checkpoint inhibitors.Learning pointsProgrammed cell death 1 (PD1) inhibitors such as pembrolizumab can cause endocrine immune-related adverse events (irAE), including thyroid dysfunction and type 1 diabetes mellitus (T1DM).Thyroid dysfunction is the most frequent endocrine irAE secondary to PD1 inhibitors.Autoimmune diabetes and possible resultant diabetic ketoacidosis are rare, but life-threatening adverse events associated with pembrolizumab.Pembrolizumab-induced T1DM often present with relatively low HbAlc levels, reflecting the fulminant onset of β-cell destruction.Patients treated with pembrolizumab and other immune checkpoints inhibitors should be monitored regularly for hyperglycaemia and thyroid dysfunction.

990P Endocrine immune-related adverse events (irAEs) of combined immunotherapy in solid tumors: Systematic review and meta-analysis

Immunotherapy is already a revolution in oncology. Moreover, combined immunotherapy has shown very good results in some cancers. New kind of immune-related adverse events (irAEs) have been related with immunotherapy due to the stimulation of immune system and some of them concerning endocrine system (endocrine irAEs) can be severe with significant clinical consequences.

Pan-Canadian cohort of immune checkpoint inhibitor-induced insulin-dependent diabetes mellitus (CANDIED).

2640 Background: Endocrine immune-related adverse events (irAEs) are frequent with immune checkpoint inhibitors (ICIs); however, ICI-related insulin-dependent diabetes mellitus (IDDM) is a rare but serious endocrine irAE. We describe the characteristics of patients who developed ICI-related IDDM across five academic Canadian cancer centres. Methods: In this multicentre, retrospective study, we included both patients who developed IDDM and patients with non-IDDM (NIDDM) or pre-DM who became insulin-dependent while on treatment with ICI. We collected data on primary tumor type, ICI regimen (single agent or combination), time to development of IDDM from ICI initiation, comorbidities, laboratory parameters at the time of IDDM diagnosis, tumor response and survival. A p value &lt; 0.05 was considered statistically significant. Results: We identified 27 patients between July 2016 and August 2019. Median age was 60 (39-79) years, 20 (74%) were male, 15 (55%) had melanoma and 4 each (15%) non-small cell lung cancer (NSCLC) and renal cell carcinoma. Seven (26%) patients had prior NIDDM or pre-DM; 5 (18%) had an auto-immune disease (2 psoriasis, 2 inflammatory bowel disease, and 1 systemic lupus erythematosus). Laboratory parameters at presentation and management of IDDM are presented in the Table. Mean A1c was not statistically different between patients with or without prior NIDDM or pre-DM (8.4% vs. 8.6%; p = 0.9). All IDDM events were irreversible; 1 (4%) patient died of diabetic ketoacidosis. At time of IDDM diagnosis, 17 (63%) patients were receiving single agent anti-PD1 and 10 (37%) anti-PD1-based combinations (7 anti-CTLA-4, and 3 other compounds). Median time for development of IDDM from ICI initiation was 2.7 months (95% CI 0.2-5.3). Patients receiving combination ICI developed IDDM earlier than those treated with single agent (1.4 vs 4.8 months; p = 0.05). Amongst patients with metastatic disease (n = 24), 9 (38%) had a complete response and 7 (29%) had a partial response. Two patients (8%) were treated in the adjuvant setting; 1 (4%) received consolidation ICI. IDDM led to ICI discontinuation in 12 (44%) patients. After a median follow up of 21 months from ICI initiation, median survival was 30 months (95% CI NE) and was not reached in patients with melanoma and NSCLC. Conclusions: ICI-related IDDM is a rare and typically irreversible irAE that occurs early in the course of treatment and develops earlier with combination ICI. In this cohort, patients who developed ICI-related IDDM had a high tumor response rate and prolonged survival, especially melanoma and NSCLC patients. Prospective evaluation of autoantibodies to predict development of IDDM is ongoing.[Table: see text]

Identification of RORg+T Cells as Key Players in Thyroid Autoimmunity From Checkpoint Immunotherapy

Purpose: Immune checkpoint inhibitors (ICI) are powerful new cancer therapies that leverage the body’s own immune system to attack cancer cells. Unfortunately, their use may be limited by the development of immune-related adverse events (IrAE) in up to 60% of patients. Thyroiditis is a common IrAE, with shared and distinct features from spontaneous thyroid autoimmunity, i.e. Hashimoto thyroiditis (HT). The cause of IrAE remains unknown, however, recent data suggest that toxicity can be uncoupled from anti-tumor effects. Methods: We developed a novel mouse model to study mechanisms of IrAE, in which ICI (anti-PD-1 and/or anti-CTLA-4) treatment leads to multi-organ immune infiltrates, including thyroiditis. To understand immune changes occurring with ICI-autoimmunity, we first evaluated changes in the frequency and activation status of different immune cells in our mice using immunohistochemistry (IHC) and flow cytometry. Then we confirmed these findings in peripheral blood and thyroid fine needle aspiration (FNA) specimens from patients with ICI-thyroiditis, HT, or no IrAE, using flow cytometry and single cell RNA sequencing (scRNAseq) techniques. Results: In our mouse model, ICI treatment of autoimmune-prone non-obese diabetic mice induces multi-organ autoimmunity. Modeling ICI-IrAE observed in humans, our mice developed increased immune infiltrates in multiple tissues (e.g. thyroid, colon, liver, lung), autoantibodies, and acceleration of underlying autoimmune risk (i.e. diabetes). Increased frequency of autoimmune disease was seen with combination (anti-PD-1 + anti-CTLA-4) vs. single agent ICI. We found increased IL-17A+ T cells in secondary lymphoid tissues of ICI-treated mice, a cytokine produced by RORγ + Th17 and Tc17 cells and associated with autoimmunity. IHC studies on thyroid infiltrates showed accumulation of CD4+ and CD8+ T cells and macrophages in ICI-treated vs. isotype control mice. This finding was confirmed by flow cytometry analyses of thyroid-infiltrating leukocytes in ICI-thyroiditis mice, which showed significantly increased T cells, specifically RORγ + T cells, and rare B220+ B, CD11b+ myeloid, or NKp46+ NK cells. In patients with ICI-thyroiditis, thyroid FNA showed that thyroid immune infiltrates were predominately T cells. scRNAseq studies in patients with ICI-thyroiditis showed enrichment of Th17 and Tc17 (RORγ + IL23R+ CD161+) T cells, compared to ICI-treated patients without IrAE. Conclusion: We have identified a role for RORγ + Th17 and Tc17 cells in thyroid autoimmunity from ICI using a newly developed mouse model of ICI-associated IrAE and translational studies in patients with ICI-thyroiditis. Th17 and Tc17 cells have previously been associated with spontaneous autoimmune disease, including HT, but have not yet been characterized in IrAE. These cells provide a potential therapeutic target for prevention of endocrine IrAE from ICI.

Higher baseline TSH levels predict early hypothyroidism during cancer immunotherapy

Background and purposeImmune checkpoint inhibitors (ICIs) are monoclonal antibodies that enhance the immune response against cancer cells. ICIs are generally well tolerated, although endocrine immune-related adverse events (irAEs) are common. We investigated the risk factors for thyroid irAEs in patients treated with ICIs. Moreover, we evaluated the clinical outcome of subjects who became hypothyroid compared to euthyroid patients.Patients and methodsWe retrospectively analyzed a series of 195 consecutively subjects treated with ICIs for metastatic tumors at the University of Naples “Federico II” between January 2014 and March 2020. Only subjects tested for thyroid function before and during the treatment with ICIs were included.ResultsIn the 96 patients treated with ICIs who were included [66 males, median age: 62 years (27–87)], thyroid irAEs occurred in 36 (37.5%), 16 (16.7%) a transient thyrotoxicosis, and 20 (20.8%) an hypothyroidism (in nine subjects hypothyroidism was 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 0.47–1.43; p = 0.0132) and OS (HR = 0.38 CI 95% 0.17–0.80; p = 0.011) compared to euthyroid patients.ConclusionsBaseline TSH levels above 1.67 mIU/L and presence of Ab-T are risk factors for the development of thyroid irAEs. Patients affected by thyroid irAEs showed a longer survival than patients who remained euthyroid.