A systematic review of ipilimumab-induced hypophysitis

Ipilimumab is a human monoclonal antibody against cytotoxic T-lymphocyte antigen 4 available as an immunotherapy mainly for advanced melanoma. It induces an activation of T cells, resulting in an immune-mediated anti-tumor response and also immune-related adverse events, including hypophysitis. The aim of this review is to identify and discuss features concerning ipilimumab-induced hypophysitis (IIH). A MEDLINE research of all years of publication of IIH was conducted. We gathered information regarding clinical, radiologic and laboratory features of 71 cases recorded in the literature. In our review, IIH was more frequent among older and male patients. Fatigue and headache were the most frequent initial clinical manifestations of IIH and enlargement of the pituitary gland at MRI was present in the majority of patients. Those who received more than 3 cycles of ipilimumab had more fatigue (p=0.04) and arthritis (p=0.04). Adrenal insufficiency was more prevalent in men (p=0.007). Glucocorticoid therapy and hormone replacement were required in most patients and pituitary function recovery was uncommon. Low prolactin at diagnosis tended to predict permanent pituitary dysfunction (p=0.07). Hypopituitarism as a consequence of IIH, if not promptly recognized, can lead to potentially fatal events, such as adrenal insufficiency. IIH can be easily managed with glucocorticoids and hormonal replacement; therefore, physicians should be familiar with the key aspects of this condition. More studies to develop screening protocols and therapeutic intervention algorithms should be performed to decrease morbidity related to IIH.

Hypophysitis, a rare autoimmune condition, has now emerged as an adverse effect of ipilimumab (anti-cytotoxic T lymphocyte antigen 4 (CTLA4) mAb) therapy. The occurrence of ipilimumab-induced hypophysitis (IH) in studies has varied from 0% to 17%. This condition, because of secondary adrenal insufficiency, may be life-threatening if not recognized and managed promptly. Here we present a case of hypophysitis in the setting of ipilimumab therapy for malignant melanoma. The patient initially presented to his oncologist with a headache, diplopia, fatigue, nausea, hot flashes, anorexia and decreased libido shortly following the third cycle of ipilimumab. He was found to have pituitary enlargement with heterogeneous enhancement on magnetic resonance imaging (MRI). The initial diagnosis was based on clinical features, MRI findings and laboratory evidence of central hypogonadism and adrenal insufficiency. Other hormone levels were not tested that time and were only tested 5 months later when the patient did not tolerate the discontinuation of glucocorticoids. He continued to require glucocorticoid and testosterone replacement 14 months after the diagnosis. This case demonstrates IH causing anterior hypopituitarism leading to central hypoadrenalism, central hypogonadism, reduced prolactin and possibly central hypothyroidism but preserved somatotroph function. Pituitary antibodies may be a possible method of detection of IH in addition to MRI and hormonal investigations. There is insufficient evidence to support the need for discontinuing ipilimumab or the superiority of initial high dose versus physiologic steroid and hormone replacement in the management of IH. Hypopituitarism due to IH may persist for several months or longer after ipilimumab is discontinued. This underlies the importance of continuous supplementation with all the hormones that are deficient as a consequence of hypopituitarism caused by IH. J Endocrinol Metab. 2015;5(5):299-303 doi: http://dx.doi.org/10.14740/jem287w

Hypophysitis, a rare autoimmune condition, has now emerged as an adverse effect of ipilimumab (anti-cytotoxic T lymphocyte antigen 4 (CTLA4) mAb) therapy. The occurrence of ipilimumab-induced hypophysitis (IH) in studies has varied from 0% to 17%. This condition, because of secondary adrenal insufficiency, may be life-threatening if not recognized and managed promptly. Here we present a case of hypophysitis in the setting of ipilimumab therapy for malignant melanoma. The patient initially presented to his oncologist with a headache, diplopia, fatigue, nausea, hot flashes, anorexia and decreased libido shortly following the third cycle of ipilimumab. He was found to have pituitary enlargement with heterogeneous enhancement on magnetic resonance imaging (MRI). The initial diagnosis was based on clinical features, MRI findings and laboratory evidence of central hypogonadism and adrenal insufficiency. Other hormone levels were not tested that time and were only tested 5 months later when the patient did not tolerate the discontinuation of glucocorticoids. He continued to require glucocorticoid and testosterone replacement 14 months after the diagnosis. This case demonstrates IH causing anterior hypopituitarism leading to central hypoadrenalism, central hypogonadism, reduced prolactin and possibly central hypothyroidism but preserved somatotroph function. Pituitary antibodies may be a possible method of detection of IH in addition to MRI and hormonal investigations. There is insufficient evidence to support the need for discontinuing ipilimumab or the superiority of initial high dose versus physiologic steroid and hormone replacement in the management of IH. Hypopituitarism due to IH may persist for several months or longer after ipilimumab is discontinued. This underlies the importance of continuous supplementation with all the hormones that are deficient as a consequence of hypopituitarism caused by IH. J Endocrinol Metab. 2015;5(5):299-303 doi: http://dx.doi.org/10.14740/jem287w

Renal Cell Carcinoma: Diagnosis Based on Metastatic Manifestations

Solid Renal Masses in Transplanted Allograft Kidneys: A Closer Look at the Epidemiology and Management.

BackgroundImmune checkpoint inhibitors deeply modified metastatic renal cell carcinoma’s management, and confront us to adverse events that we were not used to with conventional anti-cancer therapies. We report the case of a patient who received nivolumab as second-line treatment of a metastatic clear cell renal cell carcinoma and who developed bullous pemphigoid four years after nivolumab introduction, with persistent exacerbations even after its discontinuation.Case presentationA 66-year-old man was diagnosed with lung metastasis eight years after radical nephrectomy for a clear cell renal cell carcinoma. He firstly received an anti-angiogenic agent combination, and then received anti-programmed death 1 (PD1) nivolumab as second-line treatment. Nivolumab led to prolonged disease control, but after four years of exposure the patient developed skin lesions consistent with bullous pemphigoid. After seven years of nivolumab administration and perfect disease stability, nivolumab was discontinued and surveillance was proposed. Despite nivolumab discontinuation, the patient continued to develop bullous pemphigoid exacerbations. Metastatic renal cell carcinoma was still perfectly stable more than two years after immune checkpoint discontinuation with no further anti-cancer therapy.DiscussionWe report the case of a refractory bullous pemphigoid which occurred four years after nivolumab introduction and lasted despite nivolumab discontinuation, in a patient whose metastatic renal cell carcinoma is still controlled after more than two years without any anticancer treatment. This highlights the potential association between immune-related adverse events and response to immune checkpoint inhibitors, and underlines the occurrence of late-onset and long-lasting immune-related adverse events even after discontinuation of treatment, which must encourage us to remain vigilant in the long term.

Immune checkpoint inhibitors are a novel class of immunotherapy drugs that have improved the prognosis of melanoma, renal cell carcinoma, non-small cell lung cancer, urothelial carcinoma, and various other solid tumors. Nivolumab is an immune checkpoint inhibitor that acts by inhibiting programmed death. Its use is associated with significant immune-related adverse events, such as pneumonitis, thyroiditis, hepatitis, pruritus, vitiligo, and diarrhea. However, adrenal insufficiency and checkpoint inhibitor-related autoimmune diabetes mellitus are extremely rare adverse events related to nivolumab treatment. Here, we are highlighting cases of adrenal insufficiency and diabetes inspidus as a result of nivolumab. These rare adverse events in our case series are to raise awareness that this medication also may be the cause for this illness among oncologists, endocrinologists, internists, and other clinicians.

Hyponatremia in a Patient With Cancer

Characterization of outcomes in patients with advanced genitourinary malignancies treated with immune checkpoint inhibitors

Introduction and objectives: Neoadjuvant pembrolizumab combined with chemotherapy has become the standard of care since 2022, for patients with triple negative breast cancer (TNBC) in Australia, following the KEYNOTE-522 trial, which identified significantly higher pathological complete response (pCR) compared to placebo, acknowledging the serious immune-related adverse events (irAEs) (1). A secondary analysis of this trial included patients enrolled in Asia and found similar rates of grade 3-4 irAEs in the pembrolizumab and placebo groups (3). Reports of adverse outcomes are often overshadowed by the significant benefit of pembrolizumab in TNBC, a subtype of breast cancer with significant risk of recurrence and mortality (2). Our objective was to collect real-world data relating to the use of neoadjuvant pembrolizumab in patients with TNBC, to identify the pattern of adverse events and outcomes. Methods: Retrospective data was collected across three tertiary hospitals in Melbourne, Australia, for patients diagnosed with TNBC, who received neoadjuvant pembrolizumab; baseline demographics, medical background, primary tumour details, pembrolizumab and chemotherapy regimen, serious adverse events and their management, breast surgery and pathological response. Results: There were 54 female patients who received neoadjuvant pembrolizumab; median age 52 years and median follow up of 11 months. 4 patients had a history of autoimmune disease and 2 had immunosuppressant therapy during or within 2 years prior to treatment with pembrolizumab. At primary diagnosis, 69% had nodal involvement. At least one irAE occurred in 54% of patients; thyroiditis (22%), adrenal insufficiency (20%), colitis (7%), hepatitis (6%) rash of at least grade 3 severity (4%) and pneumonitis (4%). Other less frequent irAEs include autoimmune haemolytic anaemia, transverse myelitis, arthralgia and type 1 diabetes mellitus. Of those with irAEs, 45% were hospitalised, 1 patient required intensive care and 69% have ongoing sequelae. The median time from commencement of pembrolizumab to irAE onset was 84 days. An interruption in pembrolizumab dose occurred in 23 patients, with 70% of these discontinuing therapy early. 41 patients underwent surgical intervention, and 40 had lymph node dissection. pCR was achieved in 37%, while 60% of those who achieved pCR experienced at least one irAE. Conclusion: There are significant immune related adverse events associated with the use of neoadjuvant pembrolizumab, a notable proportion of whom required hospitalisation, which poses an important and concerning burden for patients and the healthcare system. These real-world outcomes will continue to be monitored. Further work should also look at survival outcomes and quality of life, to better inform shared-decision making.

480 Background: Immune related adverse events (IRAEs) with immune checkpoint inhibitor (ICI) therapy are well recognized, but predictors for IRAEs are not well defined. We aim to characterize the type, timing, and clinical risk factors associated with (w/) IRAEs in ICI-treated, advanced urothelial carcinoma (UC) and renal cell carcinoma (RCC) patients (pts). Methods: We retrospectively reviewed charts of pts w/ advanced UC and RCC who received at least 2 ICI doses at our institution from 1/1/10 to 10/31/18. Patient baseline characteristics, treatment course, and clinical outcomes were collected. IRAEs were identified and graded (GR) based on CTCAE (v.4.0). Fisher’s exact test was used to study the differences between pts w/ versus without IRAE. Results: Of the 71 pts identified (UC n = 53; RCC n = 18), 27 pts (38%) developed IRAEs with 42 total events (38% GR1, 60% GR2, and 2% GR≥3) [table]. The majority of pts with dermatitis (70%) also developed a secondary, systemic IRAE(s). Systemic steroid (SS) was required in 17 events. The median time to any IRAE was 17.5 weeks (w, range 1-93). ECOG ≤ 1 predicted IRAE development (p < 0.05). No other characteristics (demographics, co-morbidities, metastatic sites, ICI type, line of therapy, and duration of ICI > 12w) were associated with IRAE. Conclusions: In our study, good function status is associated with the development of IRAE. Time to IRAE ranged from immediately to 93w after initiating ICI. Clinical validation with additional datasets will be needed to confirm these findings. [Table: see text]

Background: Renal cell carcinoma is the third most prevalent urological cancer worldwide and about 30% of patients present with metastatic disease at the time of diagnosis. Systemic treatments for metastatic renal cell carcinoma have improved recently. Vascular endothelial growth factor targeting therapies were the previous standard of care. However, immune checkpoint inhibitors used in second line therapy have now been shown to improve patient survival. We report a case of metastatic renal cell carcinoma with nivolumab as a second-line therapy after progression with tyrosine kinase inhibitor therapy. Unusual adverse events in metastatic renal cell carcinoma, such as vitiligo, were observed in this patient who developed a remarkable documented pathological complete response to his renal tumor.Case presentation: A 60-year-old caucasian male was diagnosed with a pulmonary metastatic clear cell renal cell carcinoma. Sunitinib was used as first line treatment without success. He received nivolumab in second-line treatment. He developed several immune-related adverse events, most notably vitiligo. The patient had a radiological complete response on metastatic sites, with a significant decrease of renal tumor volume and underwent cytoreductive nephrectomy after 2 years of treatment, confirming the pathological complete response. The patient remains disease-free for 10 months without further systemic therapy after nivolumab discontinuation.Conclusions: Pathological complete response with nivolumab in metastatic renal cell carcinoma is rare. This case further highlights the potentially predictive role of immune-related adverse events during nivolumab therapy for metastatic renal cell carcinoma and raises questions concerning the role of nephrectomy after immune checkpoint inhibitor therapy. Further studies are needed to better identify predictive factors for treatment response to immunotherapy in metastatic renal cell carcinoma, and to better understand the role of nephrectomy after nivolumab treatment.

Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced urothelial carcinoma (UC) and renal cell carcinoma (RCC). Their expanding use in the adjuvant setting, aimed at eliminating micrometastatic disease post-surgery, holds significant promise. However, balancing potential survival benefits with the risk of immune-related adverse events (irAEs) in patients who are otherwise disease-free requires careful consideration. This review evaluates current evidence on adjuvant ICIs in UC and RCC, with emphasis on clinical efficacy, irAE profiles, and strategies for mitigating toxicity. A targeted literature search was performed across PubMed, Embase, Web of Science, Scopus, and the Cochrane Library, supplemented by manual review of American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) conference abstracts, to identify relevant studies on adjuvant ICI therapy in urological malignancies between 24 September 2024 and 25 January 2025. Relevant data on efficacy, safety, and irAE management were synthesized to highlight critical findings and research gaps. Adjuvant ICIs have shown meaningful improvements in disease-free survival for patients with high-risk UC and RCC. Grade ≥3 irAEs, particularly endocrine toxicities such as hypothyroidism, adrenal insufficiency, and hypophysitis, are relatively frequent and often irreversible, necessitating lifelong hormone replacement and long-term follow-up. Although some trials have not demonstrated overall survival advantages, emerging evidence suggests biomarkers such as circulating tumour DNA (ctDNA) could guide more precise patient selection. Optimising irAE management is pivotal, as these events can significantly affect quality of life in a population that may remain disease-free. Adjuvant immunotherapy represents a potentially significant advance in UC and RCC, offering improved outcomes for select patients. Yet, the persistent nature of irAEs calls for vigilant surveillance, robust biomarker development, and integration of patient-reported outcomes to ensure informed clinical decision-making. The next frontier will rely on better risk stratification and toxicity mitigation to translate disease-free gains into durable, life-extending benefits. Future research that refines patient selection criteria and irAE management will be crucial for translating these survival gains into long-term benefits and shaping evidence-based guidelines in urological oncology.

2659 Background: Immune checkpoint inhibitors (ICI) became widely used for treatment of various malignancies. They may cause different immune-related adverse events (irAEs), including adrenal insufficiency (irAI). IrAI was reported to be comparatively uncommon but potentially life threatening. We conducted a retrospective single center study to identify and describe the incidence and characteristics of AI associated with ICI. Methods: We reviewed the medical records of patients treated at an oncological department at Loginov Moscow Clinical Scientific Center between Sep’2019 and Jan’2023 with immunotherapy under direct cortisol monitoring every 6-8 weeks. The main criteria for AI was low serum cortisol in the absence of glucocorticoid intake. Results: A total 101 patients (pts) treated by ICI or ICI in combination with chemotherapy or targeted therapy for various malignancies were included in our retrospective analysis. 16 patients (15.8%) were diagnosed with AI: 7 pts with renal cell carcinoma (RCC), 6 pts with melanoma (2 in adjuvant setting), 1 with non-small-cell lung cancer (NSCLC), 1 with small-cell lung cancer (SCLC), 1 with MSI-high colorectal cancer (CRC). Median age was 65 (range 46-79), the majority (10 pts, 62.5%) were male. The median time of irAI onset from ICI start was 5 months (range 2-15). Assessment of serum cortisol was performed every 6-8 weeks routinely and off-schedule in patients who had new onset AI-like symptoms. The most frequent symptoms were unspecific and included fatigue and weakness (100%), loss of appetite/anorexia (69%), hypotension (50%), weight loss (44%), insomnia (38%), chills (31%), nausea/vomiting (31%), muscle pain or cramps (31% and 25% respectively), dizziness (25%), dry mouth (25%), headache (13%), fever (6%). Remarkably, laboratory detected serum cortisol decline preceded any AI symptoms in 7 patients (43.7%). Other 7 patients (43.7%) had concurrent secondary hypothyroidism which suggested panhypopituitarism. Hydrocortisone replacement led to rapid symptoms recovery in 15/16 patients. Additional treatment with fludrocortisone was required for only one patient who had primary/mixed AI due to bilateral metastases of RCC in adrenal glands. All patients resumed immunotherapy after symptoms resolved. Only 1 patient needed treatment modification (ipilimumab cessation). By 12th February 2023 median follow-up from irAI onset is 7 months (range 0.5-37), 12 patients are alive, they all remain on permanent hydrocortisone replacement therapy. Conclusions: Routine cortisol assessment during immunotherapy allowed us to detect irAI in 15.8% of patents that is higher than usually reported. Detection of irAI before clinical presentation let us prevent severe consequences including life threating. We consider that routine cortisol assessment during immunotherapy should be implemented in clinical practice.

Immune-checkpoint inhibitors are immuno-modulatory antibodies used in patients with advanced cancers like melanoma, renal cell carcinoma, non-small cell lung cancer, etc. They are associated with a wide array of side effects, commonly known as immune-related adverse events (irAEs), affecting dermatological, gastrointestinal, hepatic, endocrine, and other systems. We present a case of nivolumab-induced adrenal insufficiency in a patient presenting with refractory hypotension. The patient is a 77-year-old caucasian male with metastatic renal cell carcinoma (RCC) on nivolumab therapy, presented to his primary doctor for symptoms of fatigue, weakness, loss of appetite, and dizziness. His initial blood pressure (BP) was noted to be 78/44 mmHg, so he was referred to the emergency department. He received several liters of intravenous (IV) fluid boluses; however, BP consistently stayed in 90s systolic and 40-50 diastolic. The lab investigations showed a low sodium level at 128 mmol/L, blood urea nitrogen (BUN) elevated at 37 mg/dL, creatinine elevated at 2.7 mg/dL. A morning cortisol level was checked; it came back low at 1.3 mcg/dL. Further testing with the cosyntropin stimulation test revealed low basal cortisol of 1 mcg/dL and only a mild increase to 10.20 mcg/dL after the cosyntropin administration. Adrenocorticotrophic hormone (ACTH) was checked that came out to be low <5pg/mL, favoring a diagnosis of secondary adrenal insufficiency likely due to hypophysitis. In the meantime, the patient was started on hydrocortisone, which improved his blood pressure significantly. He was eventually weaned from IV hydrocortisone to p.o. hydrocortisone. The nivolumab was discontinued, and oncology decided on giving a nivolumab re-challenge once the patient was stabilized. Our patient presented with common manifestations of adrenal insufficiency like fatigue, hypotension, and hyponatremia, which is one of the rare irAEs occurring in <1% of the patients. These are non-specific manifestations and can be easily overlooked if adverse events of immunotherapy are not suspected. Even though rare, adrenal insufficiency is a life-threatening side-effect of immune checkpoint inhibitor drugs that need to be recognized immediately and managed with intravenous glucocorticoids.