The spectrum, incidence, kinetics and management of endocrinopathies with immune checkpoint inhibitors for metastatic melanoma

ObjectiveEndocrine immune-related adverse events (endocrinopathies) are increasingly prevalent with the use of immune checkpoint inhibitors for the treatment of metastatic melanoma and other malignancies. There are no evidence-based guidelines for the screening or management of such patients. To describe the spectrum, incidence, kinetics and management of endocrinopathies with immune checkpoint inhibitors.DesignA prospective study conducted at Melanoma Institute Australia between April 2014 and October 2015.MethodsA total of 177 patients were treated with (a) ipilimumab (n = 15), (b) anti-PD-1 (nivolumab, pembrolizumab) (n = 103) or (c) combination ipilimumab and anti-PD-1 (n = 59) and were screened and managed for the subsequent endocrinopathies. The main outcome measures were the incidence and kinetics of endocrinopathy by immunotherapy drug class.ResultsThirty-one patients (18%) developed an endocrine immune-related adverse event (thyroid dysfunction: 14%, hypophysitis: 6% and autoimmune diabetes: 0.6%). Combination immunotherapy was more likely to result in a single or multiple endocrinopathy compared to anti-PD-1 monotherapy (27% vs 9% and 7% vs 0% respectively,P < 0.01). Endocrinopathies occurred after a median of 8 weeks from treatment commencement (range: 12–225 days), with combination immunotherapy resulting in significantly earlier onset compared to ipilimumab (median: 30 vs 76 days,P = 0.046). The majority of endocrinopathies were identified in asymptomatic patients with hormonal screening. There were no baseline predictors for endocrinopathy.ConclusionsCombination immunotherapy has a greater risk of development of endocrinopathy compared to anti-PD-1 monotherapy. Regular biochemical profiling of patients, particularly within the first twelve weeks, results in early detection of endocrinopathy to minimise morbidity.

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Immune checkpoint inhibitors, endocrine adverse events, and outcomes of melanoma

Endocrine Connections ◽

10.1530/ec-21-0562 ◽

2022 ◽

Author(s):

Hanna Karhapää ◽

Siru Mäkelä ◽

Hanna Laurén ◽

Marjut Jaakkola ◽

Camilla Schalin-Jäntti ◽

...

Keyword(s):

Adverse Events ◽

Treatment Outcomes ◽

Metastatic Melanoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Autoimmune Diabetes ◽

Progression Free Survival ◽

Electronic Patient Records ◽

Melanoma Patients

Objective: Immune checkpoint inhibitors (ICI) can cause endocrine adverse events. However, endocrine AEs could be related to better treatment outcomes. Our aim was to investigate whether this holds true in a real-world setting of metastatic melanoma patients. Design: A retrospective single-institution study. Methods: We included 140 consecutive metastatic melanoma patients treated with ICI between January 2012 and May 2019. We assessed endocrine toxicity and best possible treatment outcomes from electronic patient records, including laboratory parameters, and radiological images. Results: Of the treated patients, 21 patients (15%) were treated with ipilimumab, 46 (33%) with nivolumab, 67 (48%) with pembrolizumab, and six (4%) with combination therapy (ipilimumab + nivolumab). Endocrine AEs appeared in 29% (41/140) patients. Three patients had two different endocrine AEs. Thyroid disorders were the most common: 26% (36/140), followed by hypophysitis: 4% (5/140). Three subjects (2%, 3/140) were diagnosed with autoimmune diabetes. Three patients had to terminate treatment due to endocrine toxicity. Radiological manifestations of endocrine AEs were found in 16 patients (39%, 16/41). Endocrine toxicity was associated with significantly better treatment outcomes. Median progression-free survival (8.1 months, range 5.1 – 11.1 months vs. 2.7 months, range 2.4 – 3.0 months, P < 0.001), and median overall survival (47.5 months, range 15.5 – 79.5 months vs. 23.7 months, range 15.3 – 32.1 months, P = 0.035) were longer for patients experiencing endocrine AEs. Conclusions: The higher number of endocrine AEs suggest regular laboratory monitoring aids in AE detection. Endocrine AEs in metastatic melanoma may correlate with better treatment outcomes.

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231 A novel discovery pipeline identifies melanoma-specific antibodies in patients responding to immune checkpoint inhibitors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0231 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A249-A249

Author(s):

Daniel Delitto ◽

Evan Lipson ◽

Laura Cappelli ◽

Klaus Busam ◽

Antony Rosen ◽

...

Keyword(s):

Metastatic Melanoma ◽

Treatment Response ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Tumor Regression ◽

Checkpoint Inhibitors ◽

Specific Antibodies ◽

Cancer Testis Antigens ◽

Circulating Antibodies ◽

Cancer Testis

BackgroundTumor-specific antibodies have been reported in patients with cancers responding to immune checkpoint inhibitors (ICI), and there is an increasing appreciation for the potential role of B cells in mediating ICI responses. However, the humoral immune response to melanoma remains incompletely defined. We hypothesized that screening sera for antibodies by immunoprecipitation with lysates of cultured melanoma cells would increase the likelihood of detecting circulating antibodies in melanoma patients receiving ICI, and potentially identify novel antibody targets associated with treatment response and/or immune-related adverse events (IRAEs).MethodsPre-and on/post-treatment sera or plasma from 12 clinically-annotated patients with advanced metastatic melanoma receiving ICI were assayed for tumor-specific antibodies with an established immunoprecipitation platform. 35S-methionine-labeled lysates from cultured 624Mel cells were used for immunoprecipitation. 624Mel expresses several shared non-mutated melanoma antigens (e.g., MAGEA3, tyrosinase, MART-1/Melan-A, gp75, and gp100). Antigen identity was determined using on-bead digests followed by mass spectrometry, and was confirmed by immunoprecipitation with in vitro transcription/translation (IVTT) products.ResultsAntibodies reactive against 624Mel proteins were detected in 4 of 12 (33%) patients (table 1). Mass spectrometric sequencing performed on proteins captured with sera from 3 of 4 patients identified several putative antigens. Immunoprecipitation with IVTT candidate proteins confirmed antibodies against melanoma-associated and cancer testis antigens NY-ESO-1, SSX2 and MAGEA10. Antibodies were observed in 1 of 1 (100%) patient with a complete response, 2 of 4 (50%) with a partial response, 1 of 1 (100%) with stable disease, and 0 of 6 (0%) with progressive disease. Antibody levels varied over the course of therapy, with previously undetectable specificities arising during treatment response in patients #1–3. Patient #1 with a complete tumor regression developed antibodies to SSX2 and MAGEA10 that were absent before treatment. Further, detection of these antibodies coincided with diagnosis of IRAEs (anti-SSX2 with pancreatitis and anti-MAGEA10 with dermatitis). In contrast, patient #3, initially with a partial tumor regression, demonstrated a loss of detectable anti-NY-ESO-1 antibodies upon disease progression, and subsequent metastasectomy demonstrated loss of NY-ESO-1 protein expression in the progressing tumor. Testing sera from all 12 patients with IVTT products for NY-ESO-1, SSX2 and MAGEA10 did not reveal additional humoral responses.Abstract 231 Table 1Antibodies detected in the serum or plasma of patients with metastatic melanoma treated with ICI therapy. Treatment response indicates best overall response according to RECIST v1.1. Post-treatment blood collections were drawn during or after ICI therapy.ConclusionsOur comprehensive screening platform detected circulating antibodies specific to multiple melanoma-associated and cancer testis antigens in patients deriving clinical benefit from ICI. Expanded investigations of the evolution of antibody production over the course of ICI therapy, associated with tumor response to treatment and development of IRAEs, are warranted.AcknowledgementsThis study was supported by the Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, and NIH P30-AR070254.Ethics ApprovalThis study was approved by the Johns Hopkins Institutional Review Board, approval #NA_00090257.

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Sudden Otovestibular Dysfunction in 3 Metastatic Melanoma Patients Treated With Immune Checkpoint Inhibitors

Journal of Immunotherapy ◽

10.1097/cji.0000000000000367 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Suzan H. Stürmer ◽

Axel Lechner ◽

Carola Berking

Keyword(s):

Metastatic Melanoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Melanoma Patients

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Monitoring of patients with metastatic melanoma treated with immune checkpoint inhibitors using PET–CT

Cancer Immunology Immunotherapy ◽

10.1007/s00262-018-2229-6 ◽

2018 ◽

Vol 68 (5) ◽

pp. 813-822 ◽

Cited By ~ 17

Author(s):

Antonia Dimitrakopoulou-Strauss

Keyword(s):

Metastatic Melanoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Pet Ct

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Analysis of metastatic melanoma treated with immune checkpoint inhibitors and the rates of adverse events of colitis and hepatitis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21591 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21591-e21591

Author(s):

Emily Horan ◽

Melissa Arneil ◽

Wen Xu ◽

Victoria Atkinson

Keyword(s):

Metastatic Melanoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Immune Therapy ◽

Complete Response ◽

Treatment Regimens ◽

Organ Systems ◽

Oral Steroids ◽

Intravenous Steroids

e21591 Background: Immune checkpoint inhibitors (CPI) are widely used in metastatic melanoma (MM), where it has markedly improved survival outcomes. ICI induced autoimmune adverse reactions (irAE) manifest in all organ systems and are due to over-activation of the immune system. Clinically relevant irAE are colitis and hepatitis as drivers of morbidity and mortality. Methods: Data was collected from a single centre (Princess Alexandra Hospital) from the electronic medical records system and immunotherapy prescribing software. Patient demographics, treatments, complications and outcomes were recorded from 2016-2019. Eligible patients had to have received immunotherapy (pembrolizumab, ipilimumab, or nivolumab) and experienced colitis or hepatitis toxicity. Trial patients were excluded. Results: The cohort of 337 patients who had received immune therapy, 18% (n = 61) had hepatitis or colitis, mean age was 56 years, 64% male. The majority were stage 4d 28% (n = 17). Braf wildtype accounted for 56% (n = 34). The highest rates of irAE occurred on combination ipilimumab and nivolumab 56% (n = 34), 10% nivolumab (n = 6), 3% (n = 2) ipilimumab, and 31% (n = 19) pembrolizumab monotherapy. Colitis affected 61% of patients (n = 37), 30% (n = 18) were grade 3 severity. Hepatitis affected 48% (n = 29), 18% (n = 32) were grade 1. The majority required oral steroids (80%, n = 49), followed by intravenous steroids (51%, n = 31), infliximab (18%, n = 11) and mycophenolate in 5% (n = 3). Hospitalisation occurred in 56% (n = 34), 20% (n = 12) requiring treatment cessation. Progressive disease occurred in 62% (n = 38), and 13% (n = 8) had a complete response. Conclusions: The findings of this analysis mirror current literature with immunotherapies used, rates and severity of irAE. The management of irAE also aligned with current guidelines. Further research is required to investigate patient factors increasing the risk of developing irAE, and ideal treatment regimens. Analysing this large cohort, the incidence of toxicity was 17%, predominantly colitis followed by hepatitis. Patients were severely impacted requiring significant interventions to manage toxicity, hospitalisation and morbidity.

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Behcet’s-like syndrome following pembrolizumab: An immune-related adverse event associated with programmed death receptor-1 inhibitor therapy

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155219877219 ◽

2019 ◽

Vol 26 (4) ◽

pp. 995-999 ◽

Cited By ~ 1

Author(s):

Steffi Thomas ◽

Chay Bae ◽

Tabanor Joy-Ann ◽

William Traverse

Keyword(s):

Adverse Events ◽

Metastatic Melanoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Death Receptor ◽

Programmed Death ◽

Organ Systems ◽

Wide Range ◽

The Right

Introduction The landscape for the treatment of metastatic melanoma has been revolutionized with the introduction immune checkpoint inhibitors. Immune checkpoint inhibitors have now become the standard of care for the treatment of cancers. These immune agents including programmed death receptor-1 inhibitors, programmed death-ligand 1 inhibitors and cytotoxic T-lymphocyte antigen-4 inhibitors have shown promising results but have been associated with numerous immune-related complications. Pembrolizumab, a programmed death receptor-1 inhibitor, has been associated with a number of immune-related adverse events affecting multiple organ systems including integument, ocular, endocrine, cardiovascular, pulmonary, renal, gastrointestinal, and musculoskeletal system. Case report We present a case of an 88-year-old Caucasian male with metastatic melanoma of the face with metastasis to the right fifth cranial nerve and into the right cavernous sinus. He underwent resection of the melanoma and was placed on pembrolizumab at 2 mg/kg every three weeks. Interestingly, 24 months on pembrolizumab therapy, he developed corneal erosions, oral and genital ulcerations. Management and outcome Patient completed his 24 months of pembrolizumab and was started on prednisone and colchicine with improvement in his symptoms. At his follow-up eight months, he had recurrence of an oral ulcer. Discussion Here we present a rare case of an elderly male on pembrolizumab who suffered from corneal erosions, oral and genital ulcers, a syndrome similar to Behcet’s disease. Given that pembrolizumab and other immune checkpoint inhibitors are being utilized in the treatment of cancers, physicians should be aware of the wide range immune-related adverse events including the possible Behcet’s-like syndrome presentation.

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