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

Scott, Emma; Long, Georgina V.; Guminski, Alexander; Clifton‐Bligh, Roderick; Menzies, Alexander M.; Tsang, Venessa

doi:10.1530/eje-17-0810

Cited by 122 publications

(100 citation statements)

References 28 publications

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“…None of the 26 patients recovered from central hypoadrenalism during a median follow‐up of 15 months, as likewise reported in previous studies, while recovery from central hypothyroidism occurred in almost all patients. Similarly, to our results, Albarel et al described resolution of central hypothyroidism in 11/13 patients, while Scott et al reported the same in 0/10 patients. Of note, Min et al reported recovery in 14 of 22 patients in a median of 10 weeks.…”

Section: Discussionsupporting

confidence: 86%

Endocrine‐related adverse events associated with immune‐checkpoint inhibitors in patients with melanoma

et al. 2019

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BackgroundImmune‐checkpoint inhibitors have been shown to improve survival in melanoma patients, but can also trigger immune‐related endocrinopathies, especially hypophysitis and thyroid dysfunction.MethodsTo assess the incidence and the spectrum of endocrinopathies in melanoma patients treated with immunotherapy a prospective observational study was conducted. Forty out of 339 patients, treated with immune‐checkpoint inhibitors, developed endocrinopathies. All patients had hormonal functional tests at screening (before the initiation of immunotherapy) and during follow‐up.ResultsThe total incidence of endocrinopathies was 11.8%, 13.4% due to anti‐PD1/PDL1, 5% due to anti‐CTLA4, and 18.5% due to sequential and/or combination treatment. Twenty‐one patients (6.2%) presented with isolated anterior hypophysitis, eleven (3.2%) with primary thyroid dysfunction and eight (2.4%) with both abnormalities. The most frequent anterior pituitary hormone deficiency was central adrenal insufficiency, followed by central hypothyroidism and hypogonadotrophic hypogonadism. None of the patients with corticotroph axis failure recovered during follow‐up. Endocrinopathies occurred after a median of 22 weeks (range: 4‐156) from treatment initiation. Of note, sequential and/or combination therapy with anti‐CTLA4 and anti‐PD1/anti‐PDL1 led to an almost threefold incidence of hypophysitis compared to either monotherapy. Only one of 120 patients receiving anti‐CTLA4 monotherapy developed primary hypothyroidism.ConclusionsOur cohort demonstrated an increased incidence of hypophysitis with anti‐PD1/anti‐PDL1 in contrast to the rarity of primary thyroid dysfunction with anti‐CTLA4 treatment. These results could be attributed to genetic/ethnic differences. Sequential treatment is, for the first time to our knowledge, reported to increase the risk of developing hypophysitis to a level as high as that of combination therapy.

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Section: Discussionsupporting

confidence: 86%

Endocrine‐related adverse events associated with immune‐checkpoint inhibitors in patients with melanoma

et al. 2019

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“…In any case, these data need to be taken with caution, because the age of occurrence and the sex ratio can be very different from one cancer to another (melanoma or non-small-cell lung cancer for example). The median time to occurrence is, as in this case report, between 2 and 4 months (range 4 weeks to 19 months) with anti-CTLA-4 (20,22,23,24), from 3 to 6 months with PD-1 or PD-L1 (25,26) and earlier for those on combination treatment (30 days on average) (13). It should also be noted that the development of autoimmune disease has been shown to correlate with a better response to ipilimumab therapy, especially in grade 3/4 IRAEs (6,27,28).…”

Section: Is Hypophysitis a Common Adverse Event With Immunotherapy?supporting

confidence: 68%

“…Therefore, patients treated with PD-1 inhibitors or PD-L1 inhibitors appear to more frequently develop thyroid dysfunction than hypophysitis. In this study, it is worth noting that combination treatments enhanced the prevalence of all types of endocrine IRAEs and that these also occurred earlier (12,13). The incidence of confirmed primary adrenal insufficiency is very low (case reports) and can occur with both anti-CTLA-4 and PD-1 inhibitors (12).…”

Section: Is Hypophysitis a Common Adverse Event With Immunotherapy?mentioning

confidence: 76%

MANAGEMENT OF ENDOCRINE DISEASE: Immune check point inhibitors-induced hypophysitis

Albarel

Castinetti

Brue

2019

European Journal of Endocrinology

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In recent years, the development of immunotherapy has constituted a revolution in the therapy for many cancers, with a specific toxicity profile including endocrine immune-related adverse events. Immune check point inhibitors (ICI)-induced hypophysitis is a common endocrine side effect, particularly with CTLA-4 antibodies and combination therapy, with frequent hormonal deficiencies at diagnosis. It can be difficult to evoke such diagnosis as the initial clinical symptoms are not specific (headache, asthenia…); thus, patients receiving such immunomodulatory therapies should be closely monitored by systematic hormone measurements, especially in the first weeks of treatment. Usually, hormonal deficiencies improve, except for corticotroph function. Despite a lack of large prospective studies on ICI-induced hypophysitis, some detailed longitudinal cohort studies have focused on such cases of hypophysitis and allow for optimal monitoring, follow-up and management of patients with this immune-related adverse event. In the case of ICI-induced hypophysitis, patients need long-term multidisciplinary follow-up, with specific education for those patients with corticotropin deficiency to allow them to be autonomous with their treatment. In this review, based on a clinical case, we detail the most relevant and novel aspects related to the incidence, diagnosis, treatment, evolution and management of hypophysitis induced by immunotherapy, with a focus on possible mechanisms and current recommendations and guidelines. Lastly, we emphasize several key points, such as the absence of indication to systematically treat with high-dose glucocorticoid and the pursuit of immunotherapy in such hypophysitis. These points should be kept in mind by oncologists and endocrinologists who treat and monitor patients treated by immunotherapy.

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“…Almost 90% of TAEs arose within the first 3 months, and none were found after 9 months. This finding is in line with previous reports showing time to onset of thyroid dysfunction of between 6 and 9 weeks . In accordance with the literature, time to thyrotoxicosis onset was shorter than for hypothyroidism; the median time for hyperthyroidism to evolve to hypothyroidism is known to be very short and was <45 days in the present study.…”

Section: Discussionsupporting

confidence: 93%

“…As a result, thyroid disorders are becoming more prevalent in this population, representing a challenge for oncologists, endocrinologists and general practitioners alike. 14 In the present study, 23% of patients presented TAEs, as previously reported in some studies. 15,16 Current literature data are conflicting.…”

Section: Discussionsupporting

confidence: 89%

Thyroid disorders in programmed death 1 inhibitor‐treated patients: Is previous therapy with tyrosine kinase inhibitors a predisposing factor?

Sbardella

Tenuta

Sirgiovanni

et al. 2020

Clinical Endocrinology

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Background Programmed death 1 (PD‐1) inhibitors are frequently associated with thyroid‐related adverse events (TAEs), but many aspects remain unclear. This study aims to evaluate the incidence and characteristics of such events and to find any predictive factor for its development. Methods We retrospectively analysed data from patients with advanced solid tumours (non‐small‐cell lung carcinoma, renal cell carcinoma, metastatic melanoma) treated with PD‐1 inhibitors (nivolumab, pembrolizumab) in Oncology Unit B, Policlinico Umberto I of Rome, from June 2015 to December 2018. All patients underwent baseline thyroid function evaluations repeated monthly. Results The cohort consisted of 126 patients (66.7% male, mean age 66.4 ± 9.7 years). One hundred and seven received nivolumab and 19 pembrolizumab. Twenty‐three per cent of patients experienced TAEs (mainly CTCAE grade 1), with hypothyroidism in 15.1% (subclinical: 11.9%, overt: 3.2%) and hyperthyroidism in 8.0% (subclinical: 4.8%, overt: 3.2%). Median time to TAE onset was 8.7 ± 6.8 weeks (10.4 ± 7.6 weeks for hypothyroidism, 5.4 ± 3.0 weeks for hyperthyroidism). Most TAEs (89.7%) appeared within the first 3 months, none after 8 months. Most hypothyroid patients (63.2%) had previously been treated with a tyrosine kinase inhibitor (TKI). Logistic regression analysis showed that pretreatment with a TKI was a major predisposing factor for the development of hypothyroidism (OR 9.2, 95% CI: 1.4‐59.9, P = .020). Conclusions TAEs are common during anti‐PD‐1 therapy and usually occur within the first 3 months of treatment. This is the first study evaluating the impact of previous oncologic therapies on TAEs, identifying TKI as a major risk factor for the development of hypothyroidism in patients treated with anti‐PD‐1.

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

Abstract: Combination 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.

Cited by 122 publications

References 28 publications

Endocrine‐related adverse events associated with immune‐checkpoint inhibitors in patients with melanoma

Endocrine‐related adverse events associated with immune‐checkpoint inhibitors in patients with melanoma

MANAGEMENT OF ENDOCRINE DISEASE: Immune check point inhibitors-induced hypophysitis

Thyroid disorders in programmed death 1 inhibitor‐treated patients: Is previous therapy with tyrosine kinase inhibitors a predisposing factor?

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