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

Abstract

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.

Hypophysitis (Including IgG4 and Immunotherapy)

“…The diagnosis of ICI-induced hypophysitis is based on recent use of these drugs in patients with malignancies. The commonest symptoms include fatigue and headaches in 59–73% and 21–80% of cases, respectively, whereas visual disturbances and DI are relatively rare [9, 43, 63-65]. Most cases are diagnosed during regular follow-up of pituitary function performed before every cycle of therapy for at least the first 3 months [1].…”

“…Most cases are diagnosed during regular follow-up of pituitary function performed before every cycle of therapy for at least the first 3 months [1]. Patients with ICI-induced hypophysitis usually present with TSH (84%), adrenocorticotropic hormone (80%), and gonadotropin (76%) deficiency [39, 65].…”

<p>Managing Ipilimumab-Induced Hypophysitis: Challenges and Current Therapeutic Strategies</p>

“…A recent study by our group reported for the first time that sequential treatment with anti-CTLA-4 and anti-PD1 agents increased the risk of developing hypophysitis to a level as high as that of combination therapy. 26 Furthermore, high rates of hypophysitis (grade 3 or 4 toxicity) have been reported in patients receiving adjuvant treatment with prostate cancer cell vaccine or bevacizumab. 27,28 In contrast, no increased incidence of hypophysitis was observed with the combination of ipilimumab with chemotherapeutic agents such as carboplatin, dacarbazine, paclitaxel and fotemustine or targeted agents including vemurafenib and dabrafenib compared to monotherapy with ipilimumab.…”

“…10 In fact, recent case series report that adrenocorticotropic deficiency is the most common hormonal insufficiency observed in patients with ICI-related hypophysitis. 26,47 It is characterized by a low-or low-normal early morning cortisol level in the setting of an inappropriately low or normal adrenocorticotropin hormone (ACTH). Hypogonadotropic hypogonadism is also common while the prevalence of growth hormone (GH) deficiency is unclear due to lack of confirmation of GH deficiency in most studies.…”

Multiple endocrinopathies, hypercalcaemia and pancreatitis following combined immune checkpoint inhibitor use- case report and review of literature

“…Moreover, endocrinopathies are more common when two ICIs are used together [ 2 ]. The thyroid and pituitary glands are the most commonly affected endocrine organs [ 3 ], however cases of type 1 diabetes mellitus (including diabetic ketoacidosis) [ 4 ], primary adrenal insufficiency [ 5 ], Cushing’s Syndrome [ 6 ], diabetes insipidus [ 7 ] and hypoparathyroidism [ 8 ] have all been reported. Patients can develop problems with one or multiple endocrine organs.…”