Immune-Related Endocrinopathies Associated with Ipilimumab Therapy

Le Min, MD, PhD

Uncategorized

With the recent advancements in the treatment of patients with metastatic melanoma, in particular with immunomodulating therapies, the development of unique immune-related side effects has posed novel management challenges. The first drug in this class to receive FDA approval for the treatment of unresectable stage III or IV melanoma is ipilimumab.¹ Other antigen-independent immunomodulatory agents are currently in clinical development (eg, PD-1 inhibitors, PD-L1 inhibitors, and anti-CD137 antibodies). This review will focus primarily on the immune-related endocrine side effects of ipilimumab.

Ipilimumab is a fully human monoclonal antibody that inhibits the binding of cytotoxic T-lymphocyte antigen-4 (CTLA-4) to its natural ligands on T cells, thereby augmenting antitumor T-cell activation and proliferation.² Two phase 3 randomized trials demonstrated a long-term overall survival (OS) benefit for ipilimumab.^3,4 In the first study, 676 patients with previously treated metastatic melanoma were randomized to ipilimumab 3 mg/kg (administered IV every 3 weeks for 4 cycles) in combination with the experimental vaccine gp100, ipilimumab 3 mg/kg alone, or gp100 alone.³ Relative to gp100 alone, the risk of death was significantly reduced by ipilimumab plus gp100 (hazard ratio [HR] 0.68; P<.001) and by ipilimumab alone (HR 0.66; P=.003). In the second phase 3 trial, 502 patients with treatment-naive advanced melanoma were randomized to treatment with ipilimumab 10 mg/kg (administered every 3 weeks for 4 cycles) plus dacarbazine or dacarbazine alone.⁴ The impact of ipilimumab on OS was confirmed in this study, as the median OS was significantly longer with ipilimumab plus dacarbazine compared with dacarbazine alone (11.2 vs 9.1 months; HR=0.72; P=.001).

Unlike conventional cytotoxic chemotherapy and targeted biotherapies, which act directly on tumor cells or oncogenic pathways, immunotherapies such as ipilimumab act to stimulate the body’s natural immune defense. As such, the response pattern seen with ipilim­umab is different from that observed with conventional chemotherapy and targeted agents,⁵ where responses are durable for many months to years after therapy has stopped, and delayed responses are not uncommon. Furthermore, the adverse events (AEs) that have been reported with ipilimumab are consistent with an immune phenomenon as a consequence of CTLA-4 blockade. These events, known as immune-related AEs (irAEs), may involve any organ system and are usually not severe if diligent monitoring and proactive management is in place. However, severe and even fatal irAEs have been reported in ipilimumab recipients, including enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathies.¹

Endocrinopathies are less common than most other ipilimumab-related irAEs encountered in patients with metastatic melanoma.⁶ These events typically manifest during ipilimumab treatment, although some may develop even after discontinuation of therapy. They can be particularly severe if left untreated. It is important to recognize and address symptoms of endocrinopathies early to prevent the development of more serious events. This review discusses ipilimumab-associated endocrinopathies and provides practical recommendations for timely recognition and treatment of these events.

CTLA-4 Inhibition with Ipilimumab and Associated Endocrinopathies
During the adaptive immune response to tumor cells, T cells become activated when their receptors interact with tumor-associated antigens on specialized antigen-presenting cells (APCs) in a tightly regulated cascade of reactions requiring 2 signals.^2,7-9 The first signal involves the T-cell receptor interacting with peptide–major histocompatibility complex molecules on the membrane of APCs, upregulating T-cell expression of the inhibitory molecule, CTLA-4. The second costimulatory signal involves B7 molecules on the APC surface binding with CD28 receptors on the T-cell surface. CTLA-4 competitively inhibits the binding of B7 to CD28, preventing the costimulatory signal and attenuating T-cell activation and proliferation.

Pharmacologic inhibition of CTLA-4 with ipilimumab prevents physiologic regulation of T-cell activation and proliferation, which may, in turn, elicit conditions that mimic those seen in autoimmune conditions, including endocrinopathies. Studies have shown that the gene encoding CTLA-4 is an important susceptibility locus for autoimmune-related endocrinopathies,^10-13 and variant polymorphisms of the CTLA-4 gene have been linked to the presence of Graves’ ophthalmopathy.¹⁴ The exact mechanism of ipilimumab-associated endocrinopathies has not been elucidated. However, it is hypothesized to be due to endocrine organ infiltration by lymphocytes, which leads to endocrine dysfunction. There is a predilection for anterior pituitary dysfunction in patients who develop ipilimumab-associated hypophysitis; however, it is not clear why the anterior pituitary is vulnerable to CTLA-4 blockage. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) can also occur in the setting of ipilimumab-related hypophysitis.¹⁵ Isolated SIADH in patients receiving ipilimumab appears to be rare, but it may be underreported due to confounding etiologies such as progressive illness and concomitant medication use. It is also noteworthy that an association between hyponatremia and hypopituitarism with secondary adrenal insufficiency has been reported.¹⁶

Endocrinopathies Reported in the Clinical Trials with Ipilimumab in Advanced Melanoma
A series of phase 2 and 3 trials have established the antitumor effects of ipilimumab, as well as an appropriate dose, and characterized the safety profile in patients with advanced melanoma.^3,4,17-21 In most of these studies, irAEs were monitored for up to 70 days following the last dose of treatment, a period equivalent to 5 ipilimumab half-lives. Endocrinopathies were one of the less common irAEs seen with ipilimumab, occurring in less than 10% of patients in any clinical trial (summarized in Table 1). It should be noted that specific treatment guidelines for endocrine AEs were outlined in the study protocols for the phase 2 and 3 clinical trials. These guidelines included initiation of a short course of high-dose glucocorticoids to reverse inflammation, initiation of hormone replacement therapy, and modification of ipilimumab dosing, if necessary.

In a phase 2 dose-ranging study, patients with pretreated unresectable stage III or IV melanoma were randomized to induction treatment with ipilimumab 10 mg/kg, 3 mg/kg, or 0.3 mg/kg administered every 3 weeks for 4 cycles.¹⁷ Patients without progressive disease were able to continue treatment in a maintenance phase in which they received ipilimumab every 3 months. In this study, the frequency of irAEs (including endocrine AEs) was dose related. Grade 3 hypopituitarism in the 3-mg/kg group was noted among reasons for stopping treatment. Glucocorticoids and/or hormone replacement therapy was used to manage grade 3/4 endocrine events, which were all reported to have resolved or improved within 30 days of the last ipilimumab dose.

In a single-arm phase 2 study, patients with pretreated unresectable stage III or IV melanoma received induction treatment with ipilimumab 10 mg/kg, administered every 3 weeks for 4 cycles, followed by maintenance ipilimumab every 3 months if eligible.¹⁸ Endocrine AEs were reported in 5.8% of patients at this dose and were symptomatically managed with glucocorticoids. One of the 2 patients with a grade 3/4 endocrine event did not have resolution of symptoms within the study period; therefore, median time to resolution of endocrine irAEs could not be estimated.

In an effort to determine whether prophylactic oral budesonide would reduce the rate of grade ?2 diarrhea (another, more common irAE) in patients receiving ipilimumab, Weber and colleagues performed a randomized, double-blind, phase 2 study comparing budesonide with placebo in treatment-naive and previously treated patients with advanced melanoma receiving ipilimumab 3 mg/kg, administered every 3 weeks for 4 cycles, followed by maintenance treatment if eligible.¹⁹ In this study, systemic steroids (principally oral, but also IV) were required to treat irAEs in 57% of patients in the prophylactic budesonide group and 44% in the placebo group. Interestingly, budesonide had no discernible impact on the incidence of any irAEs, including endo­crinopathies, which occurred in 9% and 11% of patients in the budesonide and placebo arms, respectively. Of note, a low systemic bioavailability of budesonide due to an extensive first-pass liver metabolism may blunt its systemic effect.²²

Hersh and colleagues evaluated ipilimumab 3 mg/kg every 4 weeks for 4 cycles administered alone and in combination with dacarbazine in a phase 2, randomized, open-label study in chemotherapy-naive patients.²⁰ Only irAEs reported in ?5% of the study participants were tabulated in this report; therefore, the incidence of endocrine AEs was not presented. However, it was noted that 1 patient receiving combination therapy developed serious or ongoing grade 2 adrenal insufficiency.

Table 1

Table 2

Table 3

In the phase 3 registrational study comparing ipilimumab 3 mg/kg plus gp100, ipilimumab 3 mg/kg alone, and gp100 alone, endocrinopathies were categorized by subtypes, providing further insight into the types of endocrine dysfunction that might be expected with ip­ilimumab (Table 2).³ Only 2 patients in the gp100 group experienced an endocrine AE, both of which were hypothyroidism. Of the 511 patients receiving ipilimumab, 25 (4.9%) reported an endocrinopathy, including hypothyroidism (1.6%), hypopituitarism (1.2%), hypophysitis (0.8%), adrenal insufficiency (1.0%), increase in serum thyrotropin level (0.6%), and decrease in serum corticotropin level (0.4%). Grade 3/4 endocrinopathies occurred in 9 ipilimumab-treated patients (1.8%), 6 of whom required hospitalization.¹ All 9 patients had hypopituitarism, with some having additional endocrinopathies, including adrenal insufficiency, hypogonadism, and hypothyroidism. The median time to onset of moderate to severe endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of treatment.¹ With the use of high-dose systemic glucocorticoids for the management of grade 3 or 4 irAEs (including endocrine irAEs), the median time to resolution of grades 2 to 4 irAEs was 6.3 weeks in the ipilimumab plus gp100 group, 4.9 weeks in the ipilimumab alone group, and 3.1 weeks in the gp100 alone group. Of the 21 patients with a grade 2 to 4 endocri­n­opathy, 17 required long-term hormone replacement therapy, including adrenal hormones (n=10) and thyroid hormones (n=13).¹ While the absolute number of ipilimumab recipients experiencing an endocrine AE is relatively small, the effects of such an event can be long-lasting; 8 of the 94 persons in this study who survived for at least 2 years after treatment initiation had residual effects of endocrine AEs that required ongoing hormone replacement therapy.

Table 4

Interestingly, no endocrinopathies were reported in the phase 3 study comparing first-line ipilimumab 10 mg/kg plus dacarbazine with dacarbazine alone.4 A single case of hypophysitis was observed in a patient in the ipilimumab plus dacarbazine group, but since this event presented on day 364 after treatment initiation, which was outside the protocol-specified reporting window of <70 days after the last dose of study medication, it was not categorized as an “on-study” event. It has been suggested that the unprecedented low endocrinopathy rate seen with ipilimumab in this study, despite its use at the higher dosage of 10 mg/kg, may be a collateral effect of coadministration of systemic glucocorticoids to manage hepatic AEs (occurring in approximately one-third of ipilimumab recipients); however, this hypothesis remains untested.

Ibrahim and colleagues have conducted a retrospective safety analysis of data from 14 ipilimumab clinical trials evaluating dosages ranging from 0.1 to 20 mg/kg (N=1498).6 Endocrine AEs were reported in 4.5% of the whole clinical trial population, with 2.3% of patients reporting grade 3/4 events (Table 3). More specifically, hypopituitarism, hypothyroidism, and adrenal insufficiency were reported in 2.7%, 1.8%, and 0.7% of ipilimumab recipients, respectively. A separate analysis of a smaller set of these trials reported time to onset and resolution of irAEs (Table 4).²³ Endocrine events were not specifically analyzed; however, within 5 pivotal phase 2 and 3 trials, median time to irAE onset during induction was 5 to 9 weeks, depending on the dose of ipilimumab and the organ class affected; events managed according to treatment guidelines generally resolved within 4 to 8 weeks.

Several case reports on endocrine irAEs in patients with melanoma and other tumor types have been published (Table 5).^15,24-30 In general, these events were reversible and manageable with glucocorticoids. Interestingly, adrenal insufficiency or corticotropin deficiency may persist despite recovery of other pituitary endocrine functions.^24,25

Clinical Management of Endocrinopathies Associated with Ipilimumab
The authors’ suggested approach for evaluating and managing ipilimumab-related endocrinopathies is presented in Figure 1. The authors recommend referral to an endocrinologist for workup and treatment in collaboration with the treating medical oncologist when an ipilimumab-associated endocrinopathy is suspected or develops. Patients treated with ipilimumab should be advised to immediately report symptoms that suggest the possible onset of an endocrinopathy, including fatigue, headache (generally described by patients as pressure behind the eyes), altered mental status, abdominal pain, unusual bowel habits, or hypotension.¹ Other signs and symptoms of an endocrinopathy include lightheadedness, fevers, visual changes (including impaired eye movement, diplopia), palpitations, anxiety, decreased appetite, nausea, decreased libido (including impotence in men), polyuria, and cold/heat intolerance. Because these symptoms are nonspecific and can be attributed to other causes, such as underlying disease or brain metastases, they may go unattended or inappropriately recognized and managed, thereby allowing the development of a more serious illness.

Table 5

Thyroid function tests, morning cortisol, and clinical chemistries should be monitored at the start of treatment, before each dose, and as clinically indicated based on signs and symptoms, particularly in the first 3 months of treatment with ipilimumab.²⁶ Abnormalities in these tests may indicate development of an ipilimumab-associated endocrinopathy. Unless an alternative etiology is identified, signs and symptoms of endocrinopathies should be considered an irAE. In patients with clinical or biochemical thyrotoxicosis, a thyroid uptake test will help to distinguish between thyroiditis and Graves’ disease. If patients have symptoms suggestive of adrenal insufficiency, paired morning cortisol and adrenocorticotropic hormone (ACTH) should be measured. Certain medications, such as opiates and glucocorticoids, can interfere with the interpretation of these studies and therefore should be held off for at least 8 to 10 hours before cortisol and ACTH tests. High-dose glucocorticoids such as dexamethasone suppress the hypothalamic-pituitary-adrenal axis (Figure 2). If primary adrenal insufficiency is suspected, a cosyntropin stimulation test should be performed to confirm the diagnosis. If the patient is on glucocorticoids (except dexamethasone), measuring aldosterone at basal level and 30 minutes after cosyntropin stimulation will help to identify primary adrenal insufficiency. A greater than 5 µg/100 mL increase in aldosterone level usually rules out primary adrenal insufficiency.³¹ When the initial workup shows central hypothyroidism or secondary adrenal insufficiency, other anterior pituitary hormone levels should also be measured to determine the underlying etiology. In patients with hypophysitis, further tests may reveal low blood levels of luteinizing hormone, follicle-stimulating hormone, insulin-like growth factor 1, and prolactin. Effects of critical illness on the hypothalamic-pituitary axis should be taken into consideration before making the diagnosis of a hypophysitis-related endocrinopathy. Symptoms and signs suggestive of diabetes insipidus or diabetes mellitus, such as polydipsia and polyuria, should be addressed during each clinic visit. During ipilimumab therapy, blood glucose levels should be monitored periodically. Ipilimumab treatment should be withheld in patients with symptoms suggestive of an endocrine event until complete resolution or the patient is stable on hormone replacement therapy. There is no consensus on glucocorticoid dosing in patients with ipilimumab-related endocrinopathies. We recommend individualized management.

Figure 1

Figure 2

Usually, systemic glucocorticoids (prednisone 1-2 mg/kg/day or equivalent) should be initiated in patients with a symptomatic endocrinopathy, together with appropriate hormone replacement therapy.¹ We recommend that all patients receiving ipilimumab also receive glucocorticoid treatment if they have clinical symptoms or biochemical evidence of adrenal insufficiency, starting with a physiologic dose of hydrocortisone or prednisone unless symptoms persist.

Some studies have suggested that systemic glucocorticoids do not appear to counteract ipilimumab activity,^19,32 although this has been questioned in other studies.²¹ Until the impact of glucocorticoids on the antitumor effects of immunotherapy has been evaluated in robust randomized trials, we advise avoiding high-dose glucocorticoids, if possible. We have successfully managed many patients with ipilimumab-related hypophysitis by utilizing a physiologic dose of glucocorticoids (?5 mg prednisone or equivalent). However, if there are any signs of adrenal crisis (ie, severe dehydration, hypotension, and shock), IV glucosteroids with mineralocorticoid activity, such as hydrocortisone, should be initiated immediately. Once symptoms and/or abnormal lab values are controlled and the patient has clinically improved, a slow steroid taper (over at least 1 month) should be initiated based on clinical judgment. The abrupt discontinuation of glucocorticoids should be avoided due to possible prolonged adrenal suppression. Rarely, a patient may persistently have an enlarged pituitary on MRI and continue to be symptomatic (eg, headache, visual disturbances). A short course of high-dose glucocorticoids, such as dexamethasone 4 mg every 6 hours, should be considered to treat the presumed underlying pituitary inflammation. Lifelong glucocorticoid therapy and/or hormone replacement therapy may be necessary. Ipilimumab should be permanently discontinued in cases where the glucocorticoid dose cannot be reduced to 7.5 mg of prednisone or equivalent per day, and in cases where the patient cannot complete the full treatment course within 16 weeks from administration of the first dose of ipilimumab.

It is important to note that growth hormone should not be used as hormone replacement therapy, as this agent is contraindicated in patients with an active malignancy. Patients with Graves’ disease should receive antithyroid treatment, such as methimazole and/or radio­iodine ablation. Antithyroid treatment should not be administered to patients with thyroiditis; rather, symptomatic patients should be treated with a beta-blocker such as propranolol or atenolol, or with glucocorticoids in patients with cardiac diseases that increase the risks for arrhythmia.

In male patients with androgen deficiency, testosterone replacement may be indicated. Prostate-specific antigen (PSA) and hematocrit should be evaluated prior to starting treatment because testosterone replacement therapy is contraindicated in several patient groups, including those with prostate cancer, PSA >4 ng/mL (>3 ng/mL in high-risk groups such as African Americans and men with a first-degree relative with prostate cancer), an unevaluated prostate nodule or induration, severe lower urinary tract symptoms associated with benign prostatic hypertrophy, and hematocrit >50%. Other contraindications include breast cancer, uncontrolled or poorly controlled congestive heart failure, and untreated sleep apnea. Testosterone levels, PSA, and hematocrit should be evaluated 3 to 6 months after initiation of testosterone replacement therapy and then periodically according to guidelines.³³

Patients with adrenal insufficiency and their families should be aware of “sick day rules” and emergency management of an adrenal crisis, including how to self-inject hydrocortisone intramuscularly. Patients with adrenal insufficiency or hypophysitis should be encouraged to wear a MedicAlert bracelet or necklace. Depending on the severity, hyperglycemia can be managed by diet control or insulin basal plus a bolus regimen.

Conclusion
Ipilimumab has improved the prognosis of patients with metastatic melanoma such that OS can now be talked about in terms of years rather than months. The majority of AEs associated with ipilimumab are considered to be immune-related and can include endocrine events. While these events are relatively uncommon and have nonspecific symptoms, they can be life threatening if left untreated. Patient education about the signs and symptoms of endocrinopathies, together with vigilance and prompt intervention on the part of the clinician, should help to ensure that endocrinopathies are appropriately managed and resolve in a timely manner. Successful management of endocrinopathies will also enable the safe administration of subsequent ipilimumab doses.

Acknowledgments
The authors take full responsibility for the content of this publication and confirm that it reflects their viewpoint and medical expertise. The authors also wish to acknowledge StemScientific, funded by Bristol-Myers Squibb, for providing writing and editorial support. Neither Bristol-Myers Squibb nor StemScientific influenced the content of the manuscript, nor did the authors receive financial compensation for authoring the manuscript.

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Case Study: Management of Ipilimumab-Associated Endocrinopathy

We describe a case to illustrate how ipilimumab­-related endocrinopathies are diagnosed and managed. A 68-year-old male with stage IV melanoma started on ipilimumab 3 mg/kg IV every 3 weeks. He developed a new-onset headache – which he described as a frontal headache with pressure behind his eyes – after 3 doses of ipilimumab, 9 weeks following initiation of ipilimumab therapy. He reported fatigue and low libido that were gradually progressive along with the headache over 2 weeks. Biochemical testing done in the morning revealed undetectable corticotropin and low cortisol, suggestive of secondary adrenal insufficiency; inappropriate normal gonadotropins and undetectable testosterone, suggestive of hypogonadotropic hypogonadism; and low thyrotropin (TSH) and slightly low thyroxine concentrations, suggestive of central hypothyroidism or nonthyroidal illness syndrome. Prior to dose 1 of ipilimumab therapy, he had normal thyroid function tests. He was treated with physiologic doses of hydrocortisone and testosterone with resolution of his symptoms. An MRI of the brain revealed dynamic changes in his pituitary gland: normal size prior to ipilimumab, prominence of the pituitary gland 1 month after initiation of ipilimumab, and normal size 5 months after ipilimumab therapy (Figure). Prior to testosterone replacement, his blood levels of PSA and hematocrit were 0.58 ng/mL and 43.8%, respectively. Ipilimumab therapy, dose 4, was resumed 1 week after he was started on hormone replacement, as he was asymptomatic. He did not receive levothyroxine replacement but had periodic monitoring of his thyroid function; his blood levels of TSH and thyroxine normalized subsequently. The patient was able to safely complete the full course of induction with ipilimumab in 16 weeks, after which subsequent scans showed stable disease. Of note, his symptoms of headaches, malaise, and decreased libido preceded the decrease in hormone levels, so vigilant monitoring is vital in making the diagnosis and management. There are cases in which the pituitary enlargement is seen on MRI prior to the drop in hormone levels; these patients should be managed symptomatically with the institution of glucocorticoids based on the degree of their symptoms (eg, headaches, visual disturbances). High-dose IV glucocorticoids (eg, methylprednisolone) may be necessary, especially if they do not respond to physiologic oral steroid replacement.

Figure

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