June 2012, Vol 1, No 2

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Management of Ipilimumab-Related Toxicities

Patrick A. Ott, MD, PhD

Melanoma

Ipilimumab, a monoclonal antibody that blocks the negative costimulatory molecule CTLA-4 on T cells, leading to augmented T-cell activation and proliferation, improves overall survival (OS) in patients with metastatic melanoma and was approved by the regulatory agencies in the United States and several other countries for the treatment of unresectable melanoma. Consistent with its mechanism of action, the drug’s toxicities are mainly manifestations of organ-specific inflammation primarily affecting the skin, gastrointestinal tract, liver, and endocrine system.

Rarely do these effects lead to serious complications such as bowel perforation and adrenal insufficiency. As ipi – limumab is moved from clinical trials into broader use by general medical oncologists, it is critical that the clinician has comprehensive knowledge of the full spectrum of these immune-related adverse events (irAEs; also called adverse events of special interest), in order to develop an individualized approach to their management. Physicians should maintain a high level of awareness for signs of symptoms of these toxicities and be prepared to intervene early and effectively when appropriate.

CTLA-4 Is an Important Immune-Regulatory Molecule in T-Cell Activation

Active immunotherapy targeted at T cells relies on the presentation or cross-presentation of antigens by tumor or antigen-presenting cells and on the induction of T effector cells that are specific to these antigens, long-lived, and capable of killing tumor cells. T-cell activation requires 2 signals. The first signal constitutes the binding of the T-cell receptor (TCR) to a tumor peptide presented by the major histocompatibility complex (MHC). For full T-cell activation, this TCR-MHCpeptide interaction must be accompanied by a second signal, which is mediated by the binding of CD28 on T cells to the costimulatory molecules CD80 and CD86 (both members of the B7 protein family) on the surface of an antigen-presenting cell.1-3 T-cell stimulation results in the proliferation of T cells and initiates effector functions such as cytokine secretion and the release of granzyme B and perforin needed for cell killing. T-cell activation also leads to up-regulation of the CD28 homolog CTLA-4 (a member of the immunoglobulin superfamily), which has a much higher binding affinity than CD28 to B7, leading to T-cell inhibition.

This interplay of positive and negative immune regulation on the surfaces of T cells and antigen-presenting cells is a tightly controlled, temporally restricted, and dynamic process aimed at containing a potentially hazardous Tcell response.4 The significance of CTLA-4 as an inhibitory molecule is illustrated by the association with autoimmune disease, as evidenced by an increased risk of autoimmunity in patients with single nucleotide CTLA-4 polymorphisms and massive lymphoproliferation in mice lacking CTLA-4 function.5-7 Other inhibitory molecules, such as programmed death (PD) molecules, are expressed on the surface of T cells and contribute to this intrinsic control of T-cell activation; PD-1 is also a target in clinical development.

Targeting CTLA-4 With Ipilimumab Is Effective in Patients With Advanced Melanoma Blockade of CTLA-4 with the fully human monoclonal antibody (IgG1κ) ipilimumab impedes its binding to B7 and thereby enhances T-cell responses. The clinical efficacy of ipilimumab in patients with meta – static melanoma was initially demonstrated in a series of phase 2 studies in which the drug was given at 10 mg/kg every 3 weeks for 4 doses, followed by maintenance therapy with infusions every 3 months.8,9 In 1 study, 2 additional dose cohorts received ipilimumab at either 0.3 or 3 mg/kg, respectively.10 These efficacy data were confirmed in 2 phase 3 trials that revealed a survival benefit. The first study was a randomized, doubleblind trial in which 676 patients were enrolled on 3 arms at a 3:1:1 ratio: 1) ipilimumab at 3 mg/kg in combination with an HLA-A2–restricted gp100 peptide vaccine, 2) ipilimumab at 3 mg/kg and placebo, and 3) gp100 peptide vaccine combined with placebo.11

Patients with clinical benefit defined as stable disease of ≥3 months’ duration or an objective response (partial response or complete response) were eligible for additional reinduction doses of the same regimen they previously received. Ipilimumab with or without the gp100 peptide vaccine led to an improvement in OS, with a 32% to 34% risk reduction of death (hazard ratios [HRs] of 0.68 and 0.66, respectively) compared with gp100 and placebo. The median OS was 10.1 months for ipi – limumab and placebo and 10.0 months for ipilimumab and gp100, compared with 6.4 months for gp100 and placebo (P<.001 and P=.003, respectively).

The lack of an OS difference between the ipilimumab arms suggests that the OS benefit is driven by ipilimumab alone. There is a subset of patients who apparently have a prolonged and durable survival benefit of treatment. The encouraging 2-year survival rate of 23.5% in this pretreated population with a high proportion of poor-risk prognostic criteria such as elevated lactate dehydrogenase, M1c disease, and brain metastases is consistent with data from prior phase 2 studies. The results from this trial led to approval of ipilimumab by the FDA for patients with unresectable stage III or stage IV melanoma.

Similar findings were reported when ipil imumab was given in the first-line setting. In a randomized phase 3 trial, patients with previously untreated metastatic melanoma received ipilimumab 10 mg/kg every 3 weeks for 4 doses plus dacarbazine or dacarbazine alone.12 Patients with an objective response or stable disease and no dose-limiting adverse events received maintenance treatment with ipilimumab or placebo every 3 months. A significantly improved OS of 11.2 months with ipilimumab and dacarbazine over 9.1 months with dacarbazine alone was seen in this study. The HR for death with ipilimumab-dacarbazine treatment was 0.72 (P<.001).

The toxicity profiles in the 2 phase 3 clinical trials were different, with more gastrointestinal toxicity in the trial using ipilimumab versus gp100 versus the combination of both, and a higher rate of hepatic toxicity in the ipilimumab-dacarbazine versus dacarbazine trial.10 The reasons for this shift are not clear but may be related to better recognition and management of immunerelated diarrhea and colitis in the former trial and the use of dacarbazine, which may also result in hepatic toxicity, in the latter trial. These observations highlight the complexity of responses to ipilimumab and suggest that careful attention to each patient, their underlying medical comorbidities, and concurrent and previous treatment history is important for monitoring and managing complications from therapy.

Immune-Related Adverse Events CTLA-4 blockade can break peripheral T-cell tolerance to self-antigens, which is an expected effect that was recognized early in the development of monoclonal antibodies specific for CTLA-4 in preclinical and initial clinical studies. Mice with B16 melanoma treated with a combination of anti–CTLA-4 antibody and a granulocyte-macrophage colony-stimulating factor–producing tumor cell vaccine developed autoimmune skin depigmentation characterized by polymorphonuclear cells infiltrating the dermis.13

Early clinical phase 1 and 2 studies using ipilimumab consistently demonstrated autoimmune manifestations such as dermatitis, rash, vitiligo, enterocolitis, hepatitis, and hypophysitis.14-16 Rare autoimmune events such as Guillain-Barré–like syndrome, myasthenia gravis, lupus nephritis, sarcoidosis, and myositis/arthritis have also been reported after treatment with ipilimumab.17,18

Because of their distinct immunologic characteristics, these manifestations are referred to as irAEs. There is some correlation between ipilimumab dosing and the severity and frequency of irAEs. This observation was apparent in several of the earlier phase 1 and 2 trials and has been the clinical experience of many investigators involved early in the clinical development of the drug.10,19,20 Consistent with these observations, in the 2 phase 3 trials discussed above, total irAEs were more frequent in the study in which ipilimumab was used at 10 mg/kg in combination with dacarbazine compared with the trial in which it was given without chemotherapy at 3 mg/kg.

However, the difference in total frequency of irAEs was mainly driven by a hepatotoxicity rate of up to 30% of the patients treated with ipilimumab at 10 mg/kg plus dacarbazine (Table 1). In contrast, hepatotoxicity was not reported in another phase 3 trial in which ipilimumab was given at 3 mg/kg. Moreover, no endocrinopathies were reported with ipilimumab at 10 mg/kg in the phase 3 setting, which is somewhat unexpected based on the phase 2 experience, in which endocrinopathies consistently occurred across studies at a rate of 4% to 11% (Table 1).8-10 The rates of high-grade (3/4) rash, colitis, and diarrhea were similar in the 2 phase 3 trials despite their use of ipilimumab at different doses.11,12

 

Table 1. irAE Profile of Metastatic Melanoma Patients Treated With Ipilimumab in Phase 2 and 3 Trials

 

The majority of irAEs occur during the 12-week induction period with ipilimumab. Fewer than 10% of long-term survivors experienced a new irAE that manifested ≥10 weeks after ipilimumab, and all but 1 event were low grade.11 Skin and gastrointestinal events are the most common irAEs and most commonly appear earlier after treatment initiation than endocrine events or hepatotoxicity. Most irAEs are low grade, can be treated symptomatically, and do not lead to dose delays or reductions. Fifteen percent to 40% are high-grade events that require immediate treatment with high doses of corticosteroids. In rare instances, irAEs are refractory to corticosteroid treatment; other immunosuppressive agents, such as infliximab or mycophenolate mofetil, have been used successfully in this situation (Table 2).

There is some controversy as to whether there is a correlation between the irAEs and the clinical activity of ipilimumab. Early clinical studies seemed to support that notion,14,21-24 however, in a meta-analysis of 3 phase 2 trials it was shown that patients with advanced melanoma can achieve a clinical benefit with ipilimumab treatment in the absence of irAEs.25,26

Dermatitis

Rash and pruritus are the most frequent irAEs associated with ipilimumab, occurring in 40% to 50% of patients. The vast majority of events are low grade and are treated symptomatically, eg, with antihistamines, while the patient remains on therapy. However, skin manifestations that persist for 1 to 2 weeks should be treated with topical or moderate doses of systemic cortico – steroids (eg, prednisone once daily). Severe rash or pruritus needs to be evaluated by a dermatologist, and a biopsy should be performed if appropriate; ipilimumab treatment must be delayed. Toxic epidermal necrolysis resulting in death has been reported in a patient treated with ipilimumab.11

High-dose corticosteroids (eg, methylprednisolone 2 mg/kg once or twice per day) are required for persistent severe skin toxicity and should be tapered over a period of at least 4 to 6 weeks once the rash or pruritus has been controlled. For grade 3 skin events that have improved to grade ≤1, reinitiation of ipilimumab can be considered. For grade 4 toxicity, treatment must be discontinued indefinitely. In complicated cases, early consultation with a dermatologist should be considered.

Gastrointestinal Toxicity

Gastrointestinal irAEs occur most commonly in the lower gastrointestinal tract, with diarrhea being the hallmark symptom. Abdominal pain, nausea and vomiting, anal/rectal pain, hematochezia, and fever have also been reported. Upper gastrointestinal involvement manifests as esophagitis and/or duodenitis. Endoscopically, the colonic mucosa appears erythematous and ulcerated; lymphocytic and/or leukocytic infiltration on histologic examination confirms an etiology of immune-mediated enterocolitis in most cases.24 Ipilimumab-induced enterocolitis can lead to intestinal perforation and death, particularly when therapeutic intervention with highdose corticosteroids is delayed. In the phase 3 trials, allgrade diarrhea and colitis were seen in approximately 35% of patients; high grades of diarrhea and colitis were reported in 6% to 10% of patients treated with ipilimumab at 3 mg/kg and in 6% of patients treated with 10 mg/kg.

In 1 trial directly comparing different doses of ipilimumab, there was a suggestion of a dose effect (15.1% gastrointestinal irAEs with 10 mg/kg, 4.2% with 3 mg/kg, and none with 0.3 mg/kg).10 In the phase 2 experience, with most patients receiving 10 mg/kg, grade 3 and 4 gastrointestinal irAEs were seen in 8.4% to 23% of patients.8-10 Most cases of grade 1 and 2 diarrhea respond to symptomatic treatment with loperamide if initiated early, preferably on the first day of occurrence.

It is critical that all patients who will receive ipilimumab are educated about the importance of this potentially life-threatening adverse event, and that symptoms are communicated to the clinician promptly and reliably. Ipilimumab can be continued for grade 1 diarrhea; if grade 2 improves to grade ≤1, ipilimumab should also be continued. Other etiologies for diarrhea need to be ruled out and treated appropriately while continuing treatment. Endoscopy should be considered in all patients with grade 3 or 4 diarrhea in addition to stool studies (WBC, calprotectin); if colitis is likely or confirmed by endoscopy, high-dose IV corticosteroids followed by a 4- to 6-week steroid taper need to be administered.

Most high-grade gastrointestinal events respond to corticosteroid therapy. In the phase 3 setting, the median time to resolution of grade 2-4 diarrhea was approximately 2 weeks.11 If no improvement is seen after 5 to 7 days of moderate to severe diarrhea, the anti–TNF-α antibody infliximab at a dose of 5 mg/kg is indicated and can be repeated after 2 weeks if no response is seen. If the diarrhea is refractory to IV steroids and infliximab, a diverting ileostomy and/or partial or complete colectomy should be considered.

Ipilimumab therapy must be permanently discontinued in patients with high-grade gastrointestinal toxicity. There is some evidence that the implementation of treatment guidelines for the management of gastrointestinal irAEs has resulted in decreased incidence in the rates of bowel perforation and the need for colectomy.27 Prophylactic treatment with budesonide does not appear to reduce the colitis rate, as documented in a randomized phase 2 trial.9

Although much less common, pancreatitis has also been reported after treatment with ipilimumab. The management consists of supportive care, early initiation of systemic corticosteroids, and close observation. A search for other causes should be considered in patients who do not respond quickly to steroids.

Hepatotoxicity

Immune-mediated hepatitis usually manifests as asymptomatic elevation in liver function tests (LFTs). Histologically, acute hepatic inflammation with ballooning degeneration of hepatocytes and predominantly lymphocytic infiltration has been reported.14 In the phase 2 trials, liver toxicity (all grades) occurred in 7% to 14% of patients who were treated with ipilimumab at 10 mg/kg. In the phase 3 setting, hepatotoxicity was reported in 4.5% of patients treated with ipilimumab monotherapy or ipilimumab plus gp100,11 whereas almost one-third of patients experienced immune-mediated hepatitis in the phase 3 trial in which ipilimumab was given at 10 mg/kg in combination with dacarbazine.12

The markedly higher incidence of hepatotoxicity when ipilimumab is given concurrently with dacarbazine highlights the importance of careful examination of its toxicity profile when given concurrently with other agents. LFTs elevated to grade ≥2 (≥2.5 the upper limit of normal [ULN]) or ≥2x above grade 1/2 elevated baseline values in a patient on ipilimumab should prompt closer monitoring with LFTs (at least every 3 days). A viral or idiopathic autoimmune hepatitis should be ruled out by serologic testing for hepatitis antibodies/antigens and antibodies to nuclei and smooth muscle. Furthermore, imaging should be performed to rule out metastases, and a liver biopsy should be considered. Ipilimumab must be held until LFTs have returned to normal or baseline values.

If LFTs rise to ≥8x ULN or bilirubin to ≥5x ULN, ipilimumab should be held. Hospitalization should be considered for close monitoring of hepatic function, consideration of liver biopsy to confirm diagnosis, and high-dose corticosteroids be administered, starting at 2 mg/kg of methylprednisolone daily. In the hospital, liver function must be monitored daily until stabilization or decrease of LFT, and subsequently at least every 3 days for a minimum of 2 weeks post-LFT peak.

For immune hepatitis refractory to corticosteroids, other immunosuppressive agents such as mycophenolate mofetil, tacrolimus, or infliximab have shown efficacy in the appropriate setting in conjunction with supportive management such as prophylaxis for opportunistic infections.25 Early consultation with a gastroenterologist or hepatologist may also be useful.

Endocrinopathies

Nonspecific symptoms such as fatigue, myalgia, headaches, visual disturbances, decreased libido, weakness, asthenia, anorexia, and constipation should raise the suspicion for an endocrinopathy of the thyroid, pituitary gland, or adrenal gland in any patient treated with ipilimumab. Endocrinopathies were reported in 4% to 11% (all grades) and 1% to 5% (grades 3/4) of patients treated in phase 2 trials with ipilimumab given at 10 mg/kg. At 3 mg/kg dosing of ipilimumab alone or in combination with gp100 in the phase 3 setting, 4% to 7% of patients experienced hypothyroidism, hypopituitarism, hypophysitis, or rarely adrenal insufficiency. Somewhat surprisingly, no cases of hypophysitis were reported with ipilimumab plus dacarbazine in a phase 3 trial.12 Endocrine toxicity is generally diagnosed at a median of 10 weeks after treatment initiation, which is later than most dermatologic and gastrointestinal irAEs become apparent.

Autoimmune hypophysitis in many cases manifests as enlargement of the hypophysis with thickening of the hypophyseal stalk on an MRI scan,28 but it can also be nonapparent on imaging. Histologically, an infiltration with lymphocytes, plasma cells, and macrophages has been described. 29 Radiologic findings may predate the onset of clinical symptoms.30 Consistent with secondary adrenal insufficiency, serum cortisol levels are low with inappropriately low adrenocorticotropic hormone (ACTH) levels in addition to low thyroid-stimulating hormone (TSH), free thyroxine (T4), and testosterone. Autoimmune thyroiditis is another relatively common endocrinopathy that can manifest as hyperthyroidism as in Graves’ disease or in hypothyroidism as in the immunemediated destruction of thyroid tissue in Hashimoto’s thyroiditis.

Antithyroxin peroxidase antibody and thyroglobulin antibody, TSH, triiodothyronine (T3), and T4 serum levels as well as a thyroid exam, in addition to imaging and more specific testing as indicated (such as radioiodine-23 thyroid uptake), will delineate the condition and determine whether sub stitution with thyroxine is necessary. Symptoms of autoimmune hypophysitis and thyroiditis can be subtle in the beginning; the clinician therefore needs to maintain a high level of suspicion in patients on ipilimumab therapy presenting with nonspecific symptoms as described above and have a low threshold for checking endocrine labs.

If an endocrinopathy is suspected, one should first determine whether the patient is in adrenal crisis, in which case empiric administration of corticosteroids with mineralocorticoid activity and aggressive IV hydration must be started immediately pending biochemical confirmation. If the patient is not in adrenal crisis, serum should be tested for TSH, free T4, T3, ACTH, morning serum cortisol, luteinizing hormone, folliclestimulating hormone, testosterone, and prolactin (prior to initiation of corticosteroids, if required). Early involvement of an endocrinologist may be helpful. An MRI of the brain with pituitary cuts should be obtained, and the patient should be started on high-dose corticosteroids and hormone replacement guided by an endocrinologist.

The recommended treatment for ipilimumab-induced hypophysitis is a short course of high-dose corticosteroids with subsequent taper, although this may not reverse the pituitary dysfunction. Generally, endocrinopathies induced by ipilimumab tend to respond more slowly to steroid therapy compared with the much more commonly seen dermatologic and gastrointestinal adverse events. Most patients with autoimmune hypophysitis require indefinite glucocorticoid replacement therapy after completion of prolonged steroid tapering, and some patients require additional support with T4 and testosterone due to persistent secondary adrenal insufficiency. In selected cases, pulse steroid administration has been advocated to preserve pituitary function, although this has not been validated.

Neuropathy

Peripheral neuropathy and neuritis have been reported with ipilimumab. In any patient on ipilimumab therapy who presents with neuropathy, nonimmune-mediated etiologies such as infection, medications, or metabolic derangements should be ruled out. Neurologic testing (electromyogram, nerve conduction studies) in addition to a comprehensive neurologic exam in close collaboration with a neurologist will help define the syndrome, grade the severity, and establish an objective baseline from which to judge further evolution of the neuropathy.

Ipilimumab should be discontinued for grade 3/4 drug-related sensory neuropathy and any grade 3/4 motor neuropathy. Ipilimumab dosing should be held for grade 2 drug-related neuropathy. For any grade 3 or 4 neuropathy considered to be caused by ipilimumab or progressing, hospitalization and IV corticosteroids need to be considered. IV immunoglobulins are an alternative if the neuropathy is refractory to steroids.

Although much less common, Guillain-Barré syndrome (GBS) and myasthenia gravis have been reported in patients treated with ipilimumab. One case was recently reported of a patient who developed a rapidly progressing generalized sensory and motor polyneuropathy after the third dose of ipilimumab, with cerebrospinal fluid (CSF) findings consistent with GBS (elevated protein, IgG, oligoclonal bands, normal glucose in the CSF).31 Importantly, high-dose corticosteroids immediately halted further worsening of the symptoms and led to complete recovery within 4 weeks. Of note, steroids are considered ineffective in classic GBS. Cases of GBS with fatal outcomes were also reported during the clinical development program of ipilimumab.

Uveitis

Uveitis is a relatively rare irAE and presents, depending on the affected portion of the uveal tract, as ocular pain, redness, photophobia, and decreased visual acuity. Patients on ipilimumab therapy should be made aware of this possible irAE, and a referral to an ophthalmologist should be made early if symptoms occur. Direct visualization by slit lamp examination reveals inflammation and/or the presence of leukocytes. Initial treatment consists of topical corticosteroids for anterior uveitis and steroid injections for posterior uveitis, while systemic corticosteroids are reserved for the treatment of resistant cases.

Concluding Remarks

Blockade of the T-cell inhibitory molecule CTLA-4 with the monoclonal antibody ipilimumab leads to an OS benefit in patients with advanced melanoma, with a subset of patients enjoying durable benefit. The drug has been approved by many regulatory agencies, including those of the United States, Canada, Europe, and Australia, and is therefore widely available to clinicians treating advanced melanoma. During the extensive clinical development program, a clear picture of the unique immune-related toxicity profile of this drug emerged. A key lesson from this experience has been that the overwhelming majority of irAEs can be well managed if they are recognized and treated early. Diarrhea and rash, the most common side effects in patients treated with ipilimumab, are easily recognized and should be managed as autoimmune enteritis/dermatitis irAEs while ruling out other etiologies. Other side effects that are less common include hepatotoxicity and peripheral neuropathy.

A host of nonspecific signs and symptoms that can be associated with endocrine toxicity are missed more easily and therefore require a structured patient assessment approach. Heightened suspicion and comprehensive knowledge of the ipi – limumab toxicity profile, including rare events such as uveitis and pancreatitis, should enable clinicians to largely avoid complications from unrecognized and therefore untreated autoimmune conditions. In order to minimize risk and facilitate the transition to the broader community of general medical oncologists, a risk evaluation and mitigation strategy has been developed by the drug manufacturer, Bristol-Myers Squibb, in collaboration with the FDA and can be accessed at www.yervoy.com/hcp/rems.aspx.

Ipilimumab is an exciting novel treatment option for patients with advanced melanoma, representing a new class of oncology drugs, that can be given safely by oncologists who are familiar with the full spectrum of irAEs and diligent in the monitoring and appropriate treatment of these toxicities.

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Conference Correspondent - June 19, 2012

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