Identification and Management of Toxicities From Immune Checkpoint–Blocking Drugs

Incidence of Immune-Related Adverse Events Associated With Ipilimumab and Pembrolizumab

Figure 1: Time After Initiation of Therapy to Onset of Various Immune-Mediated Adverse Events in 411 Patients With Advanced Melanoma Who Received Pembrolizumab

Figure 2: Ipilimumab-Related Autoimmune Dermatitis Manifesting as a Maculopapular Rash on the Arm of a Patient With Metastatic Melanoma.

Figure 3: Different Radiographic Patterns of Checkpoint Blockade–Associated Pneumonitis Seen on CT Scanning in a Single Patient Treated With Ipilimumab and Nivolumab

Immune checkpoint–blocking drugs such as ipilimumab, pembrolizumab, and nivolumab have demonstrated clinical efficacy as anticancer agents. Through modulation of immunoregulatory molecules, these novel therapeutics can produce durable cancer remissions in a variety of tumor types. As these medications are administered to an increasing number of patients, clinicians must be able to recognize and treat the associated immune-related side effects. This review summarizes the unique mechanisms of toxicity associated with immune checkpoint–blocking drugs, appropriate steps in patient evaluation, and strategies for mitigating risk and optimizing patient outcomes. Although the management of each patient receiving immune checkpoint–blockade therapy must be individualized, a conceptual framework upon which to base a multidisciplinary approach to best practices will help oncology practitioners deliver safe and effective care.

Background

Recent advances in the clinical application of agents that block immunoregulatory molecules have led to unprecedented optimism about the potential of these novel therapies for bringing about durable antitumor responses in patients with various advanced malignancies.[1] However, enhancing immune responses to cancer via modulation of these immune checkpoints is associated with drug-related toxicities that are distinct from those associated with traditional chemotherapeutic agents and molecularly targeted therapies.[2] Because the use of checkpoint blockade agents will likely be widely expanded in the near term, it is critical that healthcare practitioners caring for oncology patients have a basic familiarity with these immune-related adverse events (irAEs), their variable presentations, and recommendations regarding their evaluation and management.

To understand the mechanism of checkpoint blocker–related autoimmune toxicities, it is helpful to consider their mechanism of action. At a basic level, the role of the human immune system, and of T lymphocytes in particular, is to activate against non-self–antigens (eg, viral proteins or cancer neoantigens resulting from tumoral genetic and epigenetic alterations) and to tolerate self-antigens. Antigen recognition by a T-cell receptor is followed by interactions between a tightly regulated cadre of immunoregulatory molecules that either activate or inhibit T-cell activation.[3] Some of the best studied of these checkpoints are cytotoxic T-lymphocyte antigen 4 (CTLA-4) and the pathway composed of programmed death 1 (PD-1) and one of its major ligands, programmed death ligand 1 (PD-L1).

When they are engaged with their respective binding partners, CTLA-4 and PD-1 promote immune tolerance via downregulation of T-cell activation.[4,5] The application of antibody antagonists of these immune checkpoints promotes T-cell activation, which can lead to tumor destruction as well as clinically relevant decreases in self-tolerance. This immune dysregulation is among the mechanisms underlying the autoimmune toxicities related to immune checkpoint blockers.

Incidence of Immune Checkpoint–Blockade Toxicities

The adverse event (AE) profiles of checkpoint-blocking drugs (ie, incidence of toxicities and organ systems most frequently affected) vary depending on agent and target. In clinical studies, toxicity severity is described using the Common Terminology Criteria for Adverse Events (CTCAE), which grades toxicities on a scale of 1 (mildest) to 5 (death related to that toxicity).[6]

CTLA-4 antibodies

The CTLA-4 antibody ipilimumab is the most widely studied checkpoint-blocking agent. In 2011, after extensive clinical testing, it was approved by the US Food and Drug Administration (FDA) for use in patients with advanced melanoma. One seminal study that led to its approval was a phase III trial involving patients with advanced melanoma.[7] Ipilimumab was administered at 3 mg/kg with or without a peptide vaccine to 511 patients. Grade 3 or 4 immune-related toxicities were observed in approximately 15% of patients, and 7 patient deaths were associated with irAEs. A retrospective review of safety data from 1,498 patients treated with ipilimumab on any of 14 phase I–III clinical trials found that drug-related AEs of any grade occurred in 85% of patients.[8] About 25% of patients experienced a grade 3 or 4 drug-related toxicity, and drug-related death was observed in < 1% of patients.

Clinical trials using ipilimumab in tumor types other than melanoma have demonstrated similar AE rates. For example, in a phase III study of ipilimumab administered after patients were treated with radiotherapy for metastatic prostate cancer, 63% of patients had immune-related toxicity of any grade.[9] Similarly, in a phase II study of ipilimumab plus chemotherapy for metastatic non–small-cell lung cancer, the rate of grade 3/4 irAEs was 15% to 20%, depending on the sequence of drug administration.[10]

In a phase II trial of 245 patients with advanced melanoma, study participants were randomly assigned to ipilimumab plus granulocyte macrophage colony-stimulating factor (GM-CSF) or ipilimumab alone.[11] Of note, ipilimumab was administered at 10 mg/kg, which is higher than the FDA-approved dose of 3 mg/kg. Patients who received combination therapy experienced a significantly lower rate of high-grade AEs (45% vs 58%; two-tailed P = .038). The lower rate of high-grade AEs was accompanied by significantly improved overall survival (OS) in the GM-CSF arm (median, 17.5 vs 12.7 months; hazard ratio, 0.64; P = .014), although further study is required to determine whether the increased OS is linked to improvements in AE rates.

Another CTLA-4 antibody, tremelimumab (CP-675,206; formerly ticilimumab) has been similarly studied in patients with metastatic melanoma and other advanced cancers. In a phase II clinical trial testing tremelimumab in patients with advanced melanoma, 19% of participants had a ≥ grade 3 adverse event.[12] When tested in patients with metastatic colorectal adenocarcinoma, a similar rate of high-grade toxicities was seen, with diarrhea/colitis representing the majority of cases.[13]

PD-1 and PD-L1 antibodies

Although clinical data are still emerging, anti–PD-1 and anti–PD-L1 agents appear to have toxicity profiles that are different from those of CTLA-4 antibodies (Table 1).

Pembrolizumab is a humanized monoclonal antibody (mAb) blocking PD-1 that was approved by the FDA in September 2014 for use in treatment-refractory unresectable or metastatic melanoma. In a phase I clinical trial involving 135 patients with advanced melanoma, grade 3/4 AEs were reported in 13% of subjects.[14] An expansion cohort comprising patients whose disease was refractory to ipilimumab (and, if BRAF-mutant, refractory to BRAF inhibition) was reported separately.[15] In 173 patients, at a median follow-up of 8 months, toxicity rates were similar to those in previous reports.

Nivolumab is a genetically engineered, fully human immunoglobulin (Ig) G-4 mAb specific for human PD-1. In a phase I dose-escalation study conducted in 296 patients with multiple tumor types, grade 3/4 treatment-related toxicities occurred in 41 patients (14%). Treatment-related pneumonitis was observed in 9 patients (3%), 3 cases of which were fatal.[16] Longer-term follow-up of the entire study cohort (306 patients) demonstrated that exposure-adjusted toxicity rates were not cumulative.[17]

BMS-936559 (MDX-1105), a PD-L1–blocking antibody, was tested in a 207-patient phase I trial.[18] A 9% rate of grade 3/4 drug-related irAEs was reported. Similar findings were reported in 140 patients who received MPDL3280A, a human monoclonal IgG1 antibody engineered to block PD-L1 binding.[19] Drug-related grade 3/4 AEs were observed in 14% of patients.

Combination therapy

Preclinical evidence suggests that blockade of multiple immune checkpoints can achieve synergistic antitumor activity.[20] Several clinical trials of combinatorial regimens are underway. In a trial of ipilimumab plus nivolumab in patients with metastatic melanoma, a 53% rate of treatment-related AEs of grade 3 or 4 was reported when the drugs were administered concurrently.[21] When ipilimumab was followed sequentially by nivolumab, the rate dropped to 18%, which is closer to observed rates for the single agents.

Identification of Patients at Risk

While theoretically any immune checkpoint–blockade toxicity can occur at any time, certain toxicities have been seen more frequently earlier in the treatment course, while others generally manifest as later complications. Commonly encountered irAEs include rash/dermatitis, diarrhea/colitis, hepatitis, and endocrinopathies. However, because essentially any tissue in the body can be affected, clinicians must consider patient signs and symptoms to be autoimmune in origin until proven otherwise. The timing of adverse events from ipilimumab has been well described[22]; recently released data about the onset of irAEs in 411 patients who received pembrolizumab are illustrated in Figure 1. Familiarity with these patterns is helpful in successfully anticipating and treating these toxicities.

In the case of ipilimumab, the most common early toxicity is dermatologic toxicity.[22] The window for the highest risk for rash and other skin toxicity starts approximately 3 weeks into treatment, although late and long-lasting dermatologic toxicities have been observed. Enterocolitis most frequently occurs between weeks 5 and 10 of treatment, although gastrointestinal symptoms occurring at any time after initiation of ipilimumab could represent immune-related drug toxicity. Hepatitis is often seen slightly later than colitis, with the period of highest risk occurring between weeks 6 and 14 of treatment. Endocrinopathies generally are more unpredictable, with the risk period starting around 7 weeks after initiation of therapy. Even with optimal management, the effects of autoimmune endocrinopathies can be long-lasting, and late manifestations of hypophysitis can occur.

Patients with a history of autoimmunity are potentially at greater risk for irAEs. In clinical trials of checkpoint-blocking drugs, patients with autoimmunity were typically excluded, and a history of autoimmunity is considered a relative contraindication for immune checkpoint–blockade therapy. Although post–FDA-approval experience with ipilimumab has identified instances of successful treatment in patients with autoimmunity and other high-risk comorbidities (eg, history of organ transplant[23]), close monitoring is warranted in this patient population.

One active area of investigation is the pretreatment identification of patients who are more likely to experience irAEs. Two studies have suggested a correlation between specific genetic changes detectable in the blood and the development of colitis, the most common serious side effect observed with the anti–CTLA-4 agents.[24,25] Of note, a strategy of prophylaxis with budesonide to prevent colitis in patients being treated with ipilimumab was ineffective.[26] In that study, 115 patients were randomly assigned to budesonide at 9 mg daily or placebo at the initiation of therapy. Rates of grade 2 and higher diarrhea/colitis were similar between groups.

Identification and Characterization of Toxicities

The identification of irAEs requires effective patient-provider communication, familiarity with the potential manifestations of irAEs, and a high index of suspicion that patient complaints may reflect drug toxicity. Perhaps because irAEs have been reported to be associated with antitumor effects of therapy,[27] patients often minimize their symptoms in the hope of remaining on therapy. It is important for providers to impress upon patients that toxicities can lead to significant morbidity or even death unless they are promptly recognized and treated.

Dermatitis

Grade 1 and 2 dermatologic toxicities from checkpoint-blocking drugs are among the most commonly seen irAEs. Typically, mild dermatitis manifests as a maculopapular rash or erythroderma (Figure 2). Pruritus can accompany the rash or, less commonly, can present as an isolated complaint in the absence of skin findings. Rarely, these processes can be severe, manifesting as ulceration, bullous dermatitis, or Stevens-Johnson syndrome. Pathologic evaluations of biopsy specimens of affected skin often demonstrate eosinophilic infiltration or leukocytoclastic vasculitis; or, they may reveal a lymphocytic predominance characterized by CD8+ T cells, sometimes with tropism for melanin-containing cells. Specifically for patients with metastatic melanoma, the rash associated with immune-checkpoint inhibitors may be indicative of immune response to melanocytes and may progress to vitiligo in some cases.[28,29]

Colitis

Autoimmune enterocolitis is common in patients receiving ipilimumab and generally manifests as watery diarrhea, abdominal pain, nausea/vomiting, or hematochezia. About 30% of 511 patients who received ipilimumab in a large phase III trial experienced diarrhea of any grade.[7] In severe cases, patients may experience significant dehydration, fever, peritoneal signs, bowel perforation, or ileus. Stool cultures are negative. Endoscopy performed in these cases may identify an inflamed mucosa with ulceration, which can involve any part of the bowel but most commonly the descending colon.[30] Biopsy specimens of the colon typically reveal an inflammatory cell infiltrate (neutrophilic, lymphocytic, or mixed) with cryptitis.[31] Even in the setting of a relatively mild colitis seen grossly during endoscopy, tissue biopsies can demonstrate significant inflammation. Deaths secondary to bowel perforation have occurred.[7]

Hypophysitis

Endocrinopathies are perhaps the most elusive irAEs, due to their nonspecific presentations. A patient may have vague symptoms yet be at risk for serious morbidity or death if the endocrinopathy is not promptly identified and treated. For example, hypophysitis, which can cause pituitary inflammation with meningeal irritation, often presents as headache refractory to nonsteroidal anti-inflammatory drugs or other analgesics. Compression of the optic nerve from an inflamed pituitary may also lead to visual complaints. However, hypophysitis may manifest more nonspecifically, with symptoms secondary to hypopituitarism, such as hypotension, electrolyte disturbances, abdominal pain, weakness, behavioral changes, loss of libido, or fatigue.

Magnetic resonance imaging (MRI) of the brain typically demonstrates enlargement of the pituitary with variable contrast enhancement characteristics.[32] Patients will generally have abnormal endocrinologic laboratory test results; assessment of basic chemistries, adrenocorticotropic hormone, cortisol, thyroid-stimulating hormone (TSH), free thyroxine (T₄), prolactin, follicle-stimulating hormone, luteinizing hormone, and testosterone/estradiol is indicated.[33] Biopsy should only be considered in rare cases in which metastatic disease of the pituitary must be ruled out.

In the appropriate clinical setting, other endocrine irAEs that should be considered include thyroiditis (ie, hyper- or hypothyroidism), adrenal insufficiency, and hypogonadism. Because patients who experience irAEs often require prolonged courses of corticosteroids, resultant temporary secondary adrenal insufficiency is not uncommon.

Hepatitis

Hepatic toxicity often manifests as asymptomatic elevated levels of hepatic transaminases. Rarely, patients may complain of nonspecific symptoms, including fever, fatigue, nausea, and abdominal pain. In these cases, one must distinguish between checkpoint drug–related toxicity and other etiologies of hepatic injury, such as neoplastic disease progression in the liver, infections, and effects of other medications or alcohol intake. Titers for antibodies associated with autoimmune hepatitis, including antinuclear antibodies, anti–smooth-muscle antibodies, and anti-mitochondrial antibodies, are nonspecific and of questionable utility. Serologic testing should be performed for viral hepatitis (including hepatitis A and B), cytomegalovirus, and Epstein-Barr virus. Ultrasonograms of the liver can appear normal or may demonstrate homogenous hepatomegaly, edema, or enlarged perihepatic lymph nodes. Biopsy of the liver most commonly shows a diffuse T-cell infiltrate. Other reported pathology patterns include inflammation focused around either hepatocytes or bile ducts.[34]

Pneumonitis

Presentations of pneumonitis range from asymptomatic lung infiltrates to a mimic of severe bacterial pneumonia. For symptomatic patients, complaints and findings may include dyspnea, cough, pleuritic chest pain, and hypoxia. Workup for these patients includes chest imaging, yet there are no characteristic radiographic findings that will rule in or rule out pneumonitis. For example, a patient who experienced pneumonitis, first related to ipilimumab and later from nivolumab therapy, was found to have interstitial, lobar, and nodular infiltrates at different time points (Figure 3). Suspicion for pneumonitis must remain high regardless of radiographic findings, as pneumonitis can have highly variable appearances on chest CT scans. Tissue and lavage samples obtained by bronchoscopy can be helpful in ruling out infectious pathogens. Cryptogenic organizing pneumonia may be identified by pathologic evaluation of lung tissue.

In patients with pulmonary metastases or cardiopulmonary comorbidities, evaluation can be particularly challenging. Tumor progression (eg, lymphangitic spread), pseudoprogression (ie, inflammation of an existing metastasis), exacerbations of chronic obstructive pulmonary disease, congestive heart failure, diffuse alveolar hemorrhage, and pulmonary embolism are often possible diagnoses. Because pneumonitis can quickly escalate and become fatal, early recognition and careful management are essential.[16]

Neuromuscular toxicity

Neuromuscular toxicity is relatively uncommon but may manifest as a mild peripheral sensory neuropathy or muscle weakness. Symptoms are typically detected through a symptom-directed interview, with physical examination findings ranging from sensory changes to loss of deep-tendon reflexes. Although they are rare, severe neuropathies and myopathies have been observed.[35] Emergent cases of neuropathy can present with Guillain-Barré syndrome, transverse myelitis, or myasthenia gravis, among other diagnoses.[7,36-38] Depending on presentation, patients may require neuroimaging, nerve conduction studies, and, potentially, nerve or muscle biopsy to arrive at the diagnosis. Of note, one case of Guillain-Barré syndrome reported in the registrational phase III trial for ipilimumab was fatal.[7]

Management of Immune Checkpoint–Blockade Toxicities

Patients treated with immune-checkpoint inhibitors should be seen clinically prior to each cycle of therapy (eg, every 3 weeks for ipilimumab and pembrolizumab). The clinical visit should include a comprehensive review of systems with specific focus on common and serious toxicities, such as skin changes, diarrhea and abdominal pain, headache, fever, shortness of breath, cough, and neurologic changes. Routine laboratory testing, including hematologic profile, comprehensive metabolic panel, and TSH level, should be obtained. Any new symptoms or abnormalities in examination or laboratory test results should be evaluated prior to administration of the next dose of drug.

The diagnosis of immune checkpoint–blockade toxicity is one of exclusion. Specifically, progression of underlying malignancy, infection, and other possible causes of a particular abnormality must be ruled out prior to identifying a given toxicity as an irAE. This workup may include symptom-focused diagnostic radiologic studies and additional laboratory tests and cultures. Clinicians should feel comfortable withholding checkpoint-blockade therapy until the workup is complete.

Understanding the severity of a toxicity is key to determining the proper approach to its management. Toxicities should be graded using the CTCAE.[6] Clinicians should consult published guidelines (eg, http://www.yervoy.com/hcp/rems.aspx) for management strategies, keeping in mind that each toxicity is different and that approaches will need to be individualized. For example, grade 1 pneumonitis is a potentially life-threatening problem, while grade 1 dermatitis generally does not require dose interruption. Guidance with regard to temporary or permanent drug discontinuation can be found in the full prescribing information for pembrolizumab and ipilimumab.[39,40] In the case of pembrolizumab, withholding the drug is recommended for grade 2 pneumonitis, colitis, nephritis, or hepatitis; any grade 3 adverse reaction; and any symptomatic hypophysitis. Pembrolizumab can be restarted with improvement of these toxicities to grade ≤ 1. Permanent discontinuation is recommended for life-threatening adverse events, including grade 3 pneumonitis, nephritis, or hepatitis; any recurrent grade 3 adverse event; or inability to reduce prednisone dosage to 10 mg daily after 12 weeks. While the inability to wean a patient from corticosteroids may be a cause for permanent drug discontinuation, many practitioners would institute a course of infliximab in the case of an ongoing high-dose prednisone requirement. Thus, the need for infliximab or alternative immunosuppression would generally be an indication for permanent checkpoint inhibitor discontinuation as well.

Assessing severity

Grade 1 toxicities are mild, asymptomatic, or minimally symptomatic. Generally, patients with this level of toxicity are able to continue therapy with supportive care and increased monitoring. Examples of grade 1 toxicity include a mild rash or alteration in thyroid function test results. Follow-up should be tailored to the specific abnormality (eg, more frequent for pulmonary issues, less so for dermatologic issues).

Grade 2 toxicities generally require at least temporary discontinuation of checkpoint therapy. Patients should be monitored closely, and therapy can often be restarted if the toxicity improves to grade 1. However, for patients who have persistent grade 2 symptoms for at least one week, initiation of low-dose corticosteroid therapy is indicated. In general, these patients can be managed as outpatients with oral prednisone of 0.5 to 1.0 mg/kg/day or the equivalent. Patients must be monitored carefully, with strict instructions for reporting any worsening of symptoms. For grade 2 hepatic, renal, or hematologic abnormalities, laboratory monitoring every few days is recommended. As patients improve, the corticosteroid can be tapered over at least 1 month. For prolonged steroid tapers, prophylaxis against Pneumocystis jirovecii pneumonia (PCP; formerly Pneumocystis carinii pneumonia) should be considered.

Grade 3/4 toxicities have the potential for significant morbidity and mortality. Not infrequently, patients require hospitalization for evaluation and frequent monitoring. Permanent discontinuation of the checkpoint-blockade agent should be considered. Prompt diagnostic studies, including symptom-focused imaging (eg, pituitary MRI or chest CT), cultures and/or biopsy (eg, bronchoscopy with bronchoalveolar lavage and transbronchial biopsy or flexible sigmoidoscopy with colon biopsy) should be performed in consultation with an interventional pulmonologist or gastroenterologist. When a high-grade immunologic toxicity is suspected, corticosteroid therapy should be initiated. A dosage of 1 to 2 mg/kg/day of methylprednisolone or the equivalent is generally required; however, in the case of pneumonitis, some investigators have used a higher dosage of 2 to 4 mg/kg/day. Prophylaxis against PCP should be considered. In anticipation of possible need for anti–tumor necrosis factor (TNF) agents, patients should have viral hepatitis serologies and a tuberculosis test performed. Corticosteroids should be continued at high dose until improvement of the toxicity to grade 1, at which point a prolonged taper can be initiated. In general, patients should not be rechallenged with the same immune checkpoint–blockade agent.

Special considerations for specific toxicities

This review is meant to highlight the principles underlying the evaluation and management of irAEs associated with checkpoint-blockade agents. Although an exhaustive list of possible toxicities is beyond the scope of this article, clinicians should be aware of some of the less common irAEs, which may be hematologic (eg, hemolytic anemia, thrombocytopenia), cardiovascular (eg, myocarditis, pericarditis, vasculitis), ocular (eg, blepharitis, conjunctivitis, iritis, scleritis, uveitis), renal (eg, nephritis), or pancreatic (both endocrine and exocrine pancreatitis). Management considerations regarding several of the more common or potentially serious toxicities are described in detail below.

Enterocolitis. Autoimmune enterocolitis deserves special attention, due to its relatively high frequency in patients receiving CTLA-4 blockade and the multiple facets of its management. Patient symptoms should first be graded by combining CTCAE criteria with the overall clinical picture.

Patients with mild symptoms (eg, grade 1 abdominal pain or diarrhea) should be evaluated for infection, including Clostridium difficile infection. Antidiarrheals (eg, loperamide) and supportive measures, such as increasing oral fluid intake, should be considered.

Moderate symptoms often necessitate discontinuation of therapy, an infectious workup as above, and, if symptoms do not improve within a week, initiation of low-dose oral corticosteroids (0.5 mg/kg/day of prednisone or the equivalent). If symptoms improve and the patient is requiring the equivalent of < 7.5 mg/day of prednisone, clinicians might consider cautiously restarting checkpoint-blockade therapy. Collaboration with a gastroenterologist who is familiar with the evaluation and workup of autoimmune colitis is recommended. Visual inspection of the colon, as well as pathologic evaluation of colonic biopsies, is often useful in evaluating patients with persistent or recurrent symptoms.

Patients with severe symptoms (eg, grade 3/4 diarrhea, significant hematochezia, or peritoneal signs) require discontinuation of checkpoint therapy and should be hospitalized and closely monitored. An immediate workup for infection is appropriate, and, if perforation is suspected, surgical consultation should be obtained for operative management prior to administration of high-dose systemic corticosteroids (1 to 2 mg/kg/day of intravenous methylprednisolone or equivalent). Abdominal CT scans may be instructive. In one study of patients diagnosed with ipilimumab-associated colitis, characteristic findings included mesenteric vessel engorgement, bowel wall thickening, and fluid-filled colonic distension.[41]

Patients should continue on corticosteroids until symptoms improve, at which time a steroid taper lasting ≥ 1 month should be initiated. While patients may be concerned about corticosteroids interfering with the efficacy of treatment, one small study suggests that steroids do not affect the duration of clinical response to ipilimumab.[42] Given the risk of narcotic bowel, opiates should be used with caution in patients with abdominal pain. Administration of infliximab (5 mg/kg) should be considered for patients who do not improve within 3 to 5 days of initiation of corticosteroid therapy.[31,43] Infliximab should be used with caution in patients with sepsis from enterocolitis. The use of infliximab for steroid-refractory enterocolitis can be generalized to most other severe autoimmune toxicities, with the possible exception of hepatitis.

Hepatitis. When patients receiving checkpoint inhibition present with liver dysfunction, a high suspicion for drug-related autoimmune hepatitis is warranted. Clinicians should rule out other causes of hepatic injury, such as viruses, metabolic or cardiovascular derangements, other medications, or tumor progression.

Grade 1 elevations in liver function laboratory values require close monitoring. For grade 2 hepatotoxicity, the immune checkpoint–blockade agent should be withheld, and corticosteroids should be promptly initiated and tapered over at least 1 month. In consultation with a hepatologist, clinicians may consider liver biopsy. Grade 3/4 hepatitis requires discontinuation of drug and initiation of high-dose corticosteroids (1 to 2 mg/kg/day of prednisone). Hospitalization should be considered, as cases of death from liver failure have been reported in patients with this level of hepatotoxicity.[38] If a high-grade liver toxicity does not improve within 48 to 72 hours of initiation of high-dose corticosteroids, consideration of alternative immunosuppression agents is warranted. The alternative immunosuppression agent of choice is mycophenolate mofetil instead of infliximab, as infliximab can be independently associated with liver function abnormalities.[44] One case report describes the use of antithymocyte globulin in a patient with severe ipilimumab-related hepatitis that was found to be refractory to mycophenolate mofetil.[45] Tacrolimus 0.10 to 0.15 mg/kg/day has also been recommended by some investigators for mycophenolate-refractory hepatitis.[46]

Pneumonitis. In a 306-patient trial of nivolumab, 3 patients died as a result of drug-related pneumonitis.[16] Although it is relatively uncommon, pneumonitis has significant potential for morbidity and mortality, and this condition should be approached with great caution. Optimal evaluation and management of patients with suspected autoimmune pneumonitis has not been assessed in prospective clinical trials, and there is no consensus statement regarding the care of this patient population. In the case of grade 1 pneumonitis (asymptomatic radiographic changes only), immune checkpoint–blockade therapy should be withheld, and patients should be monitored closely (every 2 to 3 days) for the development of symptoms. Consultation with an interventional pulmonologist and an infectious-disease specialist is recommended. Repeat CT imaging of the chest is recommended within 3 weeks to document resolution or progression.

For patients with symptomatic pneumonitis (grade ≥ 2), patients should be monitored daily, with consideration given to hospitalization. In consultation with an interventional pulmonologist, performance of a bronchoscopy with bronchoalveolar lavage and tissue biopsies should be considered. Treatment with high-dose corticosteroids is recommended, along with empiric antibiotics, both of which can be administered while the above evaluation is underway. As with other severe toxicities, a lack of improvement after 48 to 72 hours of high-dose steroid treatment should prompt consideration of infliximab therapy. If possible, administration of infliximab should be delayed until a pulmonary infection has been reasonably excluded.

Dermatitis. An ipilimumab-associated rash should first be graded according to CTCAE. Macules/papules covering < 10% (grade 1) or 10% to 30% (grade 2) of body surface area with or without symptoms (eg, pruritus, burning, tightness) can often be managed with topical corticosteroids and oral over-the-counter antihistamines. In general, checkpoint-blockade therapy can be continued, although careful monitoring for progression of symptoms is warranted.

Grade 3 rash is characterized by macules/papules covering > 30% of body surface area with or without symptoms, as above. Oral corticosteroid administration (approximately 1 mg/kg/day prednisone or equivalent) frequently achieves symptom control. Temporary discontinuation of checkpoint therapy should be considered. Again, careful monitoring for progression of symptoms is warranted.

Grade 4 skin toxicity includes Stevens-Johnson syndrome; toxic epidermal necrolysis; and rash complicated by full-thickness dermal ulceration, necrosis, or hemorrhage. These symptoms require emergent administration of high-dose corticosteroids, inpatient admission, and consultation with a dermatologist.

Pruritus often accompanies a rash and can persist even after resolution of visible skin irritation. Mild, localized pruritus can be managed with moisturizing creams, topical corticosteroids, and topical antihistamines. More intense or widespread pruritus resulting in skin changes from scratching (eg, edema, papulation, excoriations, lichenification, oozing/crusts) may require low-dose oral corticosteroids or antipruritics (eg, hydroxyzine). For symptoms that limit activities of daily living or sleep or are intense or constant, clinicians could consider prescribing gabapentin, pregabalin, mirtazapine, or aprepitant.[28]

Endocrinopathies. Autoimmune endo­crinopathies can affect any organ in the hypothalamic-pituitary-adrenal axis. Patients who have hypophysitis but who are not in adrenal crisis generally require a short course of high-dose corticosteroids (eg, methylprednisolone 1 to 2 mg/kg/day or the equivalent) to address the acute inflammation; such treatment may preserve some degree of pituitary function.[47] Steroids should be tapered over at least 1 month, and patients should be followed by an endocrinologist, since many patients who develop endocrine deficiencies as a result of autoimmune hypophysitis do not experience restoration of normal hormonal function despite control of the initial inflammation with corticosteroids.[48] These patients may require long-term pituitary hormone replacement.

In rare cases, an autoimmune endocrinopathy may manifest as an adrenal crisis. These patients should receive stress-dose corticosteroids (eg, hydrocortisone 100 mg IV immediately, followed by 50 to 100 mg every 8 hours) along with fluid resuscitation as appropriate.

Patients who present with hyperthyroidism may initially require treatment (eg, beta-blockers) for alleviation of symptoms. Frequently, thyroiditis resolves over time, but then patients become hypothyroid, requiring thyroid hormone replacement. Isolated, asymptomatic hypothyroidism that can be managed with thyroid replacement alone generally does not require dose interruption or discontinuation of checkpoint-blockade drugs.

Conclusions

The successful clinical application of immune checkpoint–blockade therapies will continue to change the way we treat patients with advanced cancers. As novel immunomodulators increasingly play a role in oncologic therapy, practitioners must have strategies and protocols in place for identifying and treating immune-related toxicities. Indeed, the National Comprehensive Cancer Network (NCCN) consensus panel strongly recommends that physicians who prescribe ipilimumab participate in the corresponding Risk Evaluation and Mitigation Strategy (REMS) program.

While guidelines and algorithms are available to assist in the management of immune-related events, a patient’s entire treatment team-in particular, nurses, who are often a patient’s first point of contact in an oncology practice setting-must be familiar with and trained to properly manage these toxicities.[49,50] Patients, too, must be educated regarding possible side effects of therapy and the need for prompt symptom reporting. To facilitate effective patient-provider communication, some practitioners elect to use a standard list of questions to screen for possible irAEs at each patient encounter.

Ongoing studies aim to identify biomarkers to help identify patients at highest risk for irAEs. For now, practitioners must maintain a high level of suspicion for checkpoint-inhibitor toxicity, must understand the common and serious side effects, and must recognize that the potential exists for irAEs to affect any of the body’s organ systems.

Financial Disclosure: Dr. Lipson has served as an advisory board member for Amgen, and has received research funding from Genentech and AstraZeneca. Dr. Teply has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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