Immune-Related Adverse Events

Introduction

Discovery of immune checkpoint inhibitors has revolutionized the therapeutic landscape for the treatment of cancer. Development of immunotherapy for cancer is based on modulation of T cell function via manipulation of checkpoint proteins expressed on the cell surface. This manipulation results in T cell activation or prevention of T cells from switching off thus enhancing their ability to target and destroy cancer cells. Immune checkpoint inhibitors (ICIs) represent the largest and most frequently used type of immunotherapies.

Therapeutic targeting of immune-inhibitory and stimulatory pathways can alter the immune system’s tolerance for ‘self,’ resulting in damage to normal cells, known as immune-related adverse events (irAEs). As opposed to traditional chemotherapy that works by directly destroying rapidly dividing cells, irAEs occur when increased activation of immune effector cells/mechanisms result in damage to normal cells. Any organ system can be affected, and severity can range from mild grade 1–2 to severe grade 3-4 toxicities. Presenting symptoms for irAEs can be nonspecific and at times subtle making them difficult to be identified. It is critically important for both, patients and clinicians/practitioners to recognize these adverse events earlier in their course when appropriate measures can result in reversal of these events in 90% to 95% of cases. If these toxicities are not dealt with promptly and appropriately, irreversibility may ensue that can potentially lead to severe organ dysfunction (ie, colectomy) or even death.

The severity of adverse events is dependent on the agent/agents used. The combination of anti-PD1 antibody plus anti-CTLA4 antibody has been documented to elicit higher grade irAEs compared with anti-PD1/PD-L1 antibody monotherapy. Additionally, the dose of ICIs used may also impact the adverse event profile. The Checkmate 067 study used combination nivolumab (anti-PD1; Opdivo, Bristol Myers Squibb) at 1 mg/kg and ipilimumab (anti-CTLA4; Yervoy, Bristol Myers Squibb) 3 mg/kg for treatment of patients with unresectable/stage IV melanoma. In this study almost 60% of the patients who received the above combination experienced grade 3-4 irAEs. The Checkmate 511 study compared the above-mentioned combination with altered dosing of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg in the same patient population with significant reduction in the incidence of high-grade irAEs.

Distribution of irAEs by organ system may also vary with ICI being used. For instance, there is a higher incidence of colitis with anti-CTLA4 antibody compared with thyroid dysfunction that is more often observed with anti-PD1/PD-L1 antibodies.

Several factors including underlying or undiagnosed conditions can impact emergence of irAEs after treatment with ICIs. Those individuals with prior diagnosis of autoimmune diseases – including thyroid disorders, arthritis, skin conditions like psoriasis, inflammatory bowel disease, sarcoidosis etc. – are at very high risk for rapidly developing severe related toxicities, therefore they are usually excluded from treatment with ICIs. Additionally, some individuals may have a tendency toward developing an autoimmune disorder but have never been diagnosed. These individuals are at high risk for unmasking their autoimmune tendency and developing high-grade immune-related toxicities. While the median time of developing autoimmune breakthrough, adverse events vary from 3 to 12 weeks depending on the organ system involved, these toxicities may present themselves earlier in those with underlying conditions.

Novel immunotherapy combinations with chemotherapy or targeted agents/tyrosine kinase inhibitors are being assessed and developed for multiple indications that will add another layer of complexity to adverse events and their management. Here we provide an overview of irAEs described for current ICIs in clinical practice and their management based on review of published guidelines.

Cardiovascular

Cardiovascular toxicities represent one of the most severe immunotherapy complications. While less than 1% of patients experience cardiac toxicity, 50% of patients who experience a cardiac event discontinue immunotherapy due to the high mortality rate. This risk for cardiac toxicity increases with both combination immunotherapy and in patients who received prior chemotherapy or targeted therapy. Current literature suggests subclinical cardiovascular damage from cardiac antigen exposure during prior lines of therapy may be amplified with subsequent immunotherapy resulting in cardiac toxicity. ICI therapy has been shown to affect the heart in both an inflammatory (myocarditis, perimyocarditis, ventricular dysfunction) and non-inflammatory (asymptomatic non-inflammatory left ventricular dysfunction, arrhythmias, myocardial infarction) manner. Non-specific symptoms including fatigue, chest pain and overall body weakness present in the first 2 months of initiating immunotherapy. A full cardiac history prior to initiation of immunotherapy is essential due to the high mortality rate and rapid clinical deterioration that can lead to heart failure if not diagnosed and treated early. Clinical assessment includes serum testing, diagnostic imaging (ie, ECG and cardiac MRI to assess inflammation), cardiologist consultation, and in instances involving suspected myocarditis a cardiac biopsy is necessary.

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Dermatologic

Dermatologic toxicity is ranked among the most frequent (40%-50%) and earliest reported (2-3 weeks) irAEs and includes rash, vitiligo (loss of skin pigment) and pruritus (itchy skin). Rashes are usually mild to moderate in nature and can be associated with itching. While rare, severe skin toxicities do occur and can be life-threatening including edema, oozing and separation of the dermis. Consultation with a dermatologist is highly recommended when severe skin toxicities with blistering or bullous lesions develop. As is often seen with irAEs, combination immunotherapy increases the risk for dermatologic toxicity. Interestingly, not all dermatologic toxicities are toxic in nature. Vitiligo is most common in melanoma patients and has been associated with survival benefit. Clinical assessment includes a total body skin exam, review of prior dermatologic disorders, serum testing and potential skin biopsy. Immunotherapy can continue in low grade dermatologic irAEs (ie, mild rash), but is often discontinued with persistent and/or high grade (> 3) dermatologic irAEs.

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Endocrine

Endocrine dysfunction is frequently reported in patients receiving ICIs (5%-20%), with an average onset time within 12 weeks from treatment initiation, and higher incidence in patients receiving combination therapy compared with monotherapy. The adverse effects of ICI therapy on the endocrine system vary significantly, from commonly occurring thyroid and pituitary disorders to relatively rare adrenal insufficiency and type 1 diabetes.

Diagnosis of endocrine irAEs is often delayed due to the subtle nature of signs and symptoms that often overlap with symptoms typically experienced by patients with advanced cancer, including vomiting, headache, nausea and fatigue. While mild fatigue is common in patients receiving ICI, severe fatigue can be an indicator of a more serious underlying endocrine dysfunction. Most endocrine-related irAEs are low grade and easily managed; however, when left untreated, they can lead to life-threatening conditions. Clinical assessment involves serum testing including hormonal evaluation and an endocrinology consultation to rule out an underlying medical condition. Hormonal therapy is essential for proper treatment of most endocrine disorders.  Immunotherapy may be held and/or discontinued based on the type and grade of endocrine irAE.

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Gastrointestinal

Gastrointestinal (GI) adverse events are one of the more commonly experienced irAEs associated with ICIs, and affect the bowels, liver and pancreas. The underlying pathogenesis is still unclear but cross-reactivity of tumor neoantigens (foreign proteins) with normal GI tract antigens may play a role in inflammation and destruction of healthy tissue. The incidence of GI related irAEs is dependent on the type of immunotherapy, tumor type and dose and duration of therapy; with higher rates in patients receiving CTLA-4 inhibitor immunotherapy compared with PD-L1 therapy. Dosing with ICIs may be continued with low grade GI irAEs, however close monitoring for dehydration and adjustments to diet and nutritional requirements is warranted. High grade GI irAEs can result in serious morbidity and require endoscopy with biopsy, corticosteroid use and potential hospitalization . In severe cases where intestinal perforation or abdominal abscess forms, surgical intervention is necessary. Clinical assessment includes diagnostic imaging, possible endoscopy and stool sample analysis, and ruling out of other etiologies including infections. Additionally, as hepatic dysfunction is routinely monitored as part of all immunotherapy regimen; it is often diagnosed early by asymptomatic elevations in liver serum markers [alanine transaminase (ALT) and aspartate transaminase (AST)]. Diagnostic imaging is required to rule out other potential causes including metastasis of the primary cancer to the liver.

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Pre-existing Autoimmune Disorders

It should be noted, patients with underlying autoimmune disorders, especially those in the active stage, are at a higher risk for experiencing flare ups upon initiation of immunotherapy (about 50%-70%). Some patients with autoantibodies and subclinical autoimmune conditions may only become aware of their condition when it clinically manifests after initiating immunotherapy. Thus, patients with a familial history or presenting with potential signs of an underlying autoimmune disease may need to be screened for autoantibodies prior to initiating immunotherapy. PD-1/L1 inhibitor therapy also increases the risk for reactivation compared with CLTA-4 inhibitor therapy. Interestingly, patients on immunosuppressants at the start of immunotherapy regimen have a lower risk of developing irAEs.

Pulmonary

The incidence of ICI-induced pulmonary toxicity ranges from 2.7% to 11% for all grades and has a median onset time of 8 to 12 weeks after initiating therapy. Although the incidence is lower than other more common irAEs, it has a poor prognosis and often results in delay or discontinuation of ICIs. An increased prevalence of pulmonary dysfunction is seen in those patients receiving combination vs. monotherapy. In addition, non-small cell lung cancer (NSCLC) patients tend to be at a higher risk for developing and having earlier onset of pulmonary toxicity than other cancer subtypes. Diagnosis is challenging due to non-specific symptoms including chest pain, difficulty breathing, cough and occasionally fever. Therefore, high resolution diagnostic imaging and pulmonary function tests are highly recommended.

Pneumonitis

Inflammation of the lungs is the most common lung toxicity among patients receiving ICIs, with an estimated overall incidence of 2.7% to 5%. Pneumonitis usually presents within the first 12 weeks of treatment initiation and if not diagnosed and treated early can have poor clinical outcomes. The most common symptoms include new onset respiratory distress, difficulty breathing and cough. Clinical assessment includes diagnostic imaging, functional assessment, serum testing, and elimination of alternative diagnoses. Although most patients experience grade 1-2 pneumonitis, it can rapidly escalate to a grade 3-4 irAE with a high mortality rate (50%-60%). The optimal treatment regimen has yet to be established, however the recommendations based on the grade are listed in table below.

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Renal

Renal toxicity due to ICI therapy is relatively uncommon, occurring in up to 5% of patients, with increased risk in patients receiving combination therapy. The most common renal toxicity observed is acute injury to the renal tubules and tubular space resulting in deleterious effects on kidney filtration. Clinical assessment includes diagnostic imaging, serum testing, possible biopsy analysis and consultation with a nephrologist to reduce the risk for irreversible damage to the renal system and to rule out other potential causes of kidney injury. Renal toxicity is often resolved with corticosteroid treatment and holding and/or discontinuation of immunotherapy is based on the severity of symptoms.

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Rheumatologic

Rheumatologic toxicities arising from ICI therapy are increasingly recognized and are more often associated with symptoms that persist after cessation of immunotherapy. Personal (25%) or family (10%) history of autoimmune disorders are associated with increased predisposition to rheumatologic irAEs. Diagnosis can be challenging due to the broad range of symptoms, lack of traditional clinical presentation, and majority of knowledge based on small number of patients presented as case reports in the literature. Arthralgia, joint and muscle pain, presents one of the most common symptoms occurring in 10% to 15% of patients. Clinical assessment includes full medical and family history, exam of joints and muscle strength, diagnostic imaging, serum testing and rule out other underlying medical conditions. While rheumatological irAEs are rarely life-threatening, prompt referral to a rheumatologist is essential as delayed treatment can lead to long-term disability, chronic disorders and may require permanent immunosuppressive therapy. Immunotherapy can continue in low grade rheumatologic irAEs but is often delayed or discontinued with persistent and/or high grade (> 3) symptoms.

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Neurologic Conditions

Neurological irAEs are reported less frequently in patients receiving ICIs (1%-12%) and tend to present as low grade (1-2) within the first 3 months of starting immunotherapy. irAEs associated with the peripheral nervous system (PNS) are more common than the central nervous system (CNS), with peripheral neuropathy and myasthenia gravis being the most common. Multiple irAEs associated with neuromuscular disorders can occur simultaneously in patients taking immunotherapy, often with overlapping symptoms not often seen in the general population. Patients often present with non-specific symptoms including headache or dizziness, though more serious events (grade 3-4) occur in less than 1% of patients, with encephalitis and myasthenia gravis proving to be the most fatal. Clinical assessment includes serum testing, diagnostic imaging, respiratory function assessment, rule out other underlying conditions, potential lumbar puncture and consultation with a neurologist. Immunotherapy should be held and potentially stopped should a patient experience a grade 2 or higher neurological irAE. While no standard treatment has been established for treating neurological irAEs, immune-modulating therapy such as corticosteroids and discontinuation of ICI therapy have shown improvement in some cases.

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Summary

The development of novel immunotherapies has and will continue to change the cancer treatment landscape and in turn patient outcomes. Immunotherapy elicits its effects via modulation of the immune system; thus, each patient’s experience is unique both in terms of therapeutic response and potential adverse events. Open communication between patients and clinicians from treatment planning through survivorship is essential. While most cancer patients experience mild to moderate symptoms, high grade irAEs can be life-threatening if not diagnosed early and managed appropriately. Regardless of etiology, it is highly recommended immunotherapy be held and often discontinued if symptoms persist of become severe. The most important first step in ensuring early detection and proper management is educating patients on signs and symptoms they may experience after initiation of immunotherapy. Additionally, a multi-specialty team approach is essential for optimal management and reversal of adverse effects. As our knowledge of immunotherapies and their underlying immune mechanisms expands, so will our ability to manage and prevent associated adverse events providing cancer patients with optimal care and improved outcomes.