Managing toxicities of immune checkpoint inhibitors

Authors:

Details:

  1. Division of Cancer Medicine, Peter MacCallum Cancer Centre, Victoria, Australia.
  2. Sir Peter MacCallum, University of Melbourne, Victoria, Australia.

Abstract

Immune checkpoint inhibitors are an integral part of cancer therapy following the demonstration of substantial responses across multiple tumour types. These agents induce T-cell activation against cancer cells that have achieved immune escape. Tipping the balance of immune homeostasis can however produce undesired autoimmunity, thus giving rise to a myriad of immune-related adverse events (irAEs) that can affect every organ. Although, mostly mild and manageable, potentially life threatening irAEs may occur and require prompt recognition and management.

The incidence and severity of irAEs is likely to increase with combination immunotherapies. Clinical presentations of these irAEs are varied in onset, type and severity, often leading to delays in presentation, diagnosis and appropriate management. As immuno-oncology becomes integrated into the broader anti-cancer treatment paradigm, clinicians will be required to rapidly recognise and manage a wide range of irAEs. We provide a summary of the patterns of onset, key clinical, pathologic and radiologic features of irAEs and management guidelines. Successful management of irAEs requires education for the patient, their carers and other health personnel, good patient-physician communication and multidisciplinary input from the medical oncologist and other specialist.


The immune system is critical in recognising and eradicating cancer. It is tightly regulated to maintain homeostasis between immune surveillance, T effector cell function and averting autoimmunity. Immune checkpoints refer to a plethora co-stimulatory and co-inhibitory receptor-ligand pairs that modulate immune responses against foreign-tissue antigens whilst maintaining self-tolerance.

Cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are two key inhibitory receptors expressed on activated T cells that serve as ‘breaks’ to constrain T effector cell generation and function, thereby preventing excessive immune activation.1-8 Anti-CTLA-4 (ipilimumab) and anti-PD-1/PD ligand-1 (PD-L1) antibodies (pembrolizumab, nivolumab, atezolizumab, avelumab) block this negative signal and lead to sustained T cell activation and proliferation, thereby inducing anti-tumour immunity.9

These agents have transformed the treatment of many malignancies and are registered for use in a wide range of cancers.10-17 Combination anti-PD-1 plus anti-CTLA-4 blockade demonstrated additional benefit in the management of metastatic melanoma, renal cell carcinoma and lung cancer.13,14,16,18,19 Multiple other antagonists of immune checkpoints, agonists of T-cell costimulatory molecules, novel combinations with immune checkpoint inhibitors, adoptive T cell therapy, and bi-specific antibodies are the focus ongoing research.15,20,21

Tipping the balance of immune homeostasis is a double-edged sword, inducing the desired anti-tumour immunity, but also producing undesired disruption of self-tolerance. A hyperactivated T-cell responses with secondary epitope spreading and cross-reactivity against normal tissue underpins most irAEs.22 Exact pathogenesis however remains incompletely understood and will ultimately define optimal management.

Biological characteristics of immune-checkpoint inhibitors and toxicities

CTLA-4 and PD-1 act at different nodes of the immune system. T-cell activation in the lymphoid tissue induces CTLA-4 expression on the T cell surface where it binds to B7 and induces T cell arrest.1,2 In contrast, persistent inflammatory signals in peripheral tissue including tumours induce PD-1 ligand expression that in turn binds to PD-1 on T cells to limit T cell activation.4,5,7,8 Anti-PD-1/PD-L1 antibodies therefore reinvigorates exhausted T effector cells within the tumour bed.8,23-25

These biological differences in CTLA-4 and PD-1 lead to different toxicity patterns.25 The most common irAEs are dermatologic, gastrointestinal, hepatic, endocrine and musculoskeletal.11-13,26-28 Anti-CTLA-4 antibodies causes higher rates of toxicity than anti-PD-1/PD-L1 antibodies theoretically due to greater Treg cell suppression and a greater array of T-cell activation.12,25,29 Expectedly, higher rates of irAEs are seen with combination checkpoint inhibition (table 1).16,30

Table 1: Treatment-related adverse events by organ category

 

 

Ipilimumabb

(N=131)

Nivolumabc

(N=576)

Pembrolizumabd

(N=277)

Nivolumab and Ipilimumabe

(N=448) 

Adverse event

Any Gradea (%)

Grade 3-4 (%)

Any Grade (%)

Grade 3-4 (%)

Any Grade (%)

Grade 3-4 (%)

Any Grade (%)

Grade 3-4 (%)

Any AE

97

46

95

35

73

10

95

55

Any treatment-related  irAE

61

15

48

4

N/A

10

88

42

Gastrointestinal

N/A

N/A

13

1

N/A

N/A

N/A

N/A

Diarrhoea

28

5

13

0.5

14

1

44

10

Colitis

8

5

1

0.7

4

3

13

9

Hepatic

4

0

4

1

2

2

29

17

AST rise

0.8

0

3

0.3

2

0.4

17

6

ALT rise

2

0

2

0.7

1

0.4

18

9

Skin

44

2

34

0.7

N/A

N/A

64

7

Pruritis

24

0

17

0.2

14

0

35

2

Rash

19

0.8

13

0.3

13

0

35

4

Pulmonary

N/A

N/A

2

0

N/A

N/A

8

1

Dyspnoea

15

4

N/A

N/A

4

0

N/A

N/A

Pneumonitis

N/A

N/A

2

0

2

0.4

7

1

Endocrine

7.6

3.8

8

0.3

N/A

N/A

30

5

Hypothyroid

1.5

0

4

0

9

0

15

0.2

Hyperthyroid

   

2

0.2

3

0

8

0.7

Fatigue

42

7

25

0.3

19

0.4

37

4

Drug discontinuation treatment-related AE

 N/A

 

3

 

7

 

40

 

aThe severity of adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The most common immune-related adverse events and those of particular clinical relevance are also listed.

bAdapted from phase III study of patients receiving ipilimumab  for metastatic melanoma31.

cAdapted from a pooled analysis of patients receiving nivolumab for advanced melanoma39.

dAdapted from KEYNOTE-006 trial of patients receiving pembrolizumab (three-weekly) for advanced melanoma6.

eAdapted from a pooled analysis of patients receiving nivolumab and ipilimumab combination therapy for advanced melanoma41.

Kinetics of immune-related adverse events

Common irAEs follow predictable kinetics for both anti-CTLA-4 and anti-PD1/PDL-1 monotherapy (figure 1).31-33 Most irAEs occur within 3 to 6 months of treatment initiation, although irAEs have been documented over a year after treatment cessation.28,34-36 Dermatological toxicities tend to occur early, followed by colitis, hepatitis, and endocrinopathies.28,32,33,36 Generally, gastrointestinal and hepatic irAEs were the quickest to resolved (median: 1-3 weeks), followed by pulmonary irAEs (median: 6 weeks) and skin irAEs (median: 18 weeks). Patients often need life-long hormone replacement for endocrinopathies.13,28,30,36-39 Notably, irAEs tend to occur earlier and multiple concurrent events can occur with ipilimumab-plus-nivolumab.30

Figure 1: Time to onset of treatment-related adverse events

 

 

 

 

General advice on management of immune-related adverse events

Immune-related adverse events can affect any organ (figure 2, table 2). Education of the patient, medical oncologists, and other health professionals is key to facilitating early recognition and appropriate multidisciplinary management.

Figure 2: Common signs and symptoms of immune-related adverse events

 

 

 

 

 

Table 2: Common signs and symptoms of immune-related adverse reactions

Organ system

Monitor the following signs and symptoms

Gastrointestinal

  • Colitis
    – Diarrhoea
    – Increased frequency of bowel movements
    – Abdominal pain
    – Haematochezia (blood in stool)
    – Mucus in stools
    – Constitutional symptoms (fever, fatigue, loss of weight)
  • Gastritis
    – Nausea
    – Vomiting
    – Dyspepsia

Hepatic

  • Elevated aspartate aminotransferase (AST)
  • Elevated alanine aminotransferase (ALT)
  • Constitutional symptoms
  • Anorexia
  • Upper quadrant tenderness (rare)

Skin

  • Pruritus
  • Rash
  • Erythema
  • Vitiligo
  • Psoriasis
  • Stevens–Johnson syndrome
  • Drug reaction with eosinophilia and systemic symptoms (DRESS)

Endocrine

 

  • Non-specific symptoms of being unwell
  • Headache
  • Fatigue
  • Visual field defects
  •  Nausea
  • Dizziness
  • Electrolyte disturbances
  • Hypotension
  • Tachycardia
  • Adrenal crisis (dizziness, hypotension, shock)
  • Type 1 Diabetis (polyuria, polydipsia, hyperglycaemia, ketoacidosis)

Pneumonitis

  • Dyspnea
  • Cough
  • Fever
  • Chest pain
  • Reduced exercise tolerance
  • Constitutional symptoms 

Neurological

  • Motor neuropathy
  • Muscle weakness
  • Sensory neuropathy
  • Guillain-Barré syndrome (rare)
  • Myasthenia Gravis (rare)
  • Encephalitis (rare)

Musculoskeletal

  • Arthritis/arthralgia
  • Myositis
  • Myocarditis (rare)

Other

  • irARs can affect any organ systems. 
  • Uncommon but previously reported irARs include uveitis, eosinophilia, lipase elevation, vasculitis and glomerular nephritis, etc.

Patients due to commence immune checkpoint inhibitors should have routine bloods including assessment of renal function, liver function, electrolytes, thyroid function, complete blood count, ACTH, and cortisol levels at baseline and regularly during treatment.

Occurrence of moderate to severe irAEs necessitates the delay of immunotherapy until symptom resolution and wean of corticosteroids before retreatment. Some irAEs necessitate permanent treatment discontinuation.

Initial investigation of an irAE includes relevant blood work and imaging. Biopsy of the involved organ is generally not necessary, but should be considered in severe, atypical, refractory, and relapsing cases. Early specialist involvement is recommended in moderate to severe cases. Alternative diagnosis needs to be excluded as the diagnosis of irAEs carries significant implications for the patient’s ongoing anti-cancer therapy.

High-dose corticosteroids effectively reverses most grade 3 to 4 irAEs when implemented early. In patients with severe symptoms, investigations should not delay the use of immunomodulatory agents. Generally, corticosteroids should be tapered over at least four to six weeks to avoid rebound. During corticosteroid taper, patients should be monitored for symptom recurrence and educated to re-present if symptoms recur. Management guidelines are outlined in the Appendix.

Measures should be implemented to mitigate short and long-term corticosteroids complications. Patients at risk of fungal infections, reactivation of tuberculosis or viral hepatitis based should have baseline serology for latent Mycobacterium tuberculosis, viral hepatitis, and input from an infectious disease specialist. Recent case reports suggest that viral hepatitis should not preclude immune checkpoint inhibition however careful monitoring is required.40 Pneumocystis jiroveci prophylaxis is indicated in patients receiving greater than 15 to 20 mg prednisolone equivalent for four or more weeks.41 However the impact of antimicrobials on the microbiome remain unclear.

Patients with preexisting autoimmune disorder (AD) or irAEs are at risk of flaring their AD or developing a new irAE when re-treated with a checkpoint inhibitor. Two retrospective analyses of patients who received an anti-PD-1/PD-L1 antibody in the context of pre-existing AD, revealed that 6 to 38% of patients experienced flare of AD.42,43 In 119 patients with pre-existing AD, 15 (29%) developed other irAEs42. In a further study of 71 lung cancer patients retreated with immunotherapy after previous anti-PD-1/PD-L1 related irAE requiring dose delay, 26% experienced recurrence of the same irAE and 23% experienced a new irAE.44 In a retrospective analysis of 67 melanoma patients who received an anti-PD-1 antibody after experiencing a significant irAE with ipilimumab, 34% (14/67) of patients developed a different irAEs (21% grade 3 or 4). Eight (12%) patients had to discontinue treatment.42 Prior treatment with ipilimumab does not affect the safety profile of subsequent nivolumab in advanced melanoma patients.36 Collectively, these data highlight the need for detailed history taking and a cautious approach when considering immune checkpoint inhibitors in the setting of prior AD or irAE.

Impact of immune-mediated adverse events, treatment discontinuation, and use of immunosuppression on treatment response

Treatment discontinuation related to irAEs was reported in 3 to 7% of patients receiving single agent anti-PD-1 therapy and 40% of patients receiving combination immunotherapy.11,12,30,36,45 Melanoma patients who experienced irAEs requiring treatment discontinuation during the induction phase of combination immunotherapy had similar cancer outcomes to those who did not discontinue treatment.45 Patients who experience one or more irAEs appear to have higher objective response rate than those who did not experience any irAE.30 The use of corticosteroids and TNF-α antagonists for the management of irAE did not negatively impact on overall survival of advanced melanoma patients receiving immune checkpoint therapy.30,36,45,46 However, longer follow-up on the type and duration of immunosuppression is required to better understand the interface between type of irAE, immunosuppression, rate of response and durability of response.

Specific immune-mediated adverse effects and their management

Skin

Skin toxicity is the most common irAE in patients receiving immune checkpoint inhibition. Rash occurs in 15 to 26% of patients receiving anti-PD-1 monotherapy, 20% of patients receiving anti-CTLA-4 monotherapy and 40% of patients receiving combination nivolumab-plus-ipilimumab.12,13,26,27 Vitiligo is associated with improved response to immunotherapy in melanoma patients.47 Rashes are mostly mild and have a reticular, maculopapular, or erythematous appearance.48 Rarer skin toxicities include psoriaform or lichenoid reactions, dermatitis herpetiforme, bullous pemphigoid, Grover’s disease, Sweet’s syndrome, prurigo nodularis, Stevens-Johnson syndrome, and toxic epidermal necrolysis.49,50 Mild rashes are managed with emollients, topical steroids and oral antihistamines. Skin biopsy and dermatologist input should be sought for severe, atypical or refractory cases. Persistent grade 2 to 3 rashes despite appropriate topical management warrants escalation to oral corticosteroids. Steven-Johnson syndrome and toxic epidermal necrolysis requires hospitalization for supportive care and intravenous methylprednisolone. Immunotherapy should be deferred in patients with grade 3 toxicity and discontinued in patients with life-threatening conditions.

Gastrointestinal

Although a distinction is made between diarrhoea (increased stool frequency) and colitis (radiologic or pathologic evidence of colonic inflammation) in the reported literature, there is significant overlap between these entities. Diarrhoea/colitis usually occurs after several doses of the immune checkpoint inhibitor monotherapy but can occur as early as after one dose of combination therapy. New or severe upper gastrointestinal symptoms should be investigated on their own merits with gastroscopy and dedicated small bowel imaging to exclude gastritis or enteritis. Infective gastroenteritis and inflammatory bowel disease should be excluded with detailed history taking and appropriate investigations. A computer tomography of the abdomen is useful to exclude a perforation especially prior to implementing infliximab. It may be normal or show bowel wall thickening and associated pericolonic fat stranding. Colonoscopy can be undertaken if clinically required to exclude alternative diagnosis and detect complications. Histologic findings include crypt abscesses and atrophy, diffuse mucosal inflammation, and neutrophilic infiltrates. Most cases have rectosigmoid involvement, but enteritis can also be present.51,52 Patient with grade 2 or greater symptoms requires corticosteroids and immunotherapy interruption. Patients with grade 3 or 4 symptoms or persistent grade 2 symptoms despite 72 hours of appropriate steroid therapy should be admitted for supportive care and intravenous high-dose corticosteroids. Upon symptom resolution, corticosteroids can be tapered over four to six weeks and patients need monitoring for recurrent symptoms.52 Infliximab should be administered to patients whose symptoms persist beyond 72 hours despite high-dose corticosteroids or if symptoms rebound during corticosteroid taper. In the setting of recurrent colitis, infectious etiology such as Clostridium difficile and Cytomegalovirus colitis should also be excluded.

Hepatotoxicity

Hepatitis is commonly detected as asymptomatic liver function abnormalities.31 Thrombotic events, disease progression, viral hepatitis, and biliary obstruction should be excluded. Radiologic findings are usually non-specific and can range from normal to mild hepatomegaly, periportal edema, and periportal lymphadenopathy.53 Biopsies can be useful in complicated cases. Pathology commonly demonstrates both hepatocyte and biliary injury with sinusoidal immune infiltrates.53,54 Grade 2 hepatitis can be managed with oral corticosteroid. Grade 3 to 4 or persistent grade 2 hepatitis requires intravenous methylprednisolone. Upon return of hepatotoxicity to grade 1, steroids can be weaned over four to six weeks. Regular liver function tests should be repeated during corticosteroid taper to monitor for rebound. Infliximab carries hepatotoxicity and should be avoided. Myophenolate mofetil is used in steroid-refractory cases. Escalation to antithymocyte globulin can be useful in refractory cases.55,56

Thyroid dysfunction

Thyroid dysfunction is the commonest endocrine irAE. Hypothyroidism is more common than hyperthyroidism.12,13,26,27 Antithyroid antibodies are present in most patients. In 60% of patients, hypothyroidism was preceded by transient hyperthyroidism lasting approximately one month.57 Beta-blockers are useful for symptom control. Immunotherapy should be withheld in grade 3 to 4 endocrinopathy but can be resumed after stabilization of the endocrine dysfunction with hormone replacement, which is often required life-long. Rarely, recovery of thyroid function has occurred.39

Hypophysitis

Clinical presentation of hypophysitis is often insidious and nonspecific including headaches, dizziness, diplopia, fatigue, and focal neurology.38,58,59 There should be low threshold to evaluate the adrenal and pituitary axis. Hypophysitis is often detected during routine thyroid function testing whereby low thyroid stimulating hormone and low thyroxine suggests a central cause. MRI abnormalities include sella and pituitary enlargement. High-dose corticosteroids have not been shown to improve ipilimumab-induced hypophysitis.58 Resolution of pituitary function, recovery of secondary male hypogonadism and hypothyroidism occurred in 73%, 64%, and 45% of patients, respectively. Adrenal insufficiency was generally permanent.58 Most guidelines recommend ongoing hormone replacement with initiation of corticosteroids ahead of thyroid hormone replacement to avoid adrenal crisis.38,39,59

Cardiac toxicity

A retrospective analysis of a database of 20,594 patients treated with ipilimumab, nivolumab, or combination immunotherapy identified 18 (0.09%) cases of severe myocarditis. Given troponin testing, electrocardiograms and echocardiogram were not incorporated into routine safety assessments during clinical trials the true incidence may be higher. Myocarditis was diagnosed at a median of 17 days after initial therapy. Most patients presented with incidental elevation in cardiac enzymes with no cardiac dysfunction or arrhythmias. There have however been cases of fulminant myocarditis resulting in ventricular arrhythmias and death. Post-mortem pathology from two patients with fulminant myocarditis revealed lymphocytic infiltrates with abundance of CD4+ and CD8+ T cells within the myocardium and conduction system. Interestingly, both had preserved ejection fractions on echocardiogram. It is postulated that molecular mimicry by tumour cells exacerbated autoimmune response against shared epitopes present on myocardial and skeletal muscles.60 Patients with suspected of myocarditis should be admitted for evaluation of ventricular function and cardiac telemetry. Cardiac MRI is a valuable tool for overcoming sampling issues of cardiac biopsy but requires specific expertise in MRI interpretation.61 High-dose corticosteroids is recommended for myocarditis. In severe cases, escalation to infliximab and anti-thymocyte globulin has been required.

Neurologic

Neurologic irAEs are rare and include peripheral neuropathies, cranial nerve palsies, Guillain-Barré syndrome, aseptic meningitis, myasthenia gravis, inflammatory myelitis, chronic inflammatory demyelinating polyneuropathy, immune-mediated encephalitis, and posterior reversible encephalopathy syndrome. A review of 3,763 patients with advanced melanoma treated with nivolumab, ipilimumab or combination immunotherapy revealed 35 (0.93%) patients presenting with 43 serious neurologic irAE. Median time to onset was 45 days. Median time to resolution was 32 days. 75% of neurologic irAEs resolved.62

Encephalitis is often a diagnostic dilemma as patients present with nonspecific symptoms including altered mental state, confusion, aphasia, ataxia, seizures, and fatigue. Median time to onset was 55 days. Differential diagnoses include bacterial and viral infection, intracranial metastasis, collagen vascular disorders, paraneoplastic phenomena, and stroke.62 If suspecting immune-mediate encephalitis, high-dose corticosteroids is warranted. Empiric antivirals and antibiotics administration is reasonable. Intravenous immunoglobulin can be considered. Neurologist involvement is critical.

Pneumonitis

The incidence of pneumonitis in patients with melanoma or non-small cell lung cancer receiving anti-PD-1/PD-L1 monotherapy is 2 to 3% (grade 3-4: <1%).10,63,64 The incidence is higher with combination ipilimumab-plus-nivolumab (table 1).19,30 Rates of pneumonitis from anti-PD-1 monotherapy are lower in patients with melanoma (<1%) compared with lung cancer (1-3%) implying that pre-existing pulmonary pathology may increase this risk.10,64-66

One third of patients with pneumonitis are asymptomatic and present with incidental radiological changes. These patients can be monitored without discontinuing therapy. Symptoms of pneumonitis include dyspnoea, fevers, cough, and constitutional symptoms. Radiological changes are bilateral and non-specific including ground glass opacities, interstitial infiltrates, cryptogenic organising pneumonia (COP), and hypersensitivity. COP is associated with lung cancer or prior irradiation. It is more likely to require immunosuppression.63 Radiation recall can occur months post immunotherapy cessation.67 High-resolution computer tomography should be performed in symptomatic patients. Bronchoscopies are typically not warranted but should be considered if the diagnosis is uncertain. Bronchoscopy findings consist of diffuse lymphocytic infiltrate. Pneumonitis rapidly improves with treatment interruption and high-dose corticosteroids. Grade 2 pneumonitis should be managed with high-dose corticosteroids until resolution to grade 1. Grade 3 to 4 pneumonitis requires hospitalisation and intravenous methylprednisolone. Severe and refractory cases may necessitate escalation to infliximab and/or cyclophosphamide.

Musculoskeletal

The true incidence of musculoskeletal irAEs is unclear due to the diverse presentation and high premorbid prevalence in the general population making attribution challenging. Collectively, rheumatologic irAEs including arthritis (mono or polyarthritis), sicca syndrome, myalgia, and myositis are reported in approximately 7% of patients on anti-PD1 therapy and 12% of patients on combined ipilimumab-plus-nivolumab.30,36 Grade 1 events can be managed with simple analgesics. Grade 2 to 3 events often require intra-articular and/or oral corticosteroids. Disease-modifying anti-rheumatic drugs should be kept to a minimum.

Ophthalmic

Ocular irAEs are uncommon (<1%). They include episcleritis, conjunctivitis, ulcerative keratitis, Vogt-Koyanagi-harada syndrome, orbital inflammation, uveitis, and choroidal neoavasculiisation.68 Most are treated with topical steroids, but some cases require intraocular or systemic corticosteroids and immunotherapy discontinuation. All cases warrant ophthalmologist input.

Other rare immune toxicities

Immunotherapy-induced type 1 diabetes mellitus occurs in approximately 1 in 700 patients.27 Symptoms are typical of uncontrolled type 1 diabetes. Presence of anti-glutamic acid decarboxylase antibodies, anti-islet cell antibodies, and increased diabetes antigen-specific CD8+ T cells in these patients provides insight into a pathophysiological basis in both cellular and humoral autoimmunity.69 Long-term insulin replacement is required. Immunotherapy can be recommenced upon stabilisation of blood sugar levels.

Immunotherapy-induced nephrotoxicity can present as a variety of pathologies: acute tubulointerstitial nephritis, glomerulonephritis, and thrombotic microangiopathy. Most cases respond to high dose corticosteroids.70,71

Pancreatitis is a rare complication of immunotherapy. Isolated amylase and lipase elevation can be monitored.72 Symptomatic patients need supportive care, oral or intravenous corticosteroids, and delay of checkpoint inhibitor therapy or discontinuation depending on severity.

Conclusion

As immune checkpoint inhibitors become an integral part of cancer therapy, medical oncologists and other medical specialists need to be trained to promptly identify and manage these toxicities. Optimal management of irAEs requires excellent patient education, effective communication between the patients and their physicians, as well as timely involvement of other specialists when required.

Prospective collaborative efforts is needed to collect longitudinal clinical data and biospecimens in order to characterise the aetiology of irAEs and interrogate the interface between AD, irAEs, and anti-cancer responses. This will also aid the identification of predictive biomarkers of immunotherapy toxicity.

Appendix

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