Immune checkpoint inhibitors and immune-related adverse events

Case

A 51-year-old gentleman with metastatic clear cell renal cell carcinoma presented to the emergency department with fever, breathlessness, tachypnoea and tachycardia, prior to his third cycle of treatment with the immune checkpoint inhibitors (ICIs) ipilimumab and nivolumab. This treatment is administered every 3 weeks for 4 cycles as induction therapy for this indication, followed by nivolumab maintenance therapy. The patient tolerated cycle 1 of treatment well, but developed a rash and a dry cough after cycle 2.

In the emergency department, the patient was initially suspected to have bilateral lower lobe pneumonia, based on examination findings and imaging. He was admitted to hospital and underwent bronchoscopy, which excluded an infectious cause for his symptoms. Pneumonitis related to ICI therapy was diagnosed (Grade 3 toxicity: severe symptoms requiring oxygen)* and the patient was commenced on intravenous methylprednisolone, with rapid improvement in symptoms. During a subsequent admission to hospital, an incidental finding of abnormal liver biochemistry was attributed to ICI-related hepatitis (Grade 3 toxicity: liver enzymes greater than 5 times the upper limit of normal).

Treatment for this patient’s immune-related adverse events (irAEs) (rash, pneumonitis, hepatitis) included intravenous and oral corticosteroids, as well as oral mycophenolate mofetil as a steroid-sparing agent, over a period of 1.5 years. The ICI therapies were ceased prematurely as a result of the irAEs and the patient was treated with the next line of treatment – cabozantinib, an oral tyrosine kinase inhibitor.

A timeline of key patient events and management is shown in Table 1.

Table 1 Timeline of key patient events and management

Weeks since start of ICI therapy	Patient events and management [NB1]
0	Cycle 1 ipilimumab and nivolumab administered. Patient education provided by cancer pharmacist, clinical nurse consultant (CNC) and medical oncologist.
3	Cycle 2 ipilimumab and nivolumab administered.
4	Cough and a slightly itchy rash on back (possibly heat rash) reported by the patient to CNC in a routine follow-up phone call.
5	Dry cough and itchy rash on parts of the back, chest, legs, arms and hands reported by the patient to CNC in a follow-up phone call. Diagnosis of ICI-related rash (Grade 2 toxicity: rash covering 10 to 30% of body surface area with or without symptoms), treated with an oral antihistamine and hydrocortisone 1% cream.
5 to 6	Admitted to hospital with fever and hypoxia. Diagnosis of ICI-induced pneumonitis (Grade 3 toxicity: severe symptoms requiring oxygen), treated with intravenous methylprednisolone followed by oral prednisolone, with a plan to wean. Discharged after 6 days.
7	Oncology review: decision to stop ipilimumab and nivolumab. Prednisolone weaning continued.
11	Admitted to hospital with fever and hypoxia, treated with antibiotics for potential infective cause. Incidental finding of ICI-induced hepatitis (Grade 3 toxicity: liver enzymes greater than 5 times the upper limit of normal), treated with intravenous methylprednisolone followed by oral prednisolone, with a plan to wean. Discharged after 5 days.
15 to 16	Admitted to hospital with fever, and hepatitis flare associated with weaning of prednisolone. Hepatology review recommended adding mycophenolate mofetil as a steroid-sparing agent, which assisted in resolving the hepatitis.
23 onwards	Follow-up hepatology review recommended restarting prednisolone (which had been stopped in the preceding days) and increasing the dose of mycophenolate mofetil because liver enzyme concentrations remained high. After liver enzymes improved, prednisolone was weaned and stopped. Mycophenolate mofetil was continued for a further 14.5 months.
ICI = immune checkpoint inhibitor NB1: Immune-related adverse events are graded according to the Common Terminology Criteria for Adverse Events in cancer therapy, which categorises toxicity on a scale of 1 to 5 in ascending order of severity.

 

Comment

Immune checkpoint inhibitors enhance the action of the immune system against tumour cells by blocking negative regulators of T cells. This can disrupt immunological homeostasis and result in adverse events that present as autoimmune-like or inflammatory conditions. These irAEs differ in presentation, onset and duration compared with the adverse events associated with conventional chemotherapy. Immune-related adverse events can affect multiple organs concurrently (Figure 1),¹ and can range from mild (e.g. a rash covering less than 10% of the body) to potentially life-threatening (e.g. colitis), or can be permanent (e.g. thyroid dysfunction).² They can be acute in onset (occurring shortly after starting treatment), or delayed (occurring months to years after stopping ICI treatment).^2-4 Skin effects, for example, generally occur 2 to 5 weeks after starting treatment with combination ICI therapy, while liver toxicity generally occurs after 6 to 15 weeks; however, these effects can occur at any time.⁵ Some irAEs can become chronic, with up to 35.5% of patients experiencing irAEs one year after completion of ICI treatment.⁶

The risk of irAEs is higher when patients are treated with combinations of ICIs that target both the cytotoxic T‑lymphocyte associated antigen 4 (CTLA‑4) and programmed cell death 1 (PD‑1) molecule pathways. With combination therapy, irAEs are more common, more severe (55% are Grade 3 or higher), develop earlier, and may last longer compared with irAEs associated with monotherapy. The occurrence of irAEs does not necessarily preclude further ICI therapy; this depends on the type and grade of irAE.²

 

Conclusion and recommendations

When taking a medication history from a patient who has had a diagnosis of cancer, practitioners should ask about current and previous treatment with ICI therapy. If no obvious cause can be found for a patient’s presenting complaint or out-of-range laboratory result, an irAE should be considered, since any organ can be affected and irAEs can present in a variety of ways (e.g. pruritus, colitis, pneumonitis, endocrinopathies).^2,7-9 If an irAE is suspected, early notification of the patient’s cancer treatment team is recommended.² The majority of irAEs are reversible if identified and treated early.⁹ Immune-related adverse events should be reported to the Therapeutic Goods Administration (TGA).

In addition to providing education and written information, practitioners caring for patients receiving ICIs must regularly remind them of the possibility of irAEs, and should check for signs of irAEs by questioning the patient and reviewing pathology tests. Identification and management of irAEs requires a multidisciplinary approach involving pharmacists and nursing staff, with input from relevant specialists when required (e.g. neurologist, gastroenterologist, hepatologist, respiratory physician, endocrinologist).

Finally, prescribers of ICI therapy are encouraged to include details about the initiation of these medicines, and the risk of irAEs (including the potential for their delayed onset), in their correspondence to the patient’s general practitioner and other members of the care team.

*Immune-related adverse events are graded according to the Common Terminology Criteria for Adverse Events in cancer therapy, which categorises toxicity on a scale of 1 to 5 in ascending order of severity.

Patient consent for publication of this case study was obtained by the authors.

Conflicts of interest: none declared

This article is peer reviewed.

 

References

1. Esfahani K, Meti N, Miller WH, Jr., Hudson M. Adverse events associated with immune checkpoint inhibitor treatment for cancer. CMAJ 2019;191:E40-E6.
2. Cancer Care Ontario. Clinical Practice Guideline: Immune Checkpoint Inhibitor Toxicity Management. 2018. [cited 2024 Aug 12]
3. Owen CN, Bai X, Quah T, Lo SN, Allayous C, Callaghan S, et al. Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma. Ann Oncol 2021;32:917-25.
4. Nakai Y, Otsuka T, Inoue T, Nawa T, Hatano K, Yamamoto Y, et al. Two cases of delayed onset of immune-related adverse events after discontinuation of nivolumab in patients with metastatic renal cell cancer. IJU Case Rep 2021;4:326-9.
5. Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 2019;16:563-80.
6. Schulz TU, Zierold S, Sachse MM, Pesch G, Tomsitz D, Schilbach K, et al. Persistent immune-related adverse events after cessation of checkpoint inhibitor therapy: Prevalence and impact on patients' health-related quality of life. Eur J Cancer 2022;176:88-99.
7. Cancer Institute NSW. Management of immune-related adverse events (irAEs). eviQ Cancer Treatments Online; 2022. [cited 2024 Feb 11]
8. Ardolino L, Joshua A. Immune checkpoint inhibitors in malignancy. Aust Prescr 2019;42:62-7.
9. Yeoh HL, Freilich K, Voskoboynik M, Moore M, Andrews MC, Shackleton M, et al. Immune-related adverse events secondary to immunotherapy in oncology: A guide for general practice. Aust J Gen Pract 2023;52:378-85.

 

Further reading

Ardolino L, Joshua A. Immune checkpoint inhibitors in malignancy. Aust Prescr 2019;42:62-7. https://doi.org/10.18773/austprescr.2019.012

Cancer Care Ontario. Clinical Practice Guideline: Immune Checkpoint Inhibitor Toxicity Management. 2018. https://www.cancercareontario.ca/en/guidelines-advice/types-of-cancer/52976 [cited 2024 Aug 12]

Cancer Institute NSW. Management of immune-related adverse events (irAEs). eviQ Cancer Treatments Online; 2022. 1993-Management of immune-related adverse events (irAEs) | eviQ [cited 2024 Feb 11]

Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins S, Anadkat M, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO Guideline update. J Clin Oncol 2021;39:4073-126. https://doi.org/10.1200/JCO.21.01440

Yeoh H, Freilich K, Voskoboynik M, Moore M, Andrews MC, Shackleton M, Haydon AM. Immune-related adverse events secondary to immunotherapy in oncology: A guide for general practice. 2023;52(6):378-385. https://doi.org/10.31128/AJGP-04-22-6408