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Toxicity Management for Immune Checkpoint Inhibitors

Eris Tollkuci, PharmD BCOP
Assistant Professor of Pharmacy Practice
Rosalind Franklin University of Medicine and Science
North Chicago, IL
Clinical Pharmacy Specialist, Hematology/Oncology/Cell Therapy
Rush University Medical Center
Chicago, IL

Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have become the mainstay of therapy for numerous oncologic indications (Table 1 - see PDF). Most U.S. Food and Drug Administration approvals pertain to treatment of advanced or metastatic cancers; however, agents such as atezolizumab have gained approval in the first-line setting (IMpower133).1 An increasing number of patients are exposed to these therapies; therefore, it is imperative for healthcare providers in community and academic medical center settings to recognize and appropriately manage these unique toxicities. The purpose of this article is to provide an overview of immune checkpoint inhibitor (ICI) toxicity management while also highlighting resources available for clinicians managing these therapies in various clinical settings.

Checkpoint inhibitor–based immunotherapies have varying toxicity profile incidence and timing, which are often related to their unique mechanism of action, setting them apart from traditional cytotoxic chemotherapies. Toxicities can be divided into three categories: infusion reactions, immune-related adverse events (irAEs), and adverse events of special interest. The skin, colon, endocrine organs, liver, and lungs are the organs most frequently affected by irAEs.2

Infusion-Related Reactions

Most infusion-related reactions are mild and are typically associated with low-grade fever, chills, headaches, or nausea (Table 2 - see PDF). Severe reactions are reported in less than 1% of patients. Infusion-related reactions have most commonly been reported with avelumab, with any-grade reactions occurring in 25% of patients. Recommendations for the management of infusion-related reactions are summarized in Table 2. The National Comprehensive Cancer Network (NCCN) guidelines recommend that clinicians refer to each product’s prescribing information for premedication recommendations.9 Mild reactions are generally transient and do not require therapy interruption or any other interventions. Moderate reactions are generally managed by withholding the infusion or slowing down the rate of infusion per institutional guidelines. Treatment with antihistamines, acetaminophen, nonsteroidal anti-inflammatory drugs, narcotics, or intravenous (IV) fluids may be used but typically isn’t required for longer than a 24-hour period. Severe reactions require urgent management and permanent discontinuation of the ICI.

Immune-Related Adverse Events

Successful management of irAEs begins with toxicity recognition and grading. Some of the most common toxicities and their management are highlighted in (Table 3 - see PDF). Clinicians should refer to national or institution-specific clinical guidelines to determine when withholding immunotherapy may be an appropriate management option for irAEs. Early recognition of symptoms is crucial for prompt intervention and treatment; counseling of patients regarding symptom recognition is therefore important before initiation of ICI therapy. Immunosuppression with corticosteroids is the mainstay of therapy, except in the case of selected endocrine irAEs, which may be managed with hormonal supplementation.9

Dosing for systemic steroids such as prednisone or methylprednisolone depends on the toxicity grade or severity and can range between 0.5 and 2 mg/kg/day. Myocarditis is a rare but potentially severe adverse event of ICI therapy. Its symptoms are nonspecific, and management requires pulse-dose methylprednisolone administration at 1,000 mg IV daily for 3–5 days.9 Steroid therapy is generally administered until symptoms resolve to grade 1 or lower (unless otherwise specified), followed by a taper over a 4- to 6-week period. Important considerations with high-dose or prolonged steroid therapy include the following: hyperglycemia, opportunistic fungal or bacterial infections, osteoporosis, and gastritis. Additional immunosuppression may be required for severe irAEs not responding to initial corticosteroid therapy in 48–72 hours. Consultation with any appropriate and relevant medical specialist is recommended at this point.10

Tumor necrosis factor inhibitors such as infliximab can be used in steroid-refractory cases by means of targeting and inhibiting proinflammatory cytokines (IL-1 and IL-6).11 These agents are particularly effective for immune-mediated colitis and inflammatory arthritis. Duration of therapy is not well defined in the setting of irAEs but is typically a single dose. Vedolizumab is a monoclonal antibody that binds and inhibits the interaction of α4β7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1).

A multicenter study evaluating vedolizumab in 28 patients with steroid-refractory enterocolitis found favorable outcomes and yielded good safety data.12 Mycophenolic acid and mycophenolate mofetil (MMF) are immunosuppressive agents that decrease the proliferation of B and T cells, induce T-cell apoptosis, and suppress dendritic cells and IL-1. These agents have been used in steroid-refractory irAEs involving the liver, kidney, pancreas, and eyes.9,13 Intravenous immunoglobulin (IVIG), with its immunomodulatory mechanism, can be used to manage neurologic inflammatory or autoimmune conditions.9 Plasmapheresis or IVIG may be considered for severe or steroid-refractory neurological irAEs.14,15 Additional therapies cited in the NCCN guidelines include rituximab, tacrolimus, tocilizumab, cyclosporine, cyclophosphamide, methotrexate, and antirheumatic agents.9,16,17

Conclusion

The role of PD-1/PD-L1 inhibitors in the treatment of various cancers is rapidly expanding, and it is important for clinicians and patients to understand the unique toxicities associated with these therapies. Prompt symptom reporting and toxicity identification is imperative for appropriate toxicity management. To date, three clinical guidelines discuss the differences and similarities in the management of ICI toxicities: those of the National Comprehensive Cancer Network, the American Society of Clinical Oncology, and the European Society of Medical Oncology.2,9,15 Understanding the available guidelines and resources is an important step for institutions as they develop and practice site-specific protocols for the management of irAEs.

References

  1. Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med.2018;379:2220–2229.
  2. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol. 2017;28:iv119–iv142. Published correction appears in Ann Oncol. 2018;29:iv264-iv266
  3. Libtayo (cemiplimab-rwlc) [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals Inc.; 2019.
  4. Opdivo (nivolumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb Co.; 2019.
  5. Keytruda (pembrolizumab) [package insert]. Whitehouse Station, NJ: Merck Sharpe and Dohme Corp.; 2019.
  6. Tecentriq (atezolizumab) [package insert]. South San Francisco, CA: Genentech Inc.; 2019.
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  8. Imfinzi (durvalumab) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2018.
  9. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Management of Immunotherapy-Related Toxicities. Version 1.2020 (December 16, 2019). Available at www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed February 6, 2020.
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  13. Trinh S, Le A, Gowani S, La-Beck NM. Management of immune-related adverse events associated with immune checkpoint inhibitor therapy: a minireview of current clinical guidelines. Asia Pac J Oncol Nurs. 2019;6(2):154–160.
  14. Fellner A, Makranz C, Lotem M, et al. Neurologic complications of immune checkpoint inhibitors. J Neurooncol. 2018;137(3):601–609.
  15. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36:1714–1768.
  16. Stroud CR, Hegde A, Cherry C, et al. Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade. J Oncol Pharm Pract. 2019;25:551–557.
  17. Naidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26: 2375–2391. Published correction appears in Ann Oncol. 2016 Jul;27:1362.
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