Immune checkpoint inhibitors (ICPi) have revolutionized the treatment of many types of cancers. ICPis work by blocking pathways, called checkpoints, and these checkpoint pathways are mechanisms for the human immune system to control the immune response. The immune checkpoint proteins, cytotoxic T lymphocyte–associated 4 (CTLA-4) and programmed death 1 (PD-1), are receptors that are expressed on the surface of cytotoxic T cells that interact with their ligands—CD80/CD86 in the case of CTLA-4, and programmed death ligand-1 in the case of PD-1. These pathways can be co-opted to help cancer cells evade cytotoxic T cell–mediated death.1 ICPis prevent receptors and ligands from binding to each other, thereby disrupting signaling.1
Currently, there are several ICPis that have been approved by the US Food and Drug Administration. Ipilimumab, an anti–CTLA-4 antibody, was the first agent approved for use in patients with advanced melanoma.2 Pembrolizumab and nivolumab target PD-1 and have been approved for the treatment of melanoma, metastatic non–small-cell lung cancer, head and neck squamous cancers, urothelial carcinoma, gastric adenocarcinoma, and mismatch repair–deficient solid tumors as well as classical Hodgkin lymphoma.2 Nivolumab is also approved for use in hepatocellular carcinoma and patients with renal cell carcinoma. In addition, the combination of ipilimumab and nivolumab for patients with advanced melanoma has received US Food and Drug Administration approval.2 Most recently, the programmed death ligand-1 antibodies, atezolizumab (approved for use in urothelial cancers and non–small-cell lung cancer), durvalumab (approved for use in urothelial cancers), and avelumab (approved for use in Merkel cell carcinoma and urothelial carcinoma), have also been developed to block the PD-1 pathway. Indications for use continue to expand at a rapid pace. Development of novel ICPi agents and combinations continue to be evaluated for multiple indications; thus, this field is rapidly changing.
Despite the often-durable clinical benefits of immune checkpoint blockade therapy, its use is associated with a spectrum of adverse effects—related to the mechanism of action—that are quite different from other systemic therapies, such as cytotoxic chemotherapy. Adverse effects can affect multiple organs of the body and are most commonly observed in the skin, GI tract, lungs, and endocrine, thyroid, adrenal, pituitary, musculoskeletal, renal, nervous, hematologic, cardiovascular, and ocular systems, and there should be a high level of suspicion that any changes are treatment related. ICPi therapy can usually continue with close monitoring in the presence of mild immune-related adverse effects (irAEs); however, moderate-to-severe irAEs may be associated with severe declines in organ function and quality of life, and fatal outcomes have been reported. Hence, these toxicities require early detection and proper management. Use of ICPi in patients with preexisting autoimmune disease or history of prior organ transplantation requires an especially thoughtful discussion of the potential risks and benefits.
Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Practice Guideline
Guideline Question
How should clinicians manage irAE events in patients with cancer who are treated with ICPi therapy?
Target Population
Adult patients with cancer who receive treatment with immune checkpoint blockade inhibitors alone.
Target Audience
Health care practitioners, including oncologists, medical specialists, emergency medicine, family practitioners, nurses, and pharmacists who provide care to patients with cancer, as well as patients and their caregivers who receive ICPis.
Methods
An Expert Panel was convened to develop clinical practice guideline recommendations on the basis of a systematic review of the medical literature.
Key Recommendations
The following are general recommendations that should be followed irrespective of affected organs. For organ-specific management, please see Tables 1 to 10 in Brahmer et al3. Of note, definitions of grades are found in each table and, for the most part, follow the Common Terminology Criteria for Adverse Events (v5.0).4
It is recommended that clinicians manage toxicities as follows:
Patients and family caregivers should receive timely and up-to-date education about immunotherapies, their mechanism of action, and the clinical profile of possible irAEs before initiating therapy and throughout treatment and survivorship.
There should be high level of suspicion that new symptoms are treatment related.
In general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities.
Hold ICPis for most grade 2 toxicities and consider resuming when symptoms and/or laboratory values revert to grade ≤ 1. Corticosteroids at an initial dose of 0.5 to 1 mg/kg/d of prednisone or equivalent may be administered.
Hold ICPis for grade 3 toxicities and initiate high-dose corticosteroids—prednisone 1–2 mg/kg/d or methylprednisolone IV 1 to 2 mg/kg/d. Corticosteroids should be tapered over the course of at least 4 to 6 weeks. If symptoms do not improve with 48 to 72 hours of high-dose corticosteroid, infliximab may be offered for some toxicities.
When symptoms and/or laboratory values revert to grade ≤ 1, rechallenging with ICPis may be offered; however, caution is advised, especially in those patients with early-onset irAEs. Dose adjustments are not recommended.
In general, grade 4 toxicities warrant the permanent discontinuation of ICPis, with the exception of endocrinopathies that have been controlled by hormone replacement.
Additional Resources:
More information, including a Methodology Supplement, slide sets, and clinical tools and resources, is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki. Patient information is available at www.cancer.net.
All recommendations in this guideline are consensus based with benefits outweighing harms.
ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should have the opportunity to participate.
In recognition of an increasing need for guidance, ASCO and the National Comprehensive Cancer Network collaborated to develop guidelines for the management of irAEs. Organizational representation from the Society for Immunotherapy of Cancer, American Society of Hematology, the Oncology Nursing Society, and informal collaboration with the Friends of Cancer Research and the Parker Institute helped to ensure the coordination of efforts and a harmonization of recommended care options for this patient population. With increasing use of immunotherapy in cancer treatment regimens, it is imperative that clinicians are knowledgeable about the symptoms associated with these agents, their recommended management, and how best to monitor for them. Additional information is available at www.asco.org/supportive-care-guidelines. Patient information is available at www.cancer.net.
Copyright © 2018 by American Society of Clinical Oncology
Conception and design: Julie R. Brahmer
Collection and assembly of data: Julie R. Brahmer, John A. Thompson
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline Summary
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jop/site/ifc/journal-policies.html.
Julie R. Brahmer
Consulting or Advisory Role: Bristol-Myers Squibb, Eli Lilly, Celgene, Syndax, Janssen Oncology, Merck
Research Funding: Bristol-Myers Squibb (Inst), Merck (Inst), AstraZeneca (Inst), Incyte (Inst), Five Prime Therapeutics (Inst), Janssen Oncology (Inst)
Travel, Accommodations, Expenses: Bristol-Myers Squibb, Merck
Other Relationship: Bristol-Myers Squibb, Merck
Christina Lacchetti
No relationship to disclose
John A. Thompson
Consulting or Advisory Role: Seattle Genetics, Nektar, Celldex, Calithera Biosciences, Boehringer Ingelheim
Research Funding: Bristol-Myers Squibb (Inst), F Hoffman-La Roche (Inst), Seattle Genetics (Inst), Pfizer (Inst), Agensys (Inst), Five Prime Therapeutics (Inst), Corvus Pharmaceuticals (Inst), Trillium Therapeutics (Inst), Merck (Inst), Novartis (Inst)
Travel, Accommodations, Expenses: Boehringer Ingelheim
ACKNOWLEDGMENT
Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology and National Comprehensive Cancer Network Clinical Practice Guideline was developed and written by: Julie R. Brahmer, Christina Lacchetti, Bryan J. Schneider, Michael B. Atkins, Kelly J. Brassil, Jeffrey M. Caterino, Ian Chau, Marc S. Ernstoff, Jennifer M. Gardner, Pamela Ginex, Sigrun Hallmeyer, Jennifer Holter Chakrabarty, Natasha B. Leighl, Jennifer S. Mammen, David F. McDermott, Aung Naing, Loretta J. Nastoupil, Tanyanika Phillips, Laura D. Porter, Igor Puzanov, Cristina A. Reichner, Bianca D. Santomasso, Carole Seigel, Alexander Spira, Maria Suarez-Almazor, Yinghong Wang, Jeffrey S. Weber, Jedd D. Wolchok, and John A. Thompson.
| 1. | Dine J, Gordon R, Shames Y, et al: Immune checkpoint inhibitors: An innovation in immunotherapy for the treatment and management of patients with cancer. Asia Pac J Oncol Nurs 4:127-135, 2017 Crossref, Medline, Google Scholar |
| 2. | Postow M, Wolchok J: Toxicities associated with checkpoint inhibitor immunotherapy. https://www.uptodate.com/contents/toxicities-associated-with-checkpoint-inhibitor-immunotherapy Google Scholar |
| 3. | Brahmer JR, Lachetti 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 doi: 10.1200/JCO.2017.77.6385 Google Scholar |
| 4. | National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE) v5.0. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50 Google Scholar |
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