Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline

Abstract

Purpose To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) therapy. Methods A multidisciplinary, multi-organizational panel of experts in medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine, nursing, trialist, and advocacy was convened to develop the clinical practice guideline. Guideline development involved a systematic review of the literature and an informal consensus process. The systematic review focused on guidelines, systematic reviews and meta-analyses, randomized controlled trials, and case series published from 2000 through 2017. Results The systematic review identified 204 eligible publications. Much of the evidence consisted of systematic reviews of observational data, consensus guidelines, case series, and case reports. Due to the paucity of high-quality evidence on management of immune-related adverse events, recommendations are based on expert consensus. Recommendations Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert to grade 1 or less. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone 1 to 2 mg/kg/d). Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory cases may require infliximab or other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, with the exception of endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki .

Conflict of interest statement

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Disclosures provided by the authors are available with this article at jco.org.

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

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/jco/site/ifc.

Julie R. Brahmer

Consulting or Advisory Role: Bristol-Myers Squibb, Eli Lilly, Celgene, Syndax, Janssen Pharmaceuticals, Merck

Research Funding: Bristol-Myers Squibb (Inst), Merck (Inst), AstraZeneca (Inst), Incyte (Inst), Five Prime Therapeutics (Inst), Janssen Pharmaceuticals (Inst)

Travel, Accommodations, Expenses: Bristol-Myers Squibb, Merck

Other Relationship: Bristol-Myers Squibb, Merck

Christina Lacchetti

No relationship to disclose

Bryan J. Schneider

Consulting or Advisory Role: Genentech, Roche

Research Funding: MedImmune (Inst), Genentech (Inst), Roche (Inst), OncoMed (Inst), Bristol-Myers Squibb (Inst), Macrogenics (Inst)

Michael B. Atkins Honoraria: Bristol-Myers Squibb

Consulting or Advisory Role: Genentech, Pfizer, Novartis, X4 Pharma, Bristol-Myers Squibb, Nektar, Merck, Exelixis, Acceleron Pharma, Peleton, Eisai, Celldex, Alexion Pharmaceuticals, AstraZeneca, MedImmune, Glactone Pharma, Agenus, Idera, Argos Therapeutics, Array BioPharma, Boehringer Ingelheim, Aduro Biotech

Kelly J. Brassil

Research Funding: Genentech, Roche Jeffrey M. Caterino

Stock or Other Ownership: Motive Medical Intelligence

Research Funding: JD Pharmaceuticals, AstraZeneca

Ian Chau

Honoraria: Taiho Pharmaceutical, Pfizer, Eli Lilly, Amgen, Gilead Sciences

Consulting or Advisory Role: Sanofi, Eli Lilly, Bristol-Myers Squibb, MSD Oncology, Bayer AG, Roche, Genentech, Five Prime Therapeutics

Research Funding: Janssen-Cilag (Inst), Sanofi (Inst), Merck Serono (Inst), Eli Lilly (Inst)

Travel, Accommodations, Expenses: MSD, Merck Serono, Sanofi, Eli Lilly, Bristol-Myers Squibb

Marc S. Ernstoff

Stock or Other Ownership: GE Healthcare

Consulting or Advisory Role: Omniseq, Celyad, Lion Biotechnologies, Bristol-Myers Squibb, EMD Serono

Research Funding: Bristol-Myers Squibb (Inst), Merck (Inst), Alkermes (Inst), Merrimack (Inst)

Travel, Accommodations, Expenses: EMD Serono

Jennifer M. Gardner

No relationship to disclose

Pamela Ginex

Honoraria: Physician Education Resource

Consulting or Advisory Role: Genentech, Roche

Sigrun Hallmeyer

Employment: Oncology Specialists, Advocate Medical

Group Leadership: Oncology Specialists, Advocate Lutheran General Hospital

Honoraria: Bristol-Myers Squibb, Pfizer

Consulting or Advisory Role: Cardinal Health, Bristol-Myers Squibb, KBL Biologics

Speakers’ Bureau: Bristol-Myers Squibb, Pfizer

Research Funding: Russell Research Institute (Inst)

Travel, Accommodations, Expenses: Bristol-Myers Squibb, Cardinal Health

Jennifer Holter Chakrabarty

No relationship to disclose

Natasha B. Leighl

Research Funding: Novartis (Inst)

Travel, Accommodations, Expenses: AstraZeneca, Merck Sharp & Dohme, Bristol-Myers Squibb, Pfizer

Jennifer S. Mammen

Stock or Other Ownership: Johnson & Johnson, Bristol-Myers Squibb

David F. McDermott

Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Genentech, Roche, Pfizer, Exelixis, Novartis, X4 Pharma, Array BioPharma

Research Funding: Prometheus Laboratories (Inst)

Aung Naing

Consulting or Advisory Role: Novartis, CytomX Therapeutics

Research Funding: National Cancer Institute, EMD Serono, MedImmune, Healios, Atterocor, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron

Travel, Accommodations, Expenses: ARMO BioSciences

Loretta J. Nastoupil

Honoraria: Celgene, TG Therapeutics, Gilead Science, AbbVie, Pharmacyclics

Research Funding: TG Therapeutics, Janssen Pharmaceuticals, Celgene, AbbVie, Genentech, Roche, Karus Therapeutics

Tanyanika Phillips

No relationship to disclose

Laura D. Porter

No relationship to disclose

Igor Puzanov

Consulting or Advisory Role: Amgen, Roche, Genentech, Bristol-Myers Squibb

Travel, Accommodations, Expenses: Amgen, Merck

Cristina A. Reichner

No relationship to disclose

Bianca D. Santomasso

Honoraria: Juno Therapeutics, Kite Pharma

Consulting or Advisory Role: Juno Therapeutics, Kite Pharma, Incysus Travel, Accommodations, Expenses: Juno Therapeutics, Kite Pharma

Carole Seigel

No relationship to disclose

Alexander Spira

Honoraria: Novartis, Roche, Clovis Oncology, ARIAD Pharmaceuticals

Consulting or Advisory Role: Roche, Genentech, ARIAD Pharmaceuticals, Clovis Oncology

Research Funding: Roche (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Astellas Pharma (Inst), Clovis Oncology (Inst), MedImmune (Inst), Novartis (Inst), Newlink Genetics (Inst), Incyte (Inst), AbbVie (Inst), BeiGene (Inst), Merck KgaA (Inst), Merck (Inst), Merrimack (Inst), CytomX Therapeutics (Inst)

Travel, Accommodations, Expenses: Roche, ARIAD Pharmaceuticals

Maria E. Suarez-Almazor

Consulting or Advisory Role: Bristol-Myers Squibb, Endo Pharmaceuticals, Pfizer, Eli Lilly

Research Funding: Pfizer

Yinghong Wang

No relationship to disclose

Jeffrey S. Weber

Stock or Other Ownership: Altor BioScience, Celldex, CytomX Therapeutics

Honoraria: Bristol-Myers Squibb, Merck, Genentech, AbbVie, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Eisai, Alto BioScience, Lion Biotechnologies, Amgen, Roche, Ichor Medical Systems, Celldex, cCam Biotherapeutics, Pieris Pharmaceuticals, CytomX Therapeutics, Nektar, Novartis, Medivation, Sellas Life Sciences, WindMIL

Consulting or Advisory Role: Celldex, Ichor Medical Systems, cCam Biotherapeutics, Lion Biotechnologies, Pieris Pharmaceuticals, Altor BioScience, Bristol-Myers Squibb, Merck, Genentech, Roche, Amgen, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, AbbVie, Eisai, CytomX Therapeutics, Nektar, Medivation, Sellas Life Sciences, WindMIL

Research Funding: Bristol-Myers Squibb (Inst), Merck (Inst), GlaxoSmithKline (Inst), Genentech (Inst), Astellas Pharma (Inst), Incyte (Inst), Roche (Inst), Novartis (Inst)

Patents, Royalties, Other Intellectual Property: Named on a patent submitted by Moffitt Cancer Center for an ipilimumab biomarker, named on a patent from Biodesix for a PD-1 antibody biomarker

Travel, Accommodations, Expenses: Bristol-Myers Squibb, GlaxoSmithKline, Daiichi Sankyo, Pieris Pharmaceuticals, cCam Biotherapeutics, Lion Biotechnologies, Roche, Celldex, Amgen, Merck, AstraZeneca, Genentech, Novartis

Jedd D. Wolchok

Stock or Other Ownership: Potenza Therapeutics, Tizona Therapeutics, Serametrix, Adaptive Biotechnologies, Trieza Therapeutics, BeiGene

Honoraria: Regeneron

Consulting or Advisory Role: Bristol-Myers Squibb, Merck, MedImmune, Polynoma, Polaris, Genentech, BeiGene, Sellas Life Sciences, Eli Lilly, Potenza Therapeutics, Tizona Therapeutics, Amgen, Chugai Pharmaceuticals, Ono Pharmaceuticals, Ascentage Pharma

Research Funding: Bristol-Myers Squibb (Inst), Merck (Inst), Genentech (Inst), Roche (Inst)

Patents, Royalties, Other Intellectual Property: Co-inventor on an issued patent for DNA vaccines for treatment of cancer in companion animals, co-inventor on a patent for use of oncolytic Newcastle Disease virus

Travel, Accommodations, Expenses: Bristol-Myers Squibb, Chugai Pharmaceuticals, Roche, Janssen Pharmaceuticals

John A. Thompson

Consulting or Advisory Role: Seattle Genetics, Nektar, Celldex, Calithera Biosciences, Boehringer Ingelheim

Research Funding: Bristol-Myers Squibb (Inst), 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

Figures

Fig A1.

Distribution of (A) grade 1 to 2 and (B) grade 3 to 5 immune-related adverse events (irAEs) for all tumor types in the main clinical trials with anti- cytotoxic T-cell lymphocyte-4 (anti–CTLA-4), anti-programmed death 1 (PD-1), or anti–PD ligand 1 (PD-L1) antibodies as single therapies. The values quoted are the median (range) irAE rates for the set of clinical trials as a whole. Adapted from European Journal of Cancer, Vol 54, J.M. Michot et al, Immune-Related Adverse Events With Immune Checkpoint Blockade: A Comprehensive Review, 139–149, Copyright 2016, with permission from Elsevier. Endoc, endocrinology; Neurol, neurology; ocul, ocular; Pulm, pulmonary.

Fig 1.

Example of an immunotherapy wallet card. Reprinted courtesy of the Oncology Nursing Society. All rights reserved.