（2026.V1）NCCN临床实践指南：免疫检查点抑制剂相关毒性的管理

指南肿瘤内科· 肿瘤治疗与综合管理 · 2026

NCCN

Ajibola Awiwoton, MBBS, MSc Lisa Hang, PhD

λ Cardio-oncology

![](1013,964,1029,988) Dermatology

Nursing

Ophthalmology

Endocrinology

Nursing

Gastroenterology

![](1275,1007,1302,1032) Ophthalmology

‡ Hematology/Hematology

∑ Pharmacology

P Internal medicine

E Pulmonary medicine

+ Medical oncology

& Rheumatology

Nephrology

* Discussion Section

Writing Committee

NCCN issued to MEDIVETELE NCCN Guidelines Version 1:2026

NCCN Guidelines Index Table of Contents Discussion

Concomprehensive TACER Network®

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Management of Immune Checkpoint Inhibitor-Related Toxicities

Panel Members

Summary of the Guidelines Updates

●Hematologic Toxicity

Immune Checkpoint Inhibitor-Related Toxicities

●Principles of Routine Monitoring(IMMUNO-1)

Unexplained Drop in Hemoglobin (ICI HEM-1)

●Conditions - Signs and Symptoms (IMMUNO-3)

Hemolytic Anemia (ICI HEM-2)

●Infusion-Related Reactions (ICI INF-1)

Aplastic Anemia (ICI HEM-3)

●Cardiovascular Toxicity

HLH-Like Syndrome (ICI_HEM-4)

Suspected Myocarditis/Pericarditis/Large Vessel Vasculitis (ICI_CARDIO-1)

Thrombocytopenia (ICI_HEM-5)

● Musculoskeletal Toxicity

● Dermatologic Toxicity

Maculopapular Rash (ICI DERM-1)

Pruritus (ICI,DERM-2)

Inflammatory Arthritis (ICI_MS-1)

Polymyalgia Rheumatica/Giant Cell Arteritis(ICI_MS-2)

Blistering Disorders (ICI_DERM-3)

Lichen Planus and Lichenoid Diseases (ICI DERM-4)

Psoriasis/Psoriasisform Diseases(ICI DERM-5)

Oral Mucosa Inflammation(ICI DERM-6)

● Nervous System Toxicity

Myasthenia Gravis/Myasthenia Gravis-Like Syndrome (ICI NEURO-1)

Sicca Syndrome/Oral Dyshesthesia (ICI_LERM-7)

Guillain-Barré Syndrome (ICI_NEURO-2)

●Endocrine Toxicity

Peripheral Neuropathy(ICI_NEURO-3)

Hyperglycemia/Diabetes Mellitus(ICI ENDO-1)

Hypothyroidism/Thyrtoxicosis (ICI ENDO-2)

Aseptic Meningitis (ICI NEURO-4)

Hypophysitis (ICI (16NDO-3)

Encephalitis (ICI NEURO-4)

●Fatigue(ICl FTG-1)

Demyelinating Disease (ICI NEURO-5)

● Gastrointestinal Toxicity

●Ocular Toxicity (ICI OCUL-1)

Upper Gastrointestinal Toxicity (ICI G1-1)

●Pulmonary Toxicity(ICI_PULM-1)

Diarrhea/Colitis (ICI GI-2)

●Renal Toxicity(ICI-RENAL-1)

Hepatobiliary Toxicities (ICI GI-5)

●Principles of Immunosuppression(IMMUNO-A)

Elevation in Lipase (ICI Gl-8)

●Principles of Immunotherapy Patient Education

Acute Pancreatitis (ICI Gl-9)

(IMMUNO-B)

●Principles of Immunotherapy Rechallenge

(IMMUNO-C)

Find an NCCN Member Institution:https://www.nccn.org/home/member-institutions.

NCCN Categories of Evidence and Consensus: All recommendations are category 2A unless otherwise indicated.

See NCCN Categories of Evidence and Consensus.

· Abbreviations(ABBR-1)

The NCCN Guidelines are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.©2025.

NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

Version 1.2026, 10/23/2025 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index Table of Contents Discussion

UPDATES Updates in Version 1.2026 of the NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities from Version 1.2025 of

the NCCN Guidelines for the Management of Immunotherapy-Related Toxicities include:Global Changes

• Guideline name changed from NCCN Guidelines for the Management of Immunotherapy-Related Toxicities to NCCN Guidelines for Management of

Immune Checkpoint Inhibitor-Related Toxicities

• Guideline content on CAR-T and Lymphocyte-engagers now published in a separate Guideline: NCCN Guidelines for the Management of CAR T-Cell and Lymphocyte Engager-Related Toxicities

• References updated throughout the Guidelines.

• Myasthenia gravis changed to 'myasthenia gravis/myasthenia gravis-like syndrome' throughout the Guidelines.

• IVIG content modified to 'IVIG 2 g/kg divided in equal doses given over 2–5 consecutive days. Refer to the FDA-approved package insert for important safety information' throughout the Guidelines.

Principles of Routine Monitoring for Immune Checkpoint Inhibitors IMMUNO-2

• Fertility section added

Conditions-Signs and Symptoms IMMUNO-3

• ENDO Overt hypothyroidism modified: Fatigue, lethargy, sensation of being cold, possible constipation, bradycardia. Patient may be asymptomatic or exhibit minimal symptoms

IMMUNO-4

• MUSCULO: Polymyalgia rheumatica (PMR) modified: PMR symptoms: stiffness with inactivity, fatigue and/or muscle and joint pain typically in shoulders and hips

IMMUNO-5

• OCULAR: Vision changes modified: Blurred/distorted vision, new floaters, itchy eyes, blind spots, change in color vision, diplopia, photophobia, tenderness/pain, eyelid swelling, and proptosis. Scleritis can cause a reddish purple discoloration of the eye. Uveitis can be associated with eye redness.

Infusion-Related Reactions ICI_INF-1

• Management

Mild transient reaction (G1), 3rd bullet modified: Consider premedication with acetaminophen, H2 blockers, and antihistamines (H1 and H2)

diphenhydramine with future infusions (Also Moderate [G2])

Dermatologic Toxicity ICI_DERM-1

• Maculopapular rash

Management

◊ Severe, 3rd bullet modified: Prednisone/IV methylprednisolone 0.5–1 mg/kg/day (increase dose up to 2 mg/kg/day if no improvement)

Continued

PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.

NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

UPDATES Updates in Version 1.2026 of the NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities from Version 1.2025 of

the NCCN Guidelines for the Management of Immunotherapy-Related Toxicities include:ICI_DERM-2

• Pruritus

Assessment/Grading

◊ 2nd bullet added: Consider testing for sources of pruritus including bullous pemphigoid antibodies, BUN/creatinine, hepatic function tests, thyroid function tests, and bile acids

Management

◊ Moderate (G2) combined with Severe (G3)

• Footnote n added: Including topical products that have the following active ingredients: hydrocortisone 0.5% or 1%, diphenhydramine, pramoxine,

camphor, menthol.

ICI_DERM-3

• Bullous dermatitis

Management, Severe (G3) OR Life-threatening (G4)

◊ 3rd bullet added: If bullous pemphigoid confirmed, dupilumab is recommended as a steroid-sparing measure

◊ 4th bullet modified: Consider alternative steroid-sparing options such as IVIG (1 g/kg/day x 2 days with monthly cycle until clear) as an adjunct to rituximab or dupilumab

• Stevens-Johnson syndrome (SJS) or Toxic epidermal necrolysis (TEN)

Management

◊ 1st bullet modified: Permanently Discontinue immunotherapy

◊ 2nd bullet added: Evaluate entire medication list for alternative culprit drug such as an antibiotic or anticonvulsant

◊ 5th bullet modified: Consider IVIG (1 g/kg/day in divided doses per package insert for 3–4 days)

ICI_DERM-4

• Lichen planus and lichenoid diseases

Management

◊ Moderate: 10%–30% BSA or not responsive to high-potency topical steroids

– 5th bullet added: Consider referral to dermatology

◊ Severe: >30% BSA

– 4th bullet, 4th sub bullet added: Dupilumab

– Bullet removed: Doxycycline and nicotinamide

ICI_DERM-5

• Psoriasis and psoriasiform diseases

Management

◊ Mild: <10% BSA

– 3rd bullet added: Consider transitioning to non-steroidal topical therapies such as tacrolimus 0.1% or calcipotriene 0.005% for long-term

management in intertriginous areas or facial locations (Also Moderate and Severe)

– Bullet removed: Topical vitamin D analogues (Also Moderate and Severe)

Continued

PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.

NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

UPDATES Updates in Version 1.2026 of the NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities from Version 1.2025 of

the NCCN Guidelines for the Management of Immunotherapy-Related Toxicities include:ICI_DERM-6

• Oral mucosa inflammation

Management, General, 1st bullet modified: Dietary modifications, nutritional evaluation and supplementation

Endocrine Toxicity ICI_ENDO-1

• Hyperglycemia

Diagnosis/Workup

◊ 4th bullet added: If fatigue or other endocrine irAEs, evaluate for hypophysitis/adrenal insufficiency (see ICI_ENDO-3)

ICI_ENDO-2

• Thyrotoxicosis recommendations moved here from ICI_ENDO-3

ICI_ENDO-3A

• Footnote t added: For pre-operative patients who had neoadjuvant therapy and cortisol status is unknown, consider a random cortisol. If less than 2 mcg/dL, treat. If between 2 mcg/dL and 5 mcg/dL, treat and refer to endocrinology.

• Footnote u added: In patients who have had chronic steroid exposure from their regimen or have questionable cortisol levels, send for cosyntropin stimulation in the outpatient setting.

Fatigue

ICI_FTG-1

• This page was revised extensively.

Gastrointestinal Toxicity ICI_GI-1

• Footnote c added: 10-20% of patients will have normal endoscopic evaluation but positive biopsies for ICI gastritis. Haryal A, et al. Cancer 2023;129:367-375.

ICI_GI-2

• Diarrhea/Colitis, Mild (G1)

Assessment/Grading, 2nd bullet modified: Based on institutional availability, Consider Fecal calprotectin ± lactoferrin/calprotectin (Also ICI_GI-3, ICI_

GI-4)

Management, 6th bullet, 2nd sub bullet modified: If negative and no infection, continue G1 management and consider adding mesalamine and/or

cholestyramine as needed

ICI_GI-3

• Diarrhea/Colitis, Moderate (G2)

Management

◊ 4th bullet, 1st sub bullet modified: If colonoscopy or flexible sigmoidoscopy shows significant ulceration, or extensive non-ulcerative inflammation, or microscopic colitis on histology, consider adding infliximab or vedolizumab (Also ICI_GI-4)

◊ 6th bullet added: For immunosuppressant-refractory colitis, fecal transplantation may be considered based on institutional availability and expertise (Also ICI_GI-4)

Continued

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NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

UPDATES Updates in Version 1.2026 of the NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities from Version 1.2025 of

the NCCN Guidelines for the Management of Immunotherapy-Related Toxicities include:ICI_GI-4

• Diarrhea/Colitis, Severe (G3-4)

Footnote removed: Fecal transplantation may be considered for immunosuppressant-refractory colitis based on institutional availability and expertise.

ICI_GI-5

• Footnote ff added: Prednisone with maximum dose of 60 mg/day has been shown to be effective in autoimmune hepatitis. Mack CL, et al. Hepatology 2020;72:671-722. (Also ICI_GI-6A)

ICI_GI-6

• Elevated ALT/AST

Management

◊ General (G3 or G4), 1st bullet modified: Monitor PT/INR weekly or more often if clinically indicated based on liver tests and patient condition

periodically

◊ G3

– 2nd bullet modified: Initiate prednisone/IV methylprednisolone 0.5-1 mg/kg/day (Also G4)

▪ 1st sub bullet modified: If no improvement after 1–2 days, consider adding mycophenolate mofetil or tacrolimus (Also G4)

▪ 1st sub sub bullet modified: If refractory to mycophenolate mofetil or tacrolimus, consider tocilizumab or other steroid-sparing

immunosuppressive therapy (Also G4)

ICI_GI-6A

• Footnote jj modified: Other steroid-sparing immunosuppressive therapy may include ATG, or azathioprine, tacrolimus, or tocilizumab. Response to

these agents may be delayed and may require prolonged therapy (≥1 week) in the treatment of irAEs.

• Footnote ll added: A total bilirubin >2.5 mg/dL plus international normalized ratio (INR) >1.5, ascites, or encephalopathy. Hountondji L et al. Aliment

Pharmacol Ther 2024;60:1561–1572.

ICI_GI-7

• Elevated alkaline phosphatase

Management

◊ G2

– 2nd bullet modified: Initiate Start prednisone 0.5–1 mg/kg/day

– 3rd bullet modified: Consider Ursodiol 13–15 mg/kg/day

◊ G3/G4

– 2nd bullet modified: Monitor PT/INR if there is a high suspicion for elevated bilirubin/AST/ALT

– 4th bullet added: Ursodiol 13–15 mg/kg/day

– Bullet removed: Consider Ursodiol 13–15 mg/kg/day

Continued

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NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

UPDATES Updates in Version 1.2026 of the NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities from Version 1.2025 of

the NCCN Guidelines for the Management of Immunotherapy-Related Toxicities include:ICI_GI-7A

• Footnote rr modified: Ursodiol is available in capsules (200 mg, 300 mg, 400 mg) and tablets (250 mg, 500 mg) as 150 mg and 300 mg capsules and can be administered as a single daily dose. Split dosing (BID or TID) with food should can be considered to enhance absorption and minimize GI side effects if patient experiences side effects such as diarrhea.

• Footnote ss modified: Other steroid-sparing immunosuppressive therapy may include ATG, azathioprine, tacrolimus, or tocilizumab. Response to these agents may be delayed and may require prolonged therapy (≥1 week) in the treatment of irAEs.

ICI_GI-8

• 1st column modified: Elevation in amylase/lipase (asymptomatic)

Assessment/Grading

◊ Mild modified: Mild ≤3 x ULN amylase and/or ≤3 x ULN lipase

◊ Moderate or Severe modified: Moderate >3–5 x ULN amylase and/or >3–5 x ULN lipase or Severe >5 x ULN amylase and/or >5 x ULN lipase

Management

◊ Mild, 3rd bullet modified: Consider other causes for elevated amylase/lipase

◊ Moderate or Severe

– 2nd bullet, 2nd sub bullet modified: If persistent moderate to severe amylase and/or lipase elevation, abdominal CT with contrast or MRCP

– 3rd bullet modified: Consider other causes for elevated amylase/lipase

• Footnote vv modified: Routine amylase/lipase assessments do not have to be performed outside of clinical suspicion of possible pancreatitis. See

Principles of Routine Monitoring for Immune Checkpoint Inhibitors (IMMUNO-1).

ICI_GI-9

• Acute pancreatitis

Assessment/Grading

◊ 5th bullet added: Assess for IgG4; If positive, manage as autoimmune pancreatitis

Management

◊ Mild (G2), 4th bullet modified: Manage as per elevation in amylase/lipase (asymptomatic) (ICI_GI-8)

◊ Moderate (G3), Bullet removed: Consider prednisone/IV methylprednisolone 0.5–1 mg/kg/day only if no improvement with hydration and pain

control (Also Severe [G4])

◊ Severe (G4), 2nd bullet added: Inpatient care

• Footnote yy modified: Asymptomatic amylase/lipase elevation OR radiologic features on CT or clinical findings concerning for pancreatitis. The

decision to hold immunotherapy is based on clinical suspicion. If amylase/lipase >3 x ULN or CT findings are prominent, holding immunotherapy is

recommended.

• Footnote zz modified: Symptomatic pain or vomiting AND any amylase/lipase elevation or CT findings suggesting pancreatitis.

• Footnotes removed:

The data supporting the use of steroids for the treatment of pancreatitis are limited.

Treat until symptoms improve to grade ≤1, then taper over 4–6 weeks.

Continued

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NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

UPDATES Updates in Version 1.2026 of the NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities from Version 1.2025 of

the NCCN Guidelines for the Management of Immunotherapy-Related Toxicities include:Hematologic Toxicity

ICI_HEM-1

• 1st column modified: Unexplained drop in hemoglobin (Hb) and/or platelets in the absence of bleeding source

• Assessment

1st bullet modified: Evaluate for common causes of anemia such as bleeding (e.g. fecal occult blood test) and iron, B12, and folate deficiencies Rule

out non-ICI–related causes (eg, other medications)

5th bullet modified: Direct antiglobulin test (DAT) and cold agglutinin study if immune hemolysis is suspected

Bullet removed: Direct antiglobulin test (DAT)

• Footnote e modified: Findings may overlap with the traditional HLH diagnostic criteria (ie, HLH2004/HLH1994). Clinical findings may include:

unexplained fever and hepatosplenomegaly sequelae of low counts, hypofibrinogenemia, elevated ferritin (≥500 ng/mL), and transaminitis. Laboratory findings may include: low counts, hypofibrinogenemia, elevated ferritin (≥500 ng/mL), elevated soluble IL-2 receptor levels (based on CD25), absent/low natural killer (NK) cell activity according to local laboratory reference, and hypertriglyceridemia and transaminitis. Histopathologic findings include: accumulation of lymphocytes/macrophages and hemophagocytosis; these may be identified via tissue biopsy, such as bone marrow, liver, or other

tissues with suspected involvement (Henter JI, et al. Pediatr Blood Cancer 2007;48:124-131). (Also ICI_HEM-4)

ICI_HEM-2

• Hemolytic anemia

Assessment

◊ 3rd bullet added: Evaluate for and rule out other non-ICI– related etiologies of hemolytic anemia

◊ 1st sub bullet added: Examples include viruses, bacteria, use of certain drugs [examples include dapsone], methemoglobinemia, bone marrow

failure syndrome, or insect or reptile bites

◊ Bullet removed: Glucose-6-phosphate dehydrogenase (G6PD)

Management, Grade 4: Hemolysis and life-threatening consequences requiring urgent intervention

◊ 5th bullet, 1st sub bullet modified: If no response to steroids and rituximab, consider IVIG, tacrolimus, cyclophosphamide, mycophenolate mofetil, or cyclosporine, ATG, or infliximab

ICI_HEM-2A

• Footnote removed: Hemolytic anemia can have non-ICI–related causes such as viruses or bacteria, insect or reptile bites, use of certain drugs (eg, dapsone), methemoglobinemia, or bone marrow failure syndrome.

ICI_HEM-3

• Aplastic anemia

Assessment, 4th bullet added: Evaluate for and rule out other non-ICI–related etiologies of aplastic anemia

◊ 1st sub bullet added: Examples include radiation exposure, certain toxins, viruses, infections, or prior treatments

Management, Severe or Very severe

◊ 4th bullet, 1st sub bullet modified: Consider IVIG, cyclosporine, ATG, mycophenolate mofetil, and or tacrolimus

• Footnote removed: Aplastic anemia can have other causes such as radiation exposure, certain toxins, viruses, infections, or prior treatments.

Continued

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NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

UPDATES Updates in Version 1.2026 of the NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities from Version 1.2025 of

the NCCN Guidelines for the Management of Immunotherapy-Related Toxicities include:ICI_HEM-4

• HLH-like syndrome

Assessment, 4th bullet added: Consider natural killer (NK) cell activity assessment per institutional guidelines

ICI_HEM-5

• Thrombocytopenia

Assessment

◊ 4th bullet added: PT/INR, partial thromboplastin time (PTT), fibrinogen

◊ Bullet removed: DAT

◊ 5th bullet added: Abdominal ultrasound

◊ 8th bullet modified: Evaluate for and rule out other non-ICI–related etiologies of thrombocytopenia

– 1st sub bullet modified: Examples include medication-related causes, infection, thrombotic thrombocytopenic purpura (TTP), hemolytic uremic

syndrome (HUS), and HLH

Musculoskeletal Toxicity

ICI_MS-1

• Inflammatory arthritis

Assessment/Grading

◊ 4th bullet modified: Consider joint ultrasound, or joint MRI with or without contrast if diagnosis of synovitis is unclear

Management

◊ Moderate, 3rd bullet, 2nd sub bullet: If unable to taper prednisone from 30 mg/day after 1 week, consider initiating csDMARD, tumor necrosis factor (TNF) inhibitors, IL-6 inhibitors (tocilizumab or sarilumab), or tumor necrosis factor (TNF) inhibitors

◊ Severe, 3rd bullet, 1st sub bullet: If unable to taper after 1 week, consider initiating csDMARD, TNF inhibitors, or IL-6 inhibitors (tocilizumab or

sarilumab) or TNF inhibitors

5th column modified: Monitor with serial rheumatologic examinations ± ESR, CRP every 4–8 6 weeks after treatment

ICI_MS-1A

• Footnote b added: ICI IA can be seen with PMR-like manifestations.

• Footnote r added: In inflammatory arthropathies that have symptoms suggestive of psoriatic arthritis or spondyloarthropathies, consider agents that are approved for these indications such as apremilast, IL-17, IL-12, or IL-23 inhibitors.

ICI_MS-2

• Page moved from ICI_MS-3

• Footnote v added: ICI PMR can be seen with peripheral arthritis.

Continued

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NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

UPDATES Updates in Version 1.2026 of the NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities from Version 1.2025 of

the NCCN Guidelines for the Management of Immunotherapy-Related Toxicities include:ICI_MS-3

• 1st column modified: Myositis (proximal muscle weakness, neck flexor weakness, dysphagia, with or without myalgias)

• Management

Severe or Life-threatening

◊ 1st bullet modified: Hold immunotherapy; consider permanent discontinuation in discontinuing for select patients

◊ 4th bullet modified: Consider IV methylprednisolone 500 mg to 1 g/day x 3 days followed by prednisone 1 mg/kg/day. After 4 weeks, taper

prednisone by 10 mg/month every two weeks to 0.5 mg/kg/day and then 10 mg/month as clinical status allows.

◊ 5th bullet modified: If significant dysphagia, life-threatening situations, or refractory to steroids with minimal improvement after 1 week, consider IVIG (2 g/kg administered in divided doses per package insert), methotrexate, mycophenolate mofetil, or rituximab for significant dysphagia, lifethreatening situations, or cases refractory to steroids

ICI_MS-3A

• Footnote aa added: Myocarditis symptoms are nonspecific (eg, chest pain, dyspnea, fatigue, palpitations [arrhythmia: heart block or ventricular ectopic beats], syncope, generalized weakness) and may occur as early as days to weeks after 1–2 doses of ICI. Although rare, myocarditis is often severe and associated with myositis/myasthenia gravis/myasthenia gravis-like syndrome (3 M’s), and more common with combination therapy. In most fatal cases, conduction abnormalities were the cause of death, and ejection fraction was preserved.

• Footnote ll added: Methotrexate 15-25 mg weekly by oral or subcutaneous route.

Nervous System Toxicity ICI_NEURO-1

• Myasthenia gravis/myasthenia gravis-like syndrome

Assessment/Grading

◊ 1st bullet: Evaluate for concomitant irAEs myocarditis (ICI_CARDIO-1) and myositis (ICI_MS-3) as myasthenia gravis/myasthenia gravis-like

syndrome can exist as an overlap syndrome, moved here from 4th bullet

Management

◊ Moderate (G2)

– 4th bullet modified: Pyridostigmine 30 mg 3 times a day TID and gradually increase to maximum of 120 mg orally 4 times a day as tolerated and based on symptoms

• Footnote b added: Myocarditis symptoms are nonspecific (eg, chest pain, dyspnea, fatigue, palpitations [arrhythmia: heart block or ventricular ectopic

beats], syncope, generalized weakness) and may occur as early as days to weeks after 1–2 doses of ICI. Although rare, myocarditis is often severe and associated with myositis/myasthenia gravis/myasthenia gravis-like syndrome (3 M’s), and more common with combination therapy. In most fatal cases, conduction abnormalities were the cause of death, and ejection fraction was preserved.

ICI_NEURO-4

• Encephalitis

Assessment

◊ 5th bullet modified: Electroencephalogram (EEG) to evaluate for non-convulsive subclinical seizure

ICI_NEURO-5

• Demyelinating Disease

Management

◊ 5th bullet added: For management of optic neuritis, see ICI_OCUL-3

Continued

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NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

UPDATES Updates in Version 1.2026 of the NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities from Version 1.2025 of

the NCCN Guidelines for the Management of Immunotherapy-Related Toxicities include:Ocular Toxicity

• This section has been extensively revised and expanded.

Pulmonary Toxicity ICI_PULM-1

• Moderate (G2) pneumonitis

4th bullet, 1st sub bullet: Consider early bronchoscopy with BAL (send for institutional immunocompromised panel) and consider transbronchial lung

biopsy if clinically feasible to evaluate for rule out progressive malignancy, fungal infections, or steroid responsive interstitial lung disease (ILD)

6th bullet, 1st sub bullet: Consider mycophenolate mofetil as a steroid-sparing immunosuppressant for steroid-dependent recurrent pneumonitis at the

time of steroid tapering

ICI_PULM-2

• Severe (G3–4) pneumonitis

1st bullet modified: Discontinue Hold immunotherapy

◊ 8th bullet

– 1st sub bullet, 2nd sub sub bullet: Tocilizumab, moved here from Other Recommended

– 2nd sub bullet, 1st sub sub bullet: Mycophenolate mofetil 1–1.5 g BID then taper in consultation with pulmonary service, moved here from

Preferred

▪ 1st sub sub sub bullet added: Consider mycophenolate mofetil as a steroid-sparing immunosuppressant for steroid-dependent pneumonitis at the time of steroid tapering

ICI_PULM-2A

• Footnote j modified: Viral pathogen assessment should include influenza, COVID-19, and respiratory syncytial virus (RSV).

Principles Of Immunosuppression For Patients Receiving Immune Checkpoint Inhibitor Immunotherapy

IMMUNO-A 1 OF 3

• Principles of Steroid Use in the Management of irAEs

5th bullet, 2nd sub bullet added: Patients who are initiated on longer steroid tapers should have close follow-up with oncologist or co-managing

disease-specific subspecialist team to monitor for side effects of steroid use, and to evaluate any need for modifying immunosuppressant regimen as

appropriate based on clinical improvement of irAE.

IMMUNO-A 3 OF 3

• Header modified: Principles of Immune Checkpoint Blockade in Patients with Pre-Existing Autoimmune/Viral Conditions or Organ Transplant Recipients

• 1st bullet modified: Patients with a history of HIV or viral hepatitis may be candidates for immunotherapy. See the NCCN Guidelines for Cancer in

People with HIV.

Continued

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NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

UPDATES Updates in Version 1.2026 of the NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities from Version 1.2025 of

the NCCN Guidelines for the Management of Immunotherapy-Related Toxicities include:Principles Of Immunotherapy Patient Education

IMMUNO-B 2 OF 3

• Health Care Provider (HCP) Information

Toxicity Management

◊ Severe AEs, 5th bullet added: Ensure appropriately timed follow-up visits with oncologist or co-managing disease-specific subspecialist team for patients who required hospitalization for severe AEs. Close monitoring is encouraged as these patients are likely to have been started on new medications such as immunosuppressive agents and hormone replacement therapy that may require further adjustment or re-evaluation after

hospitalization.

Principles Of Immunotherapy Rechallenge IMMUNO-C 1 OF 3

• Organ-Specific Considerations for Immunotherapy Rechallenge After a Hold

Eye:

◊ 1st bullet modified: Grade 2–4 irAE: Hold immunotherapy per guideline; consider resumption of immunotherapy in consultation with ophthalmology on resolution to ≤ grade 1.

IMMUNO-C 2 OF 3

• Organ-Specific Considerations for Immunotherapy Rechallenge After a Hold

Lung:

◊ 2nd bullet modified: Grade 2/3: Consider resuming Resume once pneumonitis has resolved to ≤ grade 1 and patient is off steroids. Resume once pneumonitis has resolved to ≤ grade 1 and patient is on a steroid dose of ≤10 mg/day of prednisone.

Musculoskeletal:

◊ 2nd bullet modified: Severe or life-threatening myositis (with or without myocarditis): Consider permanent discontinuation in select patients is

recommended due to high risk of morbidity/mortality.

IMMUNO-C 3 OF 3

• Organ-Specific Considerations for Immunotherapy Rechallenge After a Hold

Pancreas:

◊ 1st bullet modified: Symptomatic grade ≤3 pancreatitis: Consider resumption of immunotherapy if no clinical/radiologic evidence of pancreatitis ± improvement in amylase/lipase. Consider consultation with relevant pancreatic specialist regarding resumption.

◊ 2nd bullet modified: Permanent discontinuation is warranted for severe (grade 4) pancreatitis and other related complications (eg. abscess, fistula)Skin:

◊ 2nd bullet modified: Permanent Discontinuation of immunotherapy in the setting of severe or life-threatening bullous disease (grade 3–4), including all cases of SJS and TEN.

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Comprehensive Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index

Table of Contents Discussion

PRINCIPLES OF ROUTINE MONITORING FOR IMMUNE CHECKPOINT INHIBITORS

|Pre-Therapy Assessment|Monitoring Frequencyb|Evaluation for Abnormal Findings/Symptoms| |---|---|---| |Clinical ●Physical examination ●Patient and relevant family history of any autoimmune/ frequency/consistency) organ-specific disease,indocrinopathy, or infectious disease (ID)|Clinical examination at each visit frequency/consistency) ID screening(human immunodeficiency virus [HIV]; hepatitis A,B, C) as indicated|Follow-up testing based on findings, symptoms| |Imaging ●Cross-sectional imaging ●Brain MRI if indicated|Periodic imaging as indicated|Follow-up testing as indicated based on imaging findings| |General blood work ●Complete blood count (CBC) (with differential if indicated) ●Comprehensive metabolic panel (CMP)|Repeat prior to each treatment or every 4 weeks during immunotherapy, then in 6-12 weeks or as indicated|HbA1c for elevated glucose| |Dermatologic (ICI_DERM-1) ●Examination of skin and mucosa if history of immune-related skin disorder|Conduct/repeat as needed based on symptoms|Consider dermatology referral. Monitor affected skin and lesion type; photographic documentation. Skin biopsy if indicated.| |Pancreatic (ICI_ENDO-1) ●Baseline testing is not required|No routine monitoring needed if asymptomatic|Amylase, lipase, and consider abdominal CT with contrast or MRCP for suspected pancreatitis| |Thyroid (ICI_ENDO-2) ●Thyroid-stimulating hormone (TSH), free thyroxine (FT4)|Every 4-6 weeks during immunotherapy, then follow-up every 12 weeks as indicated|ICI_ENDO-2|

aPrior to initiating treatment, counsel patients and caregivers on the warning signs and symptoms of immune-related AEs(irAEs). See Principles of Immunotherapy Patient Education(IMMUNO-B). For guidance on general recommendations for vaccination in patients with cancer, see NCCN Guidelines for the Prevention and Treatment of Cancer-Related Infections.

bCloser monitoring may be required for patients with combination immunotherapy regimens. Refer to prescribing information for each individual immunotherapy agent for monitoring recommendations.

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Discussion

Management of Immune Checkpoint Inhibitor-Related

Toxicities

PRINCIPLES OF ROUTINE MONITORING FOR IMMUNE CHECKPOINT INHIBITORS

|Pre-Therapy Assessment|Monitoring Frequencyb|Evaluation for Abnormal Findings/Symptoms| |---|---|---| |Pituitary/Adrenal (ICI_ENDO-3) ●Consider serum cortisol(morning preferred) and thyroid function as above|Consider repeating every 4-6 weeks during immunotherapy (immuno-oncology [IO]-only regimens], then follow-up every|Morning serum cortisol, adrenocorticotropic hormone (ACTH),TSH,FT4, luteinizing hormone (LH),follice- stimulating hormone (IO)-only premenopausal individuals), and cosytropin stimulation test only as indicated| |Fertility||| |●Advise on family planning and refer to fertility preservation specialists if desired||| |Pulmonary (ICI_PULM-1) ●Oxygen saturation(resting and with ambulation) ●Consider pulmonary function tests(PFTs) with diffusion capacity for patients who are high risk(eg, interstitul lung disease[ILD] on imaging, chronic obstructive pulmonary disease[COPD], previous suspected treatment-related lung toxicity)|Repeat oxygen saturation tests|Chest CT with contrast to evaluate for pneumonitis, biopsy, or bronchoscopy with bronchoalveolar lavage (BAL) if needed to exclude other causes| |●In the absence of prior imaging, consider a chest x-ray||| |Cardiovascular (ICI_CARD201-1) ●Consider baseline electrocardiogram(ECG) ●Consider high-sensitivity troponin and N-terminal prohomorne B-type natriuretic peptide (NT-proBNP) ●Individualized assessment in consultation with cardiology as indicated|Consider periodic testing for those with abnormal baseline or symptoms|Individualized follow-up in consultation with cardiology as indicated| |Musculoskeletal (ICI_MS-1) ● Joint examination/functional assessment as needed for patients with pre-existing disease|No routine monitoring needed if asymptomatic|Consider rheumatology referral. Depending on clinical situation, consider C-reactive protein(CRP), erythrocyte sedimentation rate (ESR), or creatinine kinase (CK)|

aPrior to initiating treatment, counsel patients and caregivers on the warning signs and symptoms of irAEs. See Principles of Immunotherapy Patient Education(IMMUNO-B). For guidance on general recommendations for vaccination in patients with cancer, see NCCN Guidelines for the Prevention and Treatment of Cancer-Related Infections.

cFor regimens that require steroid premedication, routine surveillance is not recommended.

d For individuals with a high-risk profile(eg, receiving immune checkpoint inhibitor[ICI] combination therapy regimens, including those with LAG-3), consider checking high-sensitivity troponin every cycle for the first 3 cycles(which corresponds with the median time to onset of myocarditis), and then every 3 months.

Note: All recommendations are category 2A unless otherwise indicated.

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Management of Immune Checkpoint Inhibitor-Related Toxicities

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|CONDITIONS|SIGNS AND SYMPTOMS (MAY INCLUDE ONE OR MORE)| |---|---| |CARDIO: Myocarditis|Chest pain, dyspnea, fatigue, palpitations (arrhythmia: heart block or ventricular ectopic beats), syncope, generalized weakness. This AE may occur in conjunction with myositis and/or myasthenia gravis; these entities must be ruled out.| |DERM: Bullous dermatitis|Inflammation of the skin and the presence of bullae, which are filled with fluid. The most common immune-related bullous dermatitis is bullous pemphigoid. May be intense or widespread; intermittent; skin changes from scratching(eg, edema, excoriations, lichenification, oozing/crusts); limiting instrumental activities of daily living (iADLs).| |DERM: Maculopapular rash (morbilliform rash)|Macules (flat) and papules (elevated)| |DERM: Pruritus|Itching sensation, with or without rash| |DERM: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)|SJS, overlapping SJS/TEN, and TEN are characterized by separation of the dermis involving <10%, 10%-30%, and >30% body surface area (BSA), respectively.| |DERM: Lichen planus|Violaceous (dark red/purple) papules and plaques without scale over the trunk and extremities, significant pruritus. Erosions and striae (white lines intersecting) in the oral and vulvar mucosa.| |DERM: Psoriasis and psoriasis disease|Thick red scaly plaques, accentuated on extensor surfaces,scalp,umbilicus,postauricular surfaces| |DERM: Oral mucosa inflammation|Irritated dogs and/or oropharynx, red/white lesions and/or ulcers, lichen planus, mucositis| |DERM: Dry mouth (Sicca syndrome)|Dry mouth (may cause difficulty with speaking, eating, swallowing, and/or staying asleep),oral sensitivity, dysarthria, dysphagia, dysgeusia, dental caries/erosion with prolonged salivary hypofunction, dry eye, lack of lubrication| |DERM: Oral dyesthesia|Pain most often described as "burning" in the absence of, or disproportionate to, skin changes, oral sensitivity, dysgeusia, phantomgeus, or other altered sensation with normal clinical findings| |ENDO: Hyperglycemia-related diabetic ketoacidosis (DKA)|Excessive thirst,frequent urination,general weakness, vomiting,confusion,abdominal pain, dry skin, dry mouth, increased heart rate, fruity odor on the breath| |ENDO: Hypothyroidism|Fatigue, lethargy, sensation of being cold, possible constipation, bradycardia. Patient may be asymptomatic or exhibit minimal symptoms| |ENDO: Thyrotoxicosis due to thyroiditis|Most patients with thyrotoxicosis due to thyroiditis have minimal, if any symptoms. If symptoms do arise, may include(uncommonly) tachycardia, tremor,anxiety, enlarged and tender thyroid gland(rarely).| |ENDO: Hypophysitis|Acute onset headache, photophobia, nausea/emesis, fatigue, muscle weakness; may have low blood pressure| |ENDO: Primary adrenal insufficiency|High ACTH with low morning cortisol, abnormal cosytropin stimulation test. This is a rare diagnosis not usually associated with checkpoint immunotherapy.| |ENDO: Central hypothyroidism|Symptoms of overt hypothyroidism(fatigue, bradycardia, lethargy, sensation of being cold, possible constipation) plus symptoms of central adrenal insufficiency (nausea/emesis, not feeling well, generalized malaise)|

Continued

Note: All recommendations are category 2A unless otherwise indicated.

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Comprehensive Management of Immune Checkpoint Inhibitor-Related Toxicities

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|CONDITIONS|SIGNS AND SYMPTOMS (MAY INCLUDE ONE OR MORE)| |---|---| |Gl: Esophagitis/Gastritis/ Duodenitis|Nausea, vomiting,dyspepsia, abdominal pain, anorexia| |Gl: Diarrhea/Colitis|Watery diarrhea, cramping, urgency, abdominal pain, blood and mucus in the stool, fever, nocturnal bowel movements. Blood in the stool and/or fever should prompt a more thorough workup for infection and for other causes of gastrointestinal (GI) bleeding, including peptic ulcer disease (PUD) and malignant bleeding.| |Gl: Transaminitis|Elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST)| |Gl: Cholestasis|Elevated alkaline phosphatase (predominant) with or without bilirubin/AST/ALT elevation| |Gl: Pancreatitis|Acute pancreatitis: epigastric pain, nausea, possible vomiting Chronic pancreatitis: chronic abdominal pain, deficiency in pancreatic enzyme production with possible malabsorption| |HEM: Hemolytic anemia|Ashthenia, pallor, dark-colored urine, jaundice| |HEM: Aplastic anemia|Symptoms secondary to anemia, thrombocytopenia, neutropenia, and infection (dyspnea, fatigue, tachycardia, echymosis, pallor, fever)| |HEM: Hemophagocytic lymphohistosictosis (HLH)- like syndrome|Unexplained fever, hepatosplenomegaly, sequelae of low counts, hypofibrinogenemia, elevated ferritin, transaminitis| |MUSCULO: Inflammatory arthritis|Joint pain, joint swelling; inflammatory symptoms: stiffness after inactivity, improvement with activity| |MUSCULO: Myositis|Myositis is characterized by inflammation and/or weakness involving the skeletal muscles. This adverse AE may occur in conjunction with myocarditis and/or myasthenia gravis; these entities must be ruled out. Common presenting symptoms may include muscle weakness, elevated CK, elevated transaminases, and myalgias.| |MUSCULO: Polymyalgia rheumatica (PMR)|PMR symptoms: stiffness with inactivity, fatigue and/or muscle and joint pain typically in shoulders and hips| |MUSCULO: Giant cell arteritis (GCA)|Visual symptoms, headache, scalp tenderness, jaw claudication| |NEURO: Aseptic meningitis|Headache, photophobia, and neck stiffness, often afebrile but may be febrile. There may be nausea/vomiting. Mental status should be normal (distinguishes from encephalitis).| |NEURO: Encephalitis|Confusion, altered behavior, headaches, seizures, short-term memory loss, depressed level of consciousness, focal weakness, and speech abnormality| |NEURO: Guillain-Barré syndrome (GBS)|Progressive, most often symmetrical, ascending muscle weakness with absent or reduced deep tendon reflexes. May involve extremities, facial, respiratory, and bulbar and oculomotor nerves. May have dysregulation of autonomic nerves. Often starts with pain in lower back and thighs.|

Continued

Note: All recommendations are category 2A unless otherwise indicated.

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Management of Immune Checkpoint Inhibitor-Related Toxicities

|CONDITIONS|SIGNS AND SYMPTOMS (MAY INCLUDE ONE OR MORE)| |---|---| |NEURO: Myasthenia gravis/myasthenia gravis-like syndrome|Progressive or fluctuating muscle weakness, generally proximal to distal. May have bulbar involvement (ie,ptosis, extraocular movement abnormalities resulting in double vision, dysphagia, facial muscle weakness, and/or respiratory muscle weakness, May occur with myostitis and myocarditis, which must be ruled out. Respiratory symptoms may require evaluation to rule out pneumonitis. Miller Fisher variant of GBS has overlapping symptoms (ophthalmoplegia and ascending weakness).| |NEURO: Peripheral neuropathy|Asymmetric or symmetric sensory-motor deficit. Sensory deficit may be painful or painless paresthesias or potentially life-threatening autonomic(eg),myenteric plexus) dysfunction. Hypo- or areflexia. Isolated sensory deficit or sensory plus lower motor neuron deficit. Gl tract paresis due to myenteric neuritis is a rare toxicity associated with immune checkpoint inhibitor (ICI) therapy.The presentation may be fulminant with profound ileus.| |NEURO: ADEM(acute demyelinating encephalomyelitis)|Headache, confusion, seizures, depressed level of consciousness, speech abnormality, focal weakness, sensory change (numbness or tingling), ataxia/loss of balance, or vision loss.| |NEURO: Optic neuritis|Vision loss, eye pain, decreased visual acuity, visual field loss, dyschromatopsia, relative afferent pupillary defect, optic disc edema.| |NEURO: Transverse myelitis|Acute or subacute weakness or sensory changes bilaterally, often with bowel/bladder changes and spinal level to pinprick, hyperreflexia, positive Babinski.| |OCULAR: Vision changes|Blurred/distorted vision, new floaters, itchy eyes, blind spots, change in color vision, diplopia, photophobia, tenderness/pain, eyelid swelling, and proptosis. Scleritis can cause a reddish purple discoloration of the eye. Uveitis can be associated with| |PULM: Pneumonitis|Dry cough, shortness of breath, fever, chest pain| |RENAL: Acute kidney injury (AKI)|Elevation of creatinine/blood urea nitrogen (BUN), inability to maintain acid/base or electrolyte balance, and urine output change (usually decreased)|

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NCCN ismed to MEDIVE TE NCCN Guidelines Version 1:2026 Comprehensive Management of Immune Checkpoint Inhibitor-Related

![ADVERSE EVENT(S)\nASSESSMENT/GRADING\nMild transient reaction(G1)\nMild transient reaction\n●Intervention not indicated\n●Consider premedication with acetaminophen, and\nantihistamines\nH2) with future infusions\n●Treat per institutional guidelines\n●Consider holding or slowing the rate of infusion to half rate\n●Continue immunotherapy\n●Discontinue premedication with acetaminophen and\nantihistamines (H1 and H2) with future infusions\n●Severe (G3-4)^c\nModerate (G2)^b\n●Treat per institutional guidelines\n●Discontinue offending 1898\nclass\n●Continue immunotherapy\n●Consider premedication with acetaminophen and\nantihistamines (H1 and H2) with future infusions\n●Consider corticosteroids (steroids) for patients who\npremedication may be permitted in these situations\n●Treat per institutional guidelines\n●Discontinue offending immunotherapy;\n●consider alternate agents in therapeutic classl\n${}^{c}$\n](2/aj0YEe4oUhYkBdfpda0fYP/figure4fda088823f742f2b666bad396dd5f2d_0_4.png) aSymptoms include: Fever/chills/rigors, back pain, urticaria/pruritus, angioedema,flushing/headache, hypertension, hypotension, shortness of breath, cough/wheezing,hypoxemia, dizziness/syncope, sweating, and arthralgia/myalgia. Refer to prescribing information for each individual immunotherapy agent for recommendations for premedication to prevent infusion reactions.

b Therapy or infusion interruption indicated but responds promptly to symptomatic treatment(eg,antihistamines, acetaminophen, nonsteroidal anti-inflammatory drugs ≤24 hours.

cProlonged(eg, not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement.Hospitalization indicated; life-threatening consequences; urgent intervention.d If infusion reactions that are resistant to standard therapy occur in patients

a programmed cell death protein 1(PD-1) inhibitor for subsequent treatments.There are no data to guide the use of alternate ICls.

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Conprehensive Management

Management of Immune Checkpoint Inhibitor-Related Toxicities

|CARDIOVASCULAR SYMPTOMS/SIGNS ADVERSE EVENT(S)|ASSESSMENT/GRADING|MANAGEMENTf| |---|---|---| ||●Immediate cardiology consultation(preferably cardio-oncology) ● ECG (compare to baseline for any suspected cardiovascular AE)|●Management is tailored to response and acuity of presentation ●High-dose steroids such as IV methylprednisolone 1 g/day for 3-5 days If responding and stable,switch to oral prednisone (1 mg/kg/day), then taper slowly over 6-12 weeks based on clinical response and improvement of biomarkers| |Suspected myocarditis/ Pericarditis/ Large vessel vasculitisa|●Ventricular arrhythmias/ Tachycardia ● Conduction abnormalities/heart block ● Heart failure ● Cardiogenic shock ● Pericardial effusion ● Differential Myocardial infarction/ acute coronary syndrome ● Pulmonary embolism (PE); malignant involvement (PE); malignant involvement|Myocarditis → ● If no improvement within 24-48 hours on steroids, initiate additional immunosuppression (listed in alphabetical order): Abatacept Alemtuzumab h Antithymocyte globulin (ATG) Infliximah (use with extreme caution in patients with reduced LV ejection fraction [LVEF]) Intravenous immunoglobulin (lg)(IVig) Methotrexate Mycophenolate Methotrexate ● Mycophenolate mofetii ● Plasmapheresis ●Abatacept with ruxolitinib has been used in concomitant myositis and myocarditisk ● Intensive care unit (ICU)-level monitoring ●Temporary or permanent pacing as required|

NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

ICI_CARDIO-1A

a Myocarditis symptoms are nonspecific (eg, chest pain, dyspnea, fatigue, palpitations [arrhythmia: heart block or ventricular ectopic beats], syncope, generalized

weakness) and may occur as early as days to weeks after 1–2 doses of ICI. Although rare, myocarditis is often severe and associated with myositis/myasthenia gravis/myasthenia gravis-like syndrome (3 M’s), and more common with combination therapy. In most fatal cases, conduction abnormalities were the cause of death, and

ejection fraction was preserved.

b Consider high-sensitivity troponin and NT-proBNP at baseline (for identifying those at increased risk) and serially during treatment to detect abnormal blood biomarkers that may precede symptomatic myocarditis induced by ICI.

c This can also be associated with thymoma.d Consider ESR, CRP, or other inflammatory markers.e Use of multiparameter tissue characterization by MRI, including T1 and T2 mapping and application of modified Lake Louise Criteria, provides important diagnostic

value for myocarditis. If cardiac MRI is negative or myocarditis is highly suspected, consider endomyocardial biopsy.

f Principles of Immunosuppression (IMMUNO-A).g Principles of Immunotherapy Rechallenge (IMMUNO-C).h Perform a tuberculosis [TB] blood test (eg, T-Spot/QuantiFERON-TB Gold) (depending on facility) and hepatitis testing at time of suspected toxicity to facilitate

administration.

i IVIG 2 g/kg divided in equal doses given over 2–5 consecutive days. Refer to the FDA-approved package insert for important safety information.j Mycophenolate mofetil treatment (0.5–1 g every 12 h).k Salem JE, et al. Cancer Discov 2023;13:1100-1115.l Adler Y, et al. Eur Heart J 2015;36:2921-2964.

FOOTNOTES

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National Limited WFC Cancer Network®

Management of Immune Checkpoint Inhibitor-Related Toxicities

![DERMATOLOG ADVERSE EVENT(S)\nACSESSMENT/GRADING\nMild (G1)^c\nModerate (G2)^c\n×\n×\n×\n×\n×\n×\n×\nMaxmod\nMaculopapular rashà\nConderate (G2)^c\nSevere (G3)^c\n•Hold (G3)^c\n•Hold (G4)^c\n•Hold (G5)^c\n•Continue immunotherapy\n•Topical emollient and moderate potency$steroids g to affected areas\nMaculopapular rashà\n•Consider biopsy if unusual features\n•Eosinophil count, peripheral blood smear, and liver function tests (LFTs)^b\n•Overdeator (G3)^c\n•Hold (G4)^c\n•Continue immunotherapy\n•Topical emollient and moderate- to high-potency steroidsg is affected areas\n•Consider trial of oral antihistamine for symptomatic relief of pruritus\n•Continue immunotherapy\n•In addition to moderate temperature 4-15 mg/kg dayi$\times$\n](2/aj0YEe4oUhYkBdfpda0fYP/figurefeff5e44271b4d178380bed529cff0ae_0_5.png) ![Maculopapular rashà\nConsider biopsy if unusual features\n●Eosinophil count, peripheral blood smear, and liver function tests (LFTs)b\nSevere (G3)e\n●Hold immunotherapy●Treatment with high-potency topical steroids9 to affected areas\n●Prednisone/lV methylprednisolone 0.5-1 mg/kg/day●Urgent dermatology consultation, consider biopsy●Consider inpatient care\n](2/aj0YEe4oUhYkBdfpda0fYP/figuref834686cfd2c496e8ac64200427711b2_0_6.png) a Characterized by the presence of macules (flat) and papules (elevated). Also known as morbilliform rash, it is one of the most common cutaneous AEs, frequently affecting the upper trunk, spreading centripetally, and may be associated with pruritus.

b These features can be used to assist with the diagnosis of DRESS(drug reaction with eosinophilia and systemic symptoms) syndrome. This syndrome is typically characterized by a maculopapular rash that involves the face and ears and typically presents with swelling of the face and hands within 2-8 weeks after drug exposure. Note that certain classes of high-risk medications initiated in the prior few weeks may also cause maculopular rash, including antiepileptic drugs: carbamazepine, phenytoin, lamotrigine, phenobarbital;antihyperuricemics: allopurinol, febuxostat; sulfonamides and sulphones: trimethorrim sulfamethoxazole, sulfasalazine, dapsone; and other antibiotics: vancomycin, minocycline,other beta-lactams. Kardaan SH, et al. Br J Dermatol 2013;169:1071-1080.

cMacules/papules covering <10% BSA with or without symptoms(eg, pruritus, burning,tightness).

● Consider inpatient care

●Consider inpatient care

d Macules/papules covering 10%-30% BSA with or without symptoms(eg, pruritus, burning, tightness); limiting iADLs.

eMacules/papules covering >30% BSA with or without associated symptoms; limiting self-care activities of daily living (ADLs).

f Principles of Immunosuppression (IMMUNO-A).

9 Topical steroids by potency: High (eg, clobetasol 0.05% or fluocinonide 0.05% [cream or ointment]); Moderate (eg, triamcinolone 0.1% [cream,ointment, lotion] or betamethasone valerate (lotion]).

hPrinciples of Immunotherapy Rechallenge(IMMUNO-C).

i Treat until symptoms improve to grade $\le 1 $, then taper over 4-6 weeks.

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Management of Immune Checkpoint Inhibitor-Related Toxicities

![DERMATOLOG\nADVERSE EVENT(S)\nASSESSMENT/GRADING\nGeneral (G1,\nG2, or G3)\n················\n··························································································\n-Real antihistamines\n G2, or G3)\n················································································································\n\n\nPERturitusjì\nMild（G1*\n Mild (G1*\n)\n\n\ncause\nLime (G2)\n ·Assess for history of prior inflammatory\n··/Severe (G3)\nModerate (G2)\n●Hold immunotherapy\n ·················\n](2/aj0YEe4oUhYkBdfpda0fYP/figure3868f39128ef4fff9ab7a9e2bb2674cb_0_5.png) Principles of Immunosuppression(IMMUNO-A).

9Topical steroids by potency: High (eg, clobetasol 0.05% or fluocinonide 0.05% [cream or ointment]); Moderate (eg,triamcinolone 0.1% [cream, ointment, lotion] or betamethasone valerate [lotion]).

h Principles of Immunotherapy Rechallenge(IMMUNO-C).

iTreat until symptoms improve to grade ≤1, then taper over 4-6 weeks.

Characterized by an intense itching sensation with or without rash.

k Mild or localized.

Intense or widespread; intermittent; skin changes from scratching(eg, edema, population, excoriations, lichenification, oozing/crusts); limiting iADLs.

m Intense or widespread; constant; limiting self-care ADLs or sleep. Assess serum IgE and histamine; consider oral antihistamines for increased histamine and omalizumab for increased IgE.

n Including topical products that have the following active ingredients: hydrocortisone 0.5% or 1%, diphenhydramine, pramoxine, camphor, menthol.

Note: All recommendations are category 2A unless otherwise indicated.

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National NCCen Med 2025 NCCN Guidelines Version 1:2026

Conprehensive Management of Immune Checkpoint Inhibitor-Related Toxicities

|DERMATOLOGIC ADVERSE EVENT(S)|ASSESSMENT/GRADING|MANAGEMENTf · Consider holding immunotherapyh ·High-potency topical steroids9 to affected areas|| |---|---|---|---| |Bullous dermatitis,o|Urgent dermatology consultation: if unavailable, consider skin biopsy q and/or serum testing'|Mild (G1)s|● Hold immunotherapy until G1h ● Prednisone/IV methylprednisolone 0.5-1 mg/kg/day ● If no improvement after 3 days, urgent consultation to dermatology| |Bullous dermatitis1,o|Urgent dermatology consultation: if unavailable, consider skin biopsy q and/or serum testing'|Moderate (G2)t|● If no improvement after 3 days, urgent consultation to dermatology| ||Severe (G3)u OR Life-threatening (G4)v|● If no access to dermatology, consider inpatient care with dermatology access ● If diagnosis of bullous pemphigoid is confirmed by biopsy or serology, consider rituximabW or dupilumabW||

|||Severe (G2)t|Moderate (G2)t| |---|---|---|---| |Bullous dermatitis,o|OD|Rege (G3)u OR Life-threatening (G4)v|●Discontinue immunotherapyh 0|

· Discontinue immunotherapy

· Prednisone/IV methylprednisolone 1-2 mg/kg/day

● If bullous pemphigoid confirmed, dupilumab represents recommended as a steroid-sparing measure

•Consider alternative steroid-sparing options such as IVIGY,z as an adjunct to rituximab

•Inpatient care required

• Urgent dermatology consultation

|||Stevens-Johnson syndrome(SJS)P|Urgent dermatology consultation:| |---|---|---|---| |or||or|Unvasible| |Notoxic epidermal||with|unavailable,| |$$\text{Intoxic epidermal}$$||consider skin biopsy|which|

•Discontinue immunotherapy

•Evaluate entire medication list for alternative culprit drug such as an antibiotic or anticonvulsant

●Urgent dermatology,ophthalmology, and urology consultation

●Prednisone/IV methylprednisolone 1-2 mg/kg/day

•Consider IVIGZ

•Other immunosuppressive therapiesaa

● Inpatient care required

NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

ICI_DERM-3A

f Principles of Immunosuppression (IMMUNO-A).g Topical steroids by potency: High (eg, clobetasol 0.05% or fluocinonide 0.05% [cream or ointment]); Moderate (eg, triamcinolone 0.1% [cream, ointment, lotion] or

betamethasone valerate [lotion]).

h Principles of Immunotherapy Rechallenge (IMMUNO-C).i Treat until symptoms improve to grade ≤1, then taper over 4–6 weeks.l Intense or widespread; intermittent; skin changes from scratching (eg, edema, papulation, excoriations, lichenification, oozing/crusts); limiting iADLs.o Characterized by inflammation of the skin and the presence of bullae, which are filled with fluid. The most common irAE reported is bullous pemphigoid.p SJS, overlapping SJS/TEN, and TEN are characterized by separation of the dermis involving <10%, 10%–30%, and >30% BSA, respectively. The syndrome is thought to be a hypersensitivity complex affecting the skin and the mucous membranes.

q Skin biopsies should be performed on perilesional intact skin. Two biopsies should be performed with one being sent for direct immunofluorescence testing in Michel’s medium, if available, or in normal saline (if Michel’s medium not available).

r The following serologic tests may be considered for autoimmune/irAE-associated bullous disorders: bullous pemphigoid antibodies, desmoglein 1 and 3 (pemphigus)

antibodies, indirect immunofluorescence (anti-skin antibodies).

s Asymptomatic; blisters covering <10% BSA.t Blisters covering 10%–30% BSA; painful blisters; limiting iADLs.u Blisters covering >30% BSA; limiting self-care ADLs.v Blisters covering >30% BSA; associated with fluid or electrolyte abnormalities; ICU care or burn unit indicated.w 1000 mg once every 2 weeks for 2 doses (in combination with a tapering course of glucocorticoids), followed by maintenance of rituximab 500 mg at months 12 and

18 as needed. Joly P, et al. Lancet 2017;389:2031-2040.

x Shipman WD, et al. Br J Dermatol 2023;189:339-341.y Ahmed AR. J Am Acad Dermatol 2001;45:825-835.z IVIG 2 g/kg divided in equal doses given over 2–5 consecutive days. Refer to the FDA-approved package insert for important safety information.aa Immunosuppressive therapies (ie, etanercept, cyclosporine) can be considered. After a patient has widespread skin separation (blisters or erosions), the risk of

infection should be weighed against the potential benefits of immunosuppression.

FOOTNOTES

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National SUNN D to MEDIVE TO NCCN NCCN Guidelines Version 1:2026

NCCN Guidelines Index Table of Contents Discussion

National United Networks 2023 for Comprehensive Cancer Network ${}^{®}$

Management of Immune Checkpoint Inhibitor-Related Toxicities

DERMATOLOGIC ADVERSE EVENT(S)

ASSESSMENT/GRADING MANAGEMENTf

MANAGEMENTF

![Lichen planus and lichenoid diseases bb,cc\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n](2/aj0YEe4oUhYkBdfpda0fYP/figurec609410a9cee499ab37c6d775a906373_0_9.png) $\underline{f}$ Principles of Immunosuppression (IMMUNO-A).

9 Topical steroids by potency: High (eg, clobetasol 0.05% or fluocinonide 0.05% [cream or ointment]); Moderate (eg, triamcinolone 0.1% [cream, ointment, lotion] or betamethasone valerate [lotion]).

h Principles of Immunotherapy Rechallenge(IMMUNO-C).

bb Shi VJ,et al. JAMA Dermatol 2016;152:1128-1136; Masterson WM,et al. Cancer Treat Res Commun 2022;30:100506.

cc Violaceous (dark red/purple) papules and plaques without scale over the trunk and extremities, significant pruritus. Erosions and striae(white lines intersecting) in the oral and vulvar mucosa.

dd Consider gel for mucosal disease, solution for scalp disease, and cream/lotion/ointment for other affected areas.

ee Treat until symptoms improve to grade 1 then taper over 3 weeks.

ff Azathioprine, cyclosporine, hydroxychloroquine, methotrexate, and mycophenolate mofetil.

Note: All recommendations are category 2A unless otherwise indicated.

National SUNned to MEDIVE TE NCCN Guidelines Version 1:2026

NCCN Guidelines Index

NCCN Comprehensive Cancer Network®

Management of Immune Checkpoint Inhibitor-Related Toxicities

![DERMATOLOG ADVERSE EVENT(S)\nASSESSMENT/GRADING\nMild:<10% BSA\nModerate: 10%-30%BSA or not responsive\nsporiasis and psiasiform diseases ggg,hh\nConsider deater 2022\nConsider and dental evaluation\nConsider skin biopsy dermatology consultation\nModerate: 10%-30%BSA or not responsive\nsporiasiform diseases ggg,hh\nHistor and dermatology consultation\nMmod: 10%-30%BSA or not responsive\nMofilast\nMorayak\nSarek\nLindical 10% BSA\nDomining 10%-0% biologica\nHold immunotherapy\nHigh-potency topical steroids\n● High-potency topical steroids\n● Consider transitioning to non-steroidal topical therapies\nSuch as tacrolimus 0.1% or calcipotriene 0.005% for long-term management in intertrinous areas or facial locations\nSarek\n0. High-potency topical steroids\n● Consider transitioning to non-steroidal topical therapies\nConsider transitioning to non-steroidal topical therapies\nSovere: >30% BSA\nModerate: 10%-30% BSA or not responsive\nSarek\nOptilipriene 0.005% for long-period rissis\n● Near-band UVB phototherapy, if available and feasible term management in intertrinous areas or facial locations\nSarek\nOptilipriene 0.1% or calcipotriene 0.005% for long-period rissis\n● Consider: Acitrein (if no childbearing potential) Apremilist\nStereat: 01% biologica! Acitrein (if no childbearing potential) Apetilologis 2022;87:399-400.\n](2/aj0YEe4oUhYkBdfpda0fYP/figureed8aeaebd3ef4962bcb7a818a7c74378_0_5.png) ${}^{f}$ Principles of Immunosuppression (IMMUNO-A).

9Topical steroids by potency: High(eg,clobetasol 0.05% or fluocinonide 0.05% [cream or ointment]); Moderate(eg,triamcinolone 0.1% [cream, ointment, lotion] or betamethasone valerate [lotion]).

h Principles of Immunotherapy Rechallenge(IMMUNO-C).

99 Nikolaou V,et al.J Am Acad Dermatol 2021;84:1310-1320; Said JT,et al.J Am Acad Dermatol 2022;87:399-400.

hh Thick,red scaly plaques,accentuated on extensor surfaces,scalp, umbilicus, and postauricular surfaces.

$i^{i}$ Anti-TNF, IL-23, or IL-17 inhibitors.

•Consider:

Apremilast

● Acitretin(if no childbearing potential)

● Cyclosporine

Methotrexate

•Refer to dermatology for consideration of approved biologics

NCCN Guidelines Index

National NCCN pressed to MEDIVE TEM SNCN Guidelines Version 0:1:2026

Conprehensive Management of Immune Checkpoint Inhibitor-Related Toxicities

![ORAL MUCOSA ADVERSE EVENT(S)\nASSESSMENT/GRADING\nGeneral\n\nDental\nDental\nOral pathology\near, nose, and throat(ENT)oo\n● Continual atermittative\nnimum\n● Good oral hygiene (eg, chlorhexidine oral rinse)\n● Topical anti-inflammatory agents (oral liquid [for swish and spit] or gel formulation)mm\n● General\n● If progress or not responsive after 1 month, consider initiating steroid-offabilizing steric acids and er's tabilistic\n● For available, referral to: Dermatology (OHD/Oral pathology\near, nose, throat(ENT)oo\n● Complete immunotherapy\n● Continual atermittational\n● Consider immunosuppressants such as methotrexate or mycophenolate\n● Topical anesthetics 9q\n● Inspective in 10dual\n● Endal/Oral pathology\n● Endal/Oral pathology\n● Ear,nose, and throat(ENT)oo\n● Continue immunotherapy\n● Consider in 10 Computational surgical is not athetypical or the topical steroids\n● Considence\nroal mucosa\n● Consider intralesional steroids for localized mucositis (ulcers) recalcitrant\n● Topical anesthetics 9q\n● Inspective in 10dual\n● Hold immunotherapy\n● Considerive 11 diagnosis for 11 diagnosis for 12 diagnosis(ulcers) recalcitrant\n● Discison 12.26.10/23/2025-2025 National Comprehensive Cancer Network\`\`NCCN\°,All rights reserved.NCCN Guidelines \n1.4% 1.5% 1.6% 1.7% 1.8% 1.9% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.\n](2/aj0YEe4oUhYkBdfpda0fYP/figuredafd484a83e84543921c8c0af6475a4a_0_4.png) Note: All recommendations are category 2A unless otherwise indicated.

Footnotes on ICI_DERM-6A

NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

ICI_DERM-6A

f Principles of Immunosuppression (IMMUNO-A).h Principles of Immunotherapy Rechallenge (IMMUNO-C).ee Treat until symptoms improve to grade 1 then taper over 3 weeks.jj Irritated gums and/or oropharynx, red/white lesions and/or ulcers, lichen planus, or mucositis; for management of lichen planus, see ICI_DERM-4.kk The following serologic tests may be considered for autoimmune/irAE-associated blistering disease pemphigus (anti-desmoglein 1 and 3) and bullous pemphigoid (anti-bullous pemphigoid antigen 1 and 2). If immunologic tests confirm autoimmune disease, see blistering disorders on ICI_DERM-3.

ll Avoid crunchy, spicy, acidic, or hot food/drink as appropriate for comfort.mm Dexamethasone 0.5 mg/5 mL solution; compounded budesonide 3 mg/10 mL solution; or high- or super-high-potency topical corticosteroids such as fluocinonide

0.05% gel, clobetasol 0.05% gel, augmented betamethasone dipropionate 0.05% gel, or a nonsteroidal anti-inflammatory such as tacrolimus 0.1% ointment.

nn To ensure adequate hygiene and protect against the risk of dental caries; consider if mild and strongly consider if moderate or severe inflammation.oo Assist in the management of persistent mucositis or if oropharynx/larynx involved; consider if mild or strongly consider if moderate or severe (especially if airway involved).

pp Proton pump inhibitor (PPI) or H2 blockade.qq Magic mouthwash (equal parts diphenhydramine, antacid, and viscous lidocaine).

FOOTNOTES

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NCCN Guidelines Index

National NCCenad to MEDIVETEFCON Cancer

National NCC and MEDIVE TE NCCN Guidelines Version 1:2026

National NCCN Guidelines Version 1:2026

NCCN Comprehensive Management of Immune Checkpoint Inhibitor-Related Discussion 1:2026

ORAL MUCOSA ADVERSE EVENT(S) ASSESSMENT/GRADING MANAGEMENTf

![Dry mouth (Sicca syndrome' r)\n● Review medication profile and avoid medications that contribute to dry mouth if possible\n● Assess hydration status\n● Check salivary pooling in floor of mouth\n●Assess thickness of saliva\n● Evaluate dentition and gum recession\n● Anti-SS-A and anti-SS-B\n● Probing G3)(2)/severe (G3)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure8ee730a9121044168ee0cf04de4d08b4_0_7.png) ![Mild (G1)vv\n\n\n\n\n\n\n\n\n\n\nMost of pain\n●�endroce (G2)/\nModerate (G2)/\n\n•Abapentin, high-potency topical steroids(gel or rinse)or\nviscous lidocaine\nModerate (G2)/\n●Hold immunotherapy\n●Dietary modifications\n\n\nAssess location and character\nMild (G1)vv\n\■of pain\n●Topical steroids (gel or rinse)or\n\nDiscay ousinale\n■viscous lidocaine\nModerate (G2)/\n\n•Abapanentin, high-potency topical steroids(gel or rinse)or\n\nAssess severity of pain and\n●Adietary modifications\n\nMdc has been tested in any work, using this article and is provided to be reproduced in any form without the express written permission of NCCN.\n](2/aj0YEe4oUhYkBdfpda0fYP/figure874ec0f4143646dba37971511a57121c_0_8.png) Footnotes on ICI_DERM-7A

NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

FOOTNOTES

Note: All recommendations are category 2A unless otherwise indicated.

ICI_DERM-7A

f Principles of Immunosuppression (IMMUNO-A).h Principles of Immunotherapy Rechallenge (IMMUNO-C).ll Avoid crunchy, spicy, acidic, or hot food/drink as appropriate for comfort.rr Sicca syndrome is distinct from Sjogren's disease, with an abrupt onset of dry mouth causing difficulty with speaking, eating, swallowing, and/or staying asleep, and

usually without dry eyes. Dry mouth from Sicca syndrome may be partially improved with steroids but usually will require chronic care for salivary dysfunction. Warner

BM, et al. Oncologist 2019;24:1259-1269.

ss Pain most often described as "burning" in the absence of, or disproportionate to, skin changes, oral sensitivity, dysgeusia, phantogeusia, or other altered sensation with normal clinical findings.

tt Dry or thick saliva only; minimal food restrictions.uu Need for copious fluids to clear mouth of dry food; diet limited to soft, moist, or pureed foods; or unable to eat; need for oral lubricants.vv Mild discomfort; not interfering with oral intake.ww Moderate (G2): interfering with oral intake; Severe (G3): disabling pain; tube feeding or total parenteral nutrition [TPN] indicated.xx If prednisone results in initial improvement, consider dose escalation before tapering. If symptoms worsen, escalate to 0.5–1 mg/kg daily; if no improvement after 14 days at higher dose, reversal unlikely.

yy To ensure adequate hygiene and protect against the risk of dental caries. Patients with severe Sicca syndrome can lose their teeth due to the severity of dry mouth and loss of salivary protection.

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National SUNN CERdensed to MEDIVE TE NCCN Guidelines Version 1:2026

NCCN Guidelines Index

NCCN Consolidments 2026 Management of Immune Checkpoint Inhibitor-Related Toxicities

![ENDOCRINE ADVERSE EVENT(S)\nDIAGNOSIS/WORKUPd\nHyperglycemia,b\n· New-onset fasting\nOCR\n>200 mg/dLc\n· Random blood glucose >250 mg/dL\n● Random blood OR\n● History of type 2 diabetes mellitus (DM) with fasting/random glucose >250 mg/dL\n● Non-onset fasting\nOCR\n● Open and endocrine [IDE] with repeat serum glucose >200 mg/dLc 400 mg/dLc 4000 glucose >200 mg/dLc 4000 glucose >200 mg/dLc 4000 glucose >200 mg/dL\n● Random blood glucose >250 mg/dL\n● Card or >250 mg/dL\n● History of type 2 diabetes mellitus (DM) with fasting/random glucose >250 mg/dL\nguation\n● Consider measurement of autoantibodies (eg, anti-GAD, anti-sensitlet cell, IA-2, anti-insulin, ZnT8)^{e}e, g,h,i\notin [CI]\nZnT8)^{e}\n](2/aj0YEe4oUhYkBdfpda0fYP/figure1565e250d3364da8a742bf5309169f80_0_4.png) a Elevated fasting glucose <200 mg/dL should be managed per national/institutional guidelines and/or by a patient's primary care physician (PCP) or endocrinologist.

b Fasting glucose is preferred.

c In patients who are critically ill/ill-appearing with glucose>200 mg/dL(typically 300-500 mg/dL),urgent-emergent evaluation for DKA is indicated.

d High-dose steroids may induce or exacerbate hyperglycemia. Consider endocrinology referral and appropriate management if symptomatic and/or persistently uncontrolled.

e The development of ICI-T1DM can be life-threatening if insulin therapy is not provided.Once new T1DM is diagnosed, management and monitoring should be directed by endocrinology team. ICI-T1DM may be permanent. Autoantibodies are not required for diagnosis. Empiric treatment as T1DM recommended if C-peptide unknown.

f Symptomsptoms of DKA may include excessive thirst, frequent urination, general weakness,vomiting,confusion,abdominal pain,dry skin,dry mouth,increased heart rate,and fruity odor on the breath.

9 Evaluate for signs/symptoms of pancreatic exocrine insufficiency, and supplement if needed. Inufficient evidence to suggest steroids may reverse ICI-T1DM, and may complicate glycemic control.

Repeat C-peptide once euglycemic to confirm diagnosis of ICI-T1DM and insulin dependence. Patients with ICI-T1DM and/or ICI-hypophysitis with adrenal insufficiency are recommended to wear a medical alert bracelet, ensure adequate supply of medications if traveling, and notify their oncologist or endocrinologist in advance of scheduled procedures or in case of acute illness as medication doses may need to be adjusted.

k Principles of Immunotherapy Rechallenge(IMMUNO-C).

Institutional guidelines may include but are not limited to: IV fluids +/- potassium supplementation, IV insulin, hourly glucose, serum ketones, blood pH, and anion gap.

NCCN Guidelines Index

National NCC and MEDIVE TONED to MEDIVE INCCN Guidelines Version 1:2026

Conprehensive Management of Immune Checkpoint Inhibitor-Related Toxicities

![ENDOCRINE ADVERSE EVENT(S)\nASSESSMENT\n Endclinical hypothyroidism\n·TSH between 4 to <10\n·Normal FT4\n·Patient asymptomatic\nOR\n·Elevated TSH (\>10)\n·Normal FT4\n·Elevated TSH (\>10)\n●In TSH elevated,proceed based on TSH levels for TSH levels\n●Overt hypothyroidism\n·Elevated TSH\n▲-Overt HSH\n●Low FT4\n●Normal or low TSH\n●Low FT4\n●Central hypothyroidism\nHypophysitis/Central hypothyroidism(ICI_ENDO-3);exclude recovery from thyrotoxicosis and non-thyroidal illness\n●Continue immunotherapy if asymptomatic\n●Consider endocrine consultation\n●Consider endocrine consultation\n●Check serum cortisol to exclude coexistent adrenal insufficiency prior to treatment\n●In Initiate thyroid hormone supplementation with levothyroxine n'.....Repeat thyroid hormone supplementation with levothyroxine" \n● Iuate thyroid hormone supplementation can follow these experiments on other hand, which are highly synthesized and no thypyroidism\n●Systolic system's impact of hybrid histology (60.71/30.8)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure50cdc99f3f7642e9b3a951389a890ad6_0_4.png) Version 1.2026, 10/23/2025 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

ICI_ENDO-2A

m For patients without baseline thyroid function abnormalities or who are asymptomatic, can increase TFT interval to every 12–18 weeks as indicated.n Levothyroxine oral 1.2–1.4 mcg/kg/day. For patients with advanced age, cardiac risk, or prolonged hypothyroidism, initiate at 0.8–1.0 mcg/kg/day. If marked/profound hypothyroidism at diagnosis, give a double dose of levothyroxine for 2–3 days when initiating therapy.

o Defined as suppressed TSH that may be: a) subclinical if FT4 normal; or b) clinical if high FT4. The majority of suppressed TSH (<0.01) are due to transient or

progressive painless thyroiditis. Most patients with thyrotoxicosis are asymptomatic. Symptoms, if present, may include palpitations, heat intolerance, restlessness or anxiety, fine tremor, and/or weight loss. Consider thyroid autoantibodies (eg, anti-thyroid peroxidase [TPO] and anti-thyroglobulin [Tg]), but correlation with checkpoint inhibitor thyroiditis remains unknown.

p Thyrotoxicosis in this setting is usually from a destructive process, and thus anti-thyroid drugs (eg, methimazole, propylthiouracil) are not recommended. ICI-induced

thyrotoxicosis usually evolves into hypothyroidism and requires replacement therapy, but sometimes resolves to normal with long-term follow-up.

q Usual duration of thyrotoxicosis from checkpoint immunotherapy is 4–6 weeks. Graves’ disease evaluation with TSH receptor antibody (TRAb) or thyroid-stimulating Ig (TSI) measurement or thyroid uptake scan can be considered in patients with persistent thyrotoxicosis. Recommend referral to endocrinology.

FOOTNOTES

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National NCC and MEDIVE TE NCCN Guidelines Version 1:2026

NCCN Guidelines Index Table of Contents Discussion

NCCN 1990NCCancer Network®Toxicities

![ENDOCRINE ADVERSE EVENT(S)\nASSESSMENT\n\n •Cortisol and ACTH (morning preferred),t TSH,FT4,serum Na\n• Consiser LH,FSH,and sex\nHypophysitisj,r\n\n • • Resinsin efficiency\nis not recommended in acute settings\n•Brain MRI ± contrast with pituitary/ sellar cuts,especially if mass effect symptoms or concern for metastatic disease\n\n • • Cosyntropin stimulation testing is not recommended in acute settings N\n• Brain MRI ± contrast with pituitary/ sellar cuts,especially if mass effect symptoms or concern for metastatic disease\n\n\n • * Early宣鸦 inufficiency (high ACTH with low morning cortisol, abnormal)\n\n Physologic steroids in ambulatory patients and stress dosing for acute illness or surgery/procedures\n\n\n • \ - Central hypothyroid (normal or low TSH, low FT4) \n Thyroid hormone replacement, titrate to FT4 level\n](2/aj0YEe4oUhYkBdfpda0fYP/figurea179f1cdfa444db59a49bf103f0caca3_0_4.png)

MANAGEMENT

![#Hypophysitisj,r\nADVERSE EVENT(S)\n·Evaluate for symptomsr,s\n-Cortisol and ACTH(morning preferred),t{TSH,FT4,serum Na\nConsider LH,FSH, and sex\nhormonesasappropriate systemis is not recommended in acute settingsu,S\n-·\n● Brain MRI± contrast with pituitary/sellar cuts, especially if mass effect symptoms or concern for metastatic diseaser,V\n](2/aj0YEe4oUhYkBdfpda0fYP/figure7543e327b0d24970811f9ea9975373f2_0_6.png) ● Endocrine consultation and patient education

•Hold immunotherapy* until acute symptoms resolve and hormone replacement is initiated

●If severe symptoms with concern for mass effect, may consider high-dose steroids"

● Treat with physiologic hormone replacementx,y,z

●Secondary adrenal insufficiency (low ACTH, low cortisol)

Physiologic steroids in ambulatory patients and stress dosing for acute illness or surgery/proceduresj,x

●Central hypothyroidism(normal or low TSH, low FT4)

Thyroid hormone replacement, titrate to FT4 level

![Primary adrenal insufficiency (high ACTH with low morning cortisol, abnormal abnormal constrathery low morning cortisol, cosyntropin stimulation test)\n● Reare diagnosis that is not usually associated with checkpoint immunotherapy\n● If there is concern for this diagnosis, recommend endocrine consultation\n](2/aj0YEe4oUhYkBdfpda0fYP/figure130b2b76374040679cc3abaf34e2f3fe_0_15.png) Version 1.2026, 10/23/2025 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

j Patients with ICI-T1DM and/or ICI-hypophysitis with adrenal insufficiency are recommended to wear a medical alert bracelet, ensure adequate supply of medications if traveling, and notify their oncologist or endocrinologist in advance of scheduled procedures or in case of acute illness as medication doses may need to be adjusted.

k Principles of Immunotherapy Rechallenge (IMMUNO-C).r Hypophysitis typically presents with acute or subacute symptoms from pituitary hormone loss, notably adrenal insufficiency including dizziness, nausea/emesis,

anorexia, severe fatigue, confusion, lethargy, and/or low blood pressure. Labs show low serum ACTH and cortisol, and sometimes low serum sodium or abnormalities of other pituitary hormones. Some patients present with symptoms from mass effect of pituitary enlargement (eg, headache, vision change), more often with anticytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) therapies.

s Cosyntropin stimulation testing can be normal in acute secondary adrenal insufficiency and would not exclude hypophysitis. t For preoperative patients who had neoadjuvant therapy and cortisol status is unknown, consider a random cortisol. If <2 mcg/dL, treat. If between 2 mcg/dL and 5 mcg/dL, treat and refer to endocrinology.

u In patients who have had chronic steroid exposure from their regimen or have questionable cortisol levels, send for cosyntropin stimulation in the outpatient setting.v Hypophysitis from anti-PD-1/PD-L1 therapy may not show classic pituitary enlargement and enhancement on MRI as seen with anti-CTLA-4–associated hypophysitis. Consider imaging if diabetes insipidus present as rarely seen in isolated ICI-hypophysitis.w If concern for optic chiasm compression or mass effect from hypophysitis, may consider high-dose steroids (eg, IV methylprednisolone 1 mg/ kg/day) as indicated

until symptoms resolve (1–2 weeks) then rapid taper to physiologic replacement. High-dose steroids do not reverse the likelihood of permanent hormone deficit and if prolonged, may have negative impact on outcomes.

x Preferred treatment for adrenal insufficiency is with hydrocortisone, dosed at 20 mg PO every AM and 10 mg PO in the early afternoon for ambulatory patients. Dosing for physiologic replacement is considered higher in patients on immunotherapy due to underlying inflammation. Further titration is best guided by an endocrinologist. Once-daily prednisone at an equivalent dose is an alternative regimen. Acutely symptomatic or hospitalized patients or patients undergoing surgery with general

anesthesia require stress dose steroids (hydrocortisone 100 mg IV x 1, then 50 mg every 8 hours, tapered based on clinical parameters) and endocrinology

consultation. Patients should double their dose for 3 days for mild illness or fever in the outpatient setting. Patients typically require cortisol replacement indefinitely.

y See Overt hypothyroidism on ICI_ENDO-2 for levothyroxine dosing.z For central hypogonadism (low LH, low FSH, and low sex hormone, not due to underlying illness) may consider testosterone supplementation in individuals and

estrogen in premenopausal individuals if not otherwise contraindicated.

Note: All recommendations are category 2A unless otherwise indicated.

ICI_ENDO-3A

FOOTNOTES

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NCCN issued to MEDIVEIVE The following Version 1:2026

Comprehensive Cancer Network®

Management of Immune Checkpoint Inhibitor-Related Toxicities

ADVERSE EVENT(S)

![DANGER SETSMBS\nADVERSE EVENT(S)\nASSESSMENT\n SUSPECTED DIAGNOSES\nMyocarditis\nICI_CARDIO-1\nICI_ENDO-1\n4\n3\n2024\n1.2024\nUpsilon\nNCCN\nWCCN\nControl\nNon-ICI-related\nⅠ\nMyerglycemia-related DKA\nICI_ENDO-1\nICI_ENDO-2\nHypothyroidism/thyrotoxicosis\nICI_ENDO-3\nHypophysitis/primary adrenal insufficiency\nICI_ENDO-3\nUnexplained drop in hemoglobin\nICI_HEM-1\nMyositis\nICI_MS-3\nPneumonitis\nICI_PULM-1\n](2/aj0YEe4oUhYkBdfpda0fYP/figure6933bf851a41434790de5e4af255ccb2_0_5.png) a NCCN Guidelines for Distress Management.

Note: All recommendations are category 2A unless otherwise indicated.

National NCC and MEDIVE TE NCCN Guidelines Version 1:2026

NCCN 1999 to MEDIVE NCCN Guidelines Version 1:2026 Co2025 National Comprehensive Checkpoint Inhibitor-Related Discussion

![UPPER GASTROINTESTINAL ADVERSE EVENT(S)\n\nScreen for risk factors that may contribute to symptoms (eg, narcotics,anti-motility agents, nonsteroidal anti-inflammatory drugs [NSAIDs], certain cancer therapies, celiac disease)\n\nIf symptoms are moderate to severe,b consider the following:Esophagogastroduodenoscopy (EGD) evaluationc to rule out different etiologies\nModerate infectial stress and endolic system of infectial drugs, and endudumod Motility evaluation\nMSSESSMENT/GRADING\nMildd\nModerate inptoly (108,601,2024)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure86daa31cb75547e1b52159fe5f54ae7e_0_3.png) a Symptoms of upper GI AEs include nausea, vomiting, dysphagia, odynophagia, reflux, hematemesis, dyspepsia, melena,anorexia, early satiety, bloating, iron deficiency anemia, abdominal pain, diarrhea, and weight loss.

b Symptomatic, unable to eat regular diet, exhibits dehydration, weight loss, hemodynamic instability. Aggressive intervention is needed.

c 10%-20% of patients will have normal endoscopic evaluation but positive biopsies for ICI gastritis. Haryal A, et al. Cancer 2023;129:367-375.

d Symptomatic, but able to eat regular diet or maintain weight and hydration status. No aggressive intervention indicated.

e Principles of Immunotherapy Rechallenge(IMMUNO-C).

f9 mg/day for 2 weeks, then taper down by 3 mg every week for total 4 weeks.

9 Start infliximab at 5 mg/kg.

hPerform ID screening(HIV; hepatitis A, B, C) and TB blood test (eg, T-Spot/QuantiFERON-TB Gold) (depending on facility), preferably before administering first dose of infliximab or vedolizumab. In urgent situations, treatment does not need to be held for results.

i Infliximab antibody testing is generally not recommended and should not delay switch of therapy.

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Concomprehensive Management of Immune Checkpoint Inhibitor-Related NoCenNCCancer Network®

Table of Contents Discussion

NCCancer Network®

Management of Immune Checkpoint Inhibitor-Related Toxicities

GASTROINTESTINAL ADVERSE EVENT(S)

ASSESSMENT/GRADING

Cyclospora/isospora sppn

![● Diarrhea\n● Colitis\n● Moderate (G2)"\n● In our appropriate clinical contacts, consider ova \& parasites; molecular testing for Giardia, Cryptosporidium spp.,G.histolytica, microsporidia, and Cyclospora/isospora spp.\n● Fecal calprotectin±lactoferrin°\n● Diarrhea\n● Diarrhea\n● Colitis\n● Severe\n●ICI\nGI-4\nG3-4\nMild (G1)^k\n● Diarrhea\n● G(G2)^k\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● Diarrhea\n● \n](2/aj0YEe4oUhYkBdfpda0fYP/figureb3e4d43feea149df9b9745918f4784cb_0_11.png)

MANAGEMENTP

●Hydration

● Close monitoring

● Dietary modifications

●Consider holding immunotherapy

●Consider loperamide or diphenoxylate/atropine for 2-3 days as an adjunct for symptom relief

If no improvement and not already done,obtain lab tests for infectious workup

Caution is warranted to avoid masking symptoms; discontinue antidierrheals if diarrhea persists, to assess response to immunosuppressive therapy

●If persistent or progressive symptoms,check lactoferrin/calprotectin

If positive, treat as G2

If negative and no infection, continue G1 management and consider adding mesalamine and/or cholestyramine

e Principles of Immunotherapy Rechallenge (IMMUNO-C).

j Symptoms include: watery diarrhea, cramping, urgency, abdominal pain, blood and mucus in the stool, fever, and nocturnal bowel movements. Blood in the stool and/or fever should prompt a more thorough workup for infection and for other causes of Gl bleeding, including PUD and malignant bleeding.

k Fewer than 4 bowel movements above baseline per day and no colitis symptoms.

l 4-6 bowel movements above baseline per day, colitis symptoms, not interfering with ADLs. 4-More than 6 bowel movements above baseline per day, colitis symptoms, interference with ADLs, hemodynamic instability, hospitalization, serious complications(eg, ischemic bowel,perforation, toxic megacolon), or other colitis-related life-threatening conditions.

°Consider endoscopy exam within 2 weeks if either lactoferrin or calprotectin is positive. Serial monitoring of calprotectin levels while on treatment(every 2 months) may be helpful to guide treatment duration until achieving endoscopic remission.

P Principles of Immunosuppression (IMMUNO-A).

qEg,stool frequency,consistency,blood in stool,nocturnal symptoms,weight trend. If progressive, consider stool evaluation to rule out infectious etiology.

「Consider lactose-free, low-fiber diet until diarrhea subsides. Consider BRAT(bananas, rice, apple sauce, toast) diet.

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NCCN

National SUNN d to MEDIVE TO MECC

Management of Immune Checkpoint Inhibitor-Related Toxicities

GASTROINTESTINAL ADVERSE EVENT(S)

![- Diarrhea\n- Colitisj\nModerate (G2)'\n- Fecal transport of the other 22536. C. difficile\n- NAATs for Gl pathogens (other bacteria, viruses)\n- In appropriate clinical context, consider ova \& parasites; molecular testing for Giardia, Cryptosporidium spp.E.,histolytica, microsporidia, and Cyclospora/isospora spp\n- Fecal calprotectin± lactoferrin\n- Consider abdominal/pelvic CT with contrast's\n· Consider GI Consultation\nColonoscopy or flexible sigmoidoscopy\n- EGD with biopsy^{\circ}\n](2/aj0YEe4oUhYkBdfpda0fYP/figurea82cf4b213e94b0989499a95a6a15300_0_7.png)

MANAGEMENTP

● Hold immunotherapye

•For pathologically confirmed microscopic colitis,consider budesonide 9 mg daily prior to systemic steroid$^{st}$

•Prednisone/IV methylprednisoloneu, v(1-2 mg/kg/day)

If no response to oral steroids after 3 days, consider IV steroids:

If colonoscopy or flexible sigmoidoscopy shows significant ulceration, non-ulcerative inflammation,or microscopic colitis on histology,x consider adding infliximab9,h,i,y or vedolizumabh,y,z

Consider tofacitinib or ustekinab for infliximab-and/or vedolizumab-refractory colitis aa

· For persistent diarrhea that does not resolve after the management described above, consider other etiologies(eg, pancreatic exocrine insufficiency, celiac disease)

•For immunosuppressant-refractory colitis, fecal transplantation may be considered based on institutional availability and expertise

NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

ICI_GI-3A

e Principles of Immunotherapy Rechallenge (IMMUNO-C).g Start infliximab at 5 mg/kg.h Perform ID screening (HIV; hepatitis A, B, C) and TB blood test (eg, T-Spot/QuantiFERON-TB Gold) (depending on facility), preferably before administering first dose

of infliximab or vedolizumab. In urgent situations, treatment does not need to be held for results.

i Infliximab antibody testing is generally not recommended and should not delay switch of therapy.j Symptoms include: watery diarrhea, cramping, urgency, abdominal pain, blood and mucus in the stool, fever, and nocturnal bowel movements. Blood in the stool and/

or fever should prompt a more thorough workup for infection and for other causes of GI bleeding, including PUD and malignant bleeding.

l 4–6 bowel movements above baseline per day, colitis symptoms, not interfering with ADLs.n It is not necessary to wait for test results before providing therapy to manage irAEs.o Consider endoscopy exam within 2 weeks if either lactoferrin or calprotectin is positive. Serial monitoring of calprotectin levels while on treatment (every 2 months) may be helpful to guide treatment duration until achieving endoscopic remission.

p Principles of Immunosuppression (IMMUNO-A).s In cases with high suspicion for complications (eg, toxic megacolon, abscess, perforation).t Hughes MS, et al. J Immunother Cancer 2019;7:292.u IV steroid is preferred due to possible absorption impairment. v Convert to prednisone when appropriate.w Treat until symptoms improve to grade ≤1, then taper over <4 to 6 weeks. In cases where infliximab or vedolizumab is used, an attempt to taper steroids in <2

to 4 weeks should be made to minimize the complication of infection. If strong clinical suspicion for ICI diarrhea, start empiric IV steroids while waiting for EGD/

colonoscopy/flexible sigmoidoscopy results.

x For patients with severe colitis such as ulcerations on colonoscopy/flexible sigmoidoscopy, higher rates of refractory response to steroids have been reported. Early

introduction of infliximab or vedolizumab can be considered to reduce recurrence.

y Duration of therapy with infliximab or vedolizumab is not clearly defined; however, receipt of ≥3 doses (at weeks 0, 2, and 6) has been associated with less frequent

colitis recurrence. Repeat endoscopy and/or fecal calprotectin to assess endoscopic healing may be helpful to guide colitis treatment duration, but is optional. See

Principles of Immunosuppression (IMMUNO-A).

z Zou F, et al. J Immunother Cancer 2021;9:e003277.aa Esfahani K, et al. N Engl J Med 2020;382;2374-2375; Thomas AS, et al. N Engl J Med 2021;384:581-583; Bishu S, et al. Gastroenterology 2021;160:932-934;

Shirwaikar Thomas A, et al. Am J Gastroenterol 2023;118:1679-1683.

FOOTNOTES

PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.

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NCCN

National sD to MEDIVE TE NCCN Guidelines Version 1:2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

GRADING

ASSESSMENT/GRADING

· Diarrhea

· Colitis Severe(G3-4)m

●Fecal protectin± lactoferrin

●Consider abdominal/pelvic CT with contrasts

· Recommend Gl consultation

●Colonoscopy or flexible sigmoidoscopy±EGD with biopsy°

●Principles of Immunotherapy Rechallenge(IMMUNO-C).

g Start infliximab at 5 mg/kg.

$^{h}$ Perform ID screening(HIV; hepatitis A, B, C), and TB blood test(eg, T-Spot/QuantiFERON-TB Gold)(depending on facility), preferably before administering first dose of infliximab or vedolizumab. In urgent situations, treatment does not need to be held for results.

${ }^{i}$ Infliximab antibody testing is generally not recommended and should not delay switch of therapy.

mMore than 6 bowel movements above baseline per day, colitis symptoms, interference with ADLs, hemodynamic instability, hospitalization, serious complications (eg, ischemic bowel, perforation, toxic megacolon), or other colitis-related life-threatening conditions.

nIt is not necessary to wait for test results before providing therapy to manage irAEs.

○Consider endoscopy exam within 2 weeks if either lactoferrin or calprotectin is positive. Serial monitoring of calprotectin levels while on treatment(every 2 months) may be helpful to guide treatment duration until achieving endoscopic remission.

Principles of Immunosuppression(IMMUNO-A).

sIn cases with high suspicion for complications(eg, toxic megacolon, abscess, perforation).

vConvert to prednisone when appropriate.

w Treat until symptoms improve to grade $\leq 1$ , then taper steroids in $< 4$ to 6 weeks. In cases where infliximab or vedolizumab is used, an attempt to taper steroids in $< 2$ to 4 weeks should be made to minimize the complication of infection. If strong clinical suspicion for ICI diarrhea,the start empiric IV steroids while waiting for EGD/colonoscopy/flexible sigmoidoscopy results.

MANAGEMENTP

●G3: If using combination IO therapy, discontinue current therapy

●G4: Discontinue immunotherapy agent responsible for toxicity

●Consider inpatient care for provision of supportive care

●IV methylprednisolonev(1-2 mg/kg/day)

●If no response in 1-2 days or unable to transition to oral steroids, additional immunosuppression required

If colonoscopy or flexible sigmoidoscopy shows significant ulceration, non-ulcerative inflammation, or microscopic colitis on histology,x continue steroids and strongly consider adding infliximab9,h,i,y or vedolizumab.h,y,z,aa

Consider tofacitin or uketinumab for infliximab-and/or vedolizumab-refractory colitis aa

● For persistent diarrhea that does not resolve after the management described above, consider other etiologies(eg, pancreatic exocrine insufficiency, celiac disease)

●For immunosuppressant-refractory colitis, fecal

transplantation may be considered based on institutional availability and expertise

${}^{x}$ For patients with severe colitis such as ulcerations on colonoscopy/flexible sigmoidoscopy,higher rates of refractory response to steroids have been reported. Early introduction of infliximab or vedolizumab can be considered to reduce recurrence.

y Duration of therapy with infliximab or vedolizumab is not clearly defined; however, receipt of three or more doses(at weeks 0,2, and 6) has been associated with less frequent colitis recurrence. Repeat endoscopy and/or fecal calprotectin to assess endoscopic healing may be helpful to guide colitis treatment duration, but is optional. See Principles of Immunosuppression (IMMUNO-A).

Zou F,et al.J Immunother Cancer 2021;9:e003277.

aa Esfahani K,et al.N Engl J Med 2020;382;2374-2375; Thomas AS,et al.N Engl J Med 2021;384:581-583.Bishu S,et al.Gastroenterology 2021;160:932-934; Shinwaikar Thomas A,et al.Am J Gastroenterol 2023;118:1679-1683.

National NCCN pressed be MEDIVE TE NCCN Guidelines Version 1.2026

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Management of Immune Checkpoint Inhibitor-Related Toxicities

HEPATOBILIARY ADVERSE EVENT(S)

![#####Elevated ALT/AST\n$\rightarrow$\n$055527444444\nG1\n$<3\times 0$ upper limit of normal(ULN)\n$\rightarrow$\nG2\n$<3\times 0$ upper limit of normal(ULN)\n$\rightarrow$\nG3\n>5 to 20 x ULN\nG4\n>20 x ULN\nIICI GI-6\n4\n5\n2\n905\n1000\n125\n195\n180\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n195\n1\n](2/aj0YEe4oUhYkBdfpda0fYP/figured4d5cfd749774c89993b44b9941ecefd_0_6.png) e Principles of Immunotherapy Rechallenge(IMMUNO-C).

P Principles of Immunosuppression(IMMUNO-A).

bb Consider initiating steroids while waiting for results in cases of G4 ALT/AST elevations.

cc Hyperbilirubinemia of hepatic origin is generally of conjugated predominance(or conjugated hyperbilirubinemia).

dd Consider testing for viral infections based on liver test pattern, viral risk factors, and clinical presentation including hepatitis B surface antigen(HBsAg).

ee ALT,AST,alkaline phosphatase, bilirubin (total and direct), and albumin.F prednisone with maximum dose of 60 mg/day has been shown to be effective in autoimmune hepatitis. Mack CL,et al. Hepatology 2020;72:671-722.

99 When liver tests show sustained improvement or return to $\leq$ G1, initiate steroid tapering and continue to taper over at least 1 month with frequent follow-up to guide taper duration. Re-escalate as needed.

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Management of Immune Checkpoint Inhibitor-Related Toxicities

HEPATOBILIARY ADVERSE EVENT(S) ASSESSMENT/GRADINGbb,cc

![General (G3 or G4)\nGeneral (G3 or G4)\n●Elevated ALT/AST G3 >5 to 20 x ULN G4 >20 x ULN ·Concomitant elevated Gl/hepatology ∞=Reuse\n●See Assessment on ICI Gl-5 eva evaluation\nG3 G4\nG3.\n](2/aj0YEe4oUhYkBdfpda0fYP/figure7b1f1b42531a4d9d9d7bb83b3d3bf9d5_0_6.png) Version 1.2026, 10/23/2025 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Management of Immune Checkpoint Inhibitor-Related Toxicities

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Note: All recommendations are category 2A unless otherwise indicated.

ICI_GI-6A

e Principles of Immunotherapy Rechallenge (IMMUNO-C). p Principles of Immunosuppression (IMMUNO-A).bb Consider initiating steroids while waiting for results in cases of G4 ALT/AST elevations.cc Hyperbilirubinemia of hepatic origin is generally of conjugated predominance (or conjugated hyperbilirubinemia).ee ALT, AST, alkaline phosphatase, bilirubin (total and direct), and albumin.ff Prednisone with maximum dose of 60 mg/day has been shown to be effective in autoimmune hepatitis. Mack CL, et al. Hepatology 2020;72:671-722.gg When liver tests show sustained improvement or return to ≤G1, initiate steroid tapering and continue to taper over at least 1 month with frequent follow-up to guide

taper duration. Re-escalate as needed.

hh Infliximab has been associated with drug-induced liver injury, particularly drug-induced autoimmune hepatitis.ii Consider mycophenolate mofetil at a maximum dose of 1.5 g every 12 hours. Tacrolimus may be considered instead of mycophenolate mofetil in patients with

concomitant diarrhea or leukopenia or added to mycophenolate mofetil in refractory cases. Monitor renal function and check single tacrolimus trough level 2 to 3

days after initiation and if dose is increased. Snijders RJALM, et al. J Hepatol 2024;80:576-585. There is no target tacrolimus trough level; target the lowest dose that induces a biochemical response. Taper serially, starting with medications with the highest toxicity first (typically prednisone).

jj Other steroid-sparing therapy may include ATG or azathioprine. Response to these agents may be delayed and may require prolonged therapy in the treatment of

irAEs.

ll A total bilirubin >2.5 mg/dL plus international normalized ratio (INR) >1.5, ascites, or encephalopathy. Hountondji L, et al. Aliment Pharmacol Ther 2024;60:1561-1572.mm Consider early concomitant use of mycophenolate mofetil with the initiation of steroids.

FOOTNOTES

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Management of Immune Checkpoint Inhibitor-Related Toxicities

![EPEDKaline phosphatase (predominant)nn with or without bilirubin/AST/ALT elevation00\nConsider fiber infiltration of charge 5-nuclei 2020\nG1<2.5 x ULN (or baseline)\n允2.5-5 x ULN (or baseline)\nG2\n2.5-5 x ULN (or baseline)\nOPERUM\nIteathline\nG4\n20\n>20\n3\n4\nG3\n5\n-20\nx ULN (or baseline)\nOHR\n](2/aj0YEe4oUhYkBdfpda0fYP/figureb172b70f4cf44420a15c31ab396d517f_0_5.png) Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

ICI_GI-7A

e Principles of Immunotherapy Rechallenge (IMMUNO-C).p Principles of Immunosuppression (IMMUNO-A).ee ALT, AST, alkaline phosphatase, bilirubin (total and direct), and albumin.gg When liver tests show sustained improvement or return to ≤G1, initiate steroid tapering and continue to taper over at least 1 month with frequent follow-up to guide

taper duration. Re-escalate as needed.

ii Consider mycophenolate mofetil at a maximum dose of 1.5 g every 12 hours. Tacrolimus may be considered instead of mycophenolate mofetil in patients with

concomitant diarrhea or leukopenia or added to mycophenolate mofetil in refractory cases. Monitor renal function and check single tacrolimus trough level 2 to 3

kk Due to an increased risk of GI perforation with IL-6 inhibitors (tocilizumab), assess for history of clinically active diverticular disease prior to initiating IL-6 inhibitors and use with caution in those patients.mm Consider early concomitant use of mycophenolate mofetil with the initiation of steroids.nn There is no predetermined alkaline phosphatase elevation. A predominant alkaline phosphatase elevation can be indicative of cholangitis.oo If elevated AST and ALT levels, see ICI_GI-5.pp Drug-induced cholestasis may include penicillins, trimethoprim-sulfamethoxazole (TMP-SMZ), macrolides, tetracycline, antifungals, antiretrovirals, anti-inflammatories, and psychotropes.

qq Endoscopic retrograde cholangiopancreatography (ERCP) can be considered.rr Ursodiol is available in capsules (200 mg, 300 mg, 400 mg) and tablets (250 mg, 500 mg). Split dosing (BID or TID) with food should be considered to enhance

absorption and minimize GI side effects.

ss Other steroid-sparing immunosuppressive therapy may include ATG, azathioprine, tacrolimus, or tocilizumab. Response to these agents may be delayed and may

require prolonged therapy in the treatment of irAEs.

FOOTNOTES

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National NCC and MEDIVE TE NCCN Guidelines Version 1:2026

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Management of Immune Checkpoint Inhibitor-Related Toxicities

![PANCREATIC ADVERSE EVENT(S)\nASSESSMENT/GRADING\nMild\nS3 x ULN lipase\nElevation in lipase (asymptomatic)\n•Assess for signs/symptoms of pancreatitis $^{t}$ \nIf clinical concern for pancreatitis, see $^{I}$ CJI $-9$\n●If isolated elevation of enzymes without evidence of pancreatitis, consider continuing immunotherapy$\text{e}\n●Evaluate for pancreatitis ($CI_I$_G-9)\nIf evidence of pancreatitis, manage according to pancreatitis algorithm ($I_C_I$_9)\n●Consider other causes for elevated lipase $\text{uu}$\n](2/aj0YEe4oUhYkBdfpda0fYP/figure18472d62b17441e8844be7843aa0ac8c_0_5.png) e Principles of Immunotherapy Rechallenge (IMMUNO-C).

P Principles of Immunosuppression(IMMUNO-A).

tt Mild symptoms of pancreatitis can include: nausea, bloating, belching, abdominal pain, or back pain.

uU Inflammatory bowel disease, irritable bowel syndrome, bowel obstruction, gastroparesis, nausea/vomiting, medications, alcohol, and/or DM.

v Routine lipase assessments do not have to be performed outside of clinical suspicion of possible pancreatitis. See Principles of Routine Monitoring for Immune Checkpoint Inhibitors(IMMUNO-1).

Note: All recommendations are category 2A unless otherwise indicated.

![NCCN\nNational\ned MEDIVE\nNCCN\nNational\n\n](2/aj0YEe4oUhYkBdfpda0fYP/figurebd79d16d247f421ba63be180a099ddc2_0_1.png) National NCCN Published MEUNDE T NCCN Guidelines: 0:2026

Conprehensive Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

PANCREATICWW ADVERSE EVENT(S)ASSESSMENT/GRADING MANAGEMENT'

![\nAcute pancreatitisxx\n\nAssess for signs/symptoms\nof pancreatitis\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n049\n■\n■\nAssess for signs/symptoms\n\n\n\n\n\n0\nAssess for signs/symptoms\nof pancreatitis\n\n\n\n\n0ncreparitis\nAbdominal CT with contrast\n\n\n\n\n0nrevisiting{NCCN\n\n\n\n\n\n0ncreparatitis\n\nAssess for signs/symptoms\n\n\n\n\n0\nAssess for signals/symptomsments\n\n\n\n0\nof pancreatitis\n\n\n\n\n0\nAssess for signs/symptoms\nof pancreatitis\n\n\n\n0ncreparatitis\nAbdominal CT with contrast\n\n\n\n0nrevisiting\nASSESSMENT/GRADING\nGeneral\n\n·Evaluate for signs/symptoms\n\nof pancreatic\n\nof pancreatitis\n\n\n0ncreparitis\n●Assess for other causes (ie,alcohol use,biliary)\n·Assess for IgG4; If positive, manage as autoimmune pancreatitis\nPancreatitis\n\n\n\n0ncreparitis\n●Assess for signs/symptoms\nof pancreatitis\nof pancreatitis\n\n\n0ncreparitis\n●Assess for other causes (ie, alcohol use,biliary)\n$\bullet$Assess for IgG4; If positive, manage as autoimmune pancreatitis\nPancreatitis\n\n\n0creparitis\n●Overstate for signal 25°ppfical\n95°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfical\n96°ppfic\n](2/aj0YEe4oUhYkBdfpda0fYP/figure0b210b88d2324a4db3f6425321fa8060_0_6.png) e Principles of Immunotherapy Rechallenge (IMMUNO-C).

P Principles of Immunosuppression(IMMUNO-A).

WWNo requirement for routine monitoring of potential pancreatitis with imaging.

XX Provide standard medical care for signs and symptoms of acute pancreatitis,including hospital admission, aggressive fluid resuscitation, and pain control. Management and follow-up of pancreatitis should be directed by gastroenterology/pancreatic subspecialists.

yy Asymptomatic lipase elevation OR radiologic features on CT or clinical findings concerning for pancreatitis. The decision to hold immunotherapy is based on clinical suspicion. If lipase>3x ULN or CT findings are prominent,holding immunotherapy is recommended.

zz Symptomatic pain or vomiting AND any lipase elevation or CT findings suggesting pancreatitis.

${}^{aa}$ Features of pancreatitis (enzyme elevation OR CT findings) with life-threatening consequences OR hemodynamic instability OR urgent intervention indicated.

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NCCN Generalism of Immune Checkpoint Inhibitor-Related Toxicities Table of Contents Can't 2025 National Comprehensive Cancer Number Indic

![HEMATOLOGIC ADVERSE EVENT(S)\nASSESSMENT\n anemia such as bleeding (eg, fecal occult blood test) and iron, B12, and folate deficiencies\nAplastic anemiad\nICI HEM-3\nHCIEM-2\nUnexplained drop in hemoglobin (Hb)a\nUnexplained drop in hemoglobin (Hb)a$\_$ $\_$\n](2/aj0YEe4oUhYkBdfpda0fYP/figuref0f6d078fbd5489ba9119bf47bb201ed_0_3.png) ![Unexplained drop in hemoglobin (Hb)a\nAplastic anemiad\nICI HEM-3\nHLH-like syndrome,f\nICI HEM-4\nThrombocytopenia\nICI HEM-5\nAmidor\n2023\nBone marrow biopsyb/aspirate\nAplastic anemiad\nICI HEM-3\nHLH-like syndrome,f\nICI HEM-4\nThrombocytopenia\nICI HEM-5\n](2/aj0YEe4oUhYkBdfpda0fYP/figure2f3a67f2069949fe86f911049e76ccc3_0_4.png) a Mild or transient Hb decreases or otherwise explained anemia may not require extensive workup. Consider the following factors when initiating assessment: baseline Hb, rapidity of change/timeline of assessment, persistence(≥2 weeks in separate tests), and severity.

b If aplastic anemia is suspected, a bone marrow biopsy is essential.

cElevated LDH and low haptoglobin, elevated indirect bilirubin, microspherocytosis and/or red blood cell(RBC) agglutination on blood smear, DAT positivity. Note that a negative DAT alone does not rule out ICI-autoimmune membrane lymphocyte.

d Anemia with or without leukopenia and thrombocytopenia. No evidence of nutrient deficiency(eg, B12), depressed reticulocytes.

e Findings may overlap with the traditional HLH diagnostic criteria(ie, HLH2004/HLH1994). Clinical findings may include: unexplained fever and hepatosplenomegaly.Laboratory findings may include: low counts, hypofibrinogenemia, elevated ferritin(≥500 ng/mL), elevated soluble IL-2 receptor levels(based on CD25), absent/low natural killer(NK) cell activity according to local laboratory reference, hypertriglyceridemia, and transaminitis. Histopathologic findings include: accumulation of lymphocytes/macrophages and hemophagocytosis; these may be identified via tissue biopsy, such as bone marrow, liver, or other tissues with suspected involvement(Henter JI, et al. Pediatr Blood Cancer 2007;48:124-131).

fICI therapy can cause an HLH-like hyperinflammatory syndrome that may not meet the traditional diagnostic criteria for HLH. It is still unclear how the diagnosis and management of ICI-related HLH-like syndrome differ from immune effector cell(IEC)-associated HLH-like syndrome(IEC-HS) observed after chimeric antigen receptor(CAR) T-cell therapy. For IEC-HS diagnosis and management recommendations, see CART-2 in the NCCN Guidelines for Management of CAR T-Cell Therapy and Lymphocyte Engager-Related Toxicities.

Note: All recommendations are category 2A unless otherwise indicated.

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NCCN Guidelines Index

NCCN 1999$\xrightarrow{\text{National}}$Nonal.Aconcer Management of Immune Checkpoint Inhibitor-Related Toxicities

HEMATOLOGIC ASSESSMENT GRADING MANAGEMENT ADVERSE EVENT(S)▶- See Assessment on ICI_HEM-1● Increased monitoring of CBC and hemolysis labs● Evaluate for and rule out other non-ICI-HEM out other non-ICI- related related hemolytic anemia● Examples include viruses, bacteria,use of certain drugs [examples include dapsone],methomoglobulinemia,methemoglobinemia,bone marrow failure syndrome, or insect or reptile bites●Grade 4: Evidence NCCN Guidelines Version 1:2026 2025 National Comprehensive Cancer Network, Inc. All Rights Reserved NCCN Guidelines Index 2026 Management of Immune Checkpoint Inhibitor-Related Discussion

● Hold immunotherapy9

•Hold immunotherapyg9

● Consider hematology referral

•Hold immunotherapyg9 →Hold immunotherapyg\n-2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb -2.6 g drop in Hb

•Prednisone 1 mg/kg once dailyh

● Consider hematology referral

•Discontinue immunotherapy9

· Urgent hematology referral

•Consider inpatient care

•Blood transfusion per institutional guidelines

•Prednisone/IV methylprednisolone 1 mg/kg once dailyh

● If no response to steroids after 5-7 days, consider adding rituximab

If no response to steroids and rituximab, consider IVIG,$i tacrolimus,cyclophosphamide,or mycophenolatemofetil

• Discontinue immunotherapy9

•Inpatient care required with hematology consult

•Blood transfusion per institutional guidelines

•IV methylprednisolone 1 mg/kg once dailyh

● If no response to steroids after 3-5 days, consider adding rituximab

If no response to steroids and rituximab, consider IVIG,$i-tacrolimus,cyclophosphamide,mycophenolate mofetil,or cyclosporine

NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

ICI_HEM-2A

c Elevated LDH and low haptoglobin, elevated indirect bilirubin, microspherocytosis and/or RBC agglutination on blood smear, DAT positivity. Note that a negative DAT alone does not rule out ICI-autoimmune hemolytic anemia.

g Principles of Immunotherapy Rechallenge (IMMUNO-C).h Treat until Hb level is stable without transfusion then taper over 4 to 8 weeks.i IVIG 2 g/kg divided in equal doses given over 2–5 consecutive days. Refer to the FDA-approved package insert for important safety information.

FOOTNOTES

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PLEASE NCCN MedilVE TINCC NCCN MedilVE TINCC NCCN Coherent 5:20:26

NCCN Guidelines Index

NCCN Consolidments Version 1:2026 NCCN Guidelines Department Inhibitor-Related Toxicities

![HEMATOLOGIC ADVERSE EVENT(S)\nASSESSMENT\n GRADING\nNon-severe: Does not meet does not meet severe or very severe or severity\n· Hold immunotherapyg\n· Consider: Red blood cell (RBC) and/or platelet transfusion as per institutional guidelines\n·Red blood cell (RBC) and/or platelet transfusion as per institutional guidelines\nHEMATOLOGIC ADVERSE EVENT(S)\n· See Assessment on ICI HEM-1\n·Increased CBC monitoring\n·Increased CBC\nmoneturnal hemoglobinuria (PNH)\n·Very severe Ìr\n](2/aj0YEe4oUhYkBdfpda0fYP/figure43775a488db14adf88bc6ec8625aba20_0_4.png) d Anemia with or without leukopenia and thrombocytopenia. No evidence of nutrient deficiency(eg,B12), depressed reticulocytes.

9 Principles of Immunotherapy Rechallenge(IMMUNO-C).

IVIG 2 g/kg divided in equal doses given over 2-5 consecutive days. Refer to the FDA-approved package insert for important safety information.

Severe aplastic anemia must meet two of the following criteria: absolute reticulocyte count<50-60x109/L, platelet count<20x109/L, and/or absolute neutrophil count(ANC)<0.5x109/L. Very severe aplastic anemia must meet the same criteria as severe with the exception of an ANC of<0.2x109/L.

k NCCN Guidelines for Hematopoietic Growth Factors.

Treat until symptoms improve to non-severe aplastic anemia, then taper over 4 to 8 weeks.

Note: All recommendations are category 2A unless otherwise indicated.

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NCCN Comprehensive Management of Immune Checkpoint Inhibitor-Related Discussion 1.2026

HEMATOLOGIC ASSESSMENT GRADING MANAGEMENT ADVERSE EVENT(S)

● See Assessment on ICI HEM-1 No.Additional laboratory tests:● Additional laboratory tests:● Ferritin, fibrinogen, soluble- fibritin, fibrinogen, soluble- AdAeroproduction upon grading scale; individual No agreed upon grading scale; individual in settings of● HSoreg abnormalities may● Discaetive treatment of abnormal, be adAeroproduction on abnormal, be adAeroproduction by bratin: Discaetive treatment of abnormal, be adAeroproduction by bratin: Discaetive treatment of abnormal, be adAeroproduction by bratin: Discaetive treatment of abnormal, be adAeroproduction by bratin: Discaetive treatment of abnormal, be adAeroproduction by bratin: Discaetive treatment of abnormal, be adAeroproduction by bratin: Discaetive treatment of abnormal, be adAeroproduction by bratin: Discaetive treatment of abnormal, be adAeroproduction by bratin: Discaetive treatment of abnormal, be adAeroproduction by bratin: Discaetive treatment of abnormal, be adAeroproduction by bratin: Discaetive treatment of abnormal, be adAeroproduction by bratin: Discaetive treatment of abnormal, be adAeroproduction by bratin: Discaetive treatment of abnormal, be adAeroproduction by bratin: Discaetive treatment of abnormal, be adAeroproduction by bratin: Discaetive treatment of abnormal, be adAeroproduction by bratin: Discaetive treatment of abnormal, be adAeroproduction by bratin: Discaetive treatment of abnormal, be adAe

e Findings may overlap with the traditional HLH diagnostic criteria (ie, HLH2004/HLH1994). Clinical findings may include: unexplained fever and hepatosplenomegaly.Laboratory findings may include: low counts, hypofibrinogenemia, elevated ferritin (s≥500 ng/mL), elevated soluble IL-2 receptor levels (based on CD25), absent/ low NK cell activity according to local laboratory reference, hypertriglyceridemia, and transmisinitis. Histopathologic findings include: accumulation of lymphocytes/ macrophages and hemophagocytosis; these may be identified via tissue biopsy, such as bone marrow, liver, or other tissues with suspected involvement (Henter JI, et al. Pediat Blood Cancer 2007;48:124-131).

fICI therapy can cause an HLH-like hyperinflammatory syndrome that may not meet the traditional diagnostic criteria for HLH. It is still unclear how the diagnosis and management of ICI-related HLH-like syndrome differ from IEC-HS observed after CAR T-cell therapy. For IEC-HS diagnosis and management recommendations, see CART-2 in the NCCN Guidelines for Management of CAR T-Cell Therapy and Lymphocyte Engager-Related Toxicities.

9Principles of Immunotherapy Rechallenge(IMMUNO-C).

m Noseda R, et al. J Immunother Cancer 2019;7:117.

n Liu LL,et al.J Immunother Cancer 2023;11:e005841.

°HLH2004 criteria were developed for pediatric populations. The HScore has been validated in adult populations and for reactive HLH in patients not treated with ICI. Its role in diagnosis of ICI-related HLH is unclear. Fardet L, et al. Arthritis Rheumatol 2014;66:2613-2620.

p Inpatient care is recommended for most, unless an expedited workup is possible. Inpatient care is required if ICI-related HLH-like syndrome is severe or life-threatening.

gTaper slowly(eg, up to 10 mg/week for prednisone/IV methylprednisolone or dexamethasone) and titrate for response with ongoing assessments for HLH flare(eg,monitoring inflammatory markers, ferritin).

For dexamethasone dosing, see Hines MR,et al.Transplant Cell Ther 2023;29:438.e1-438.e16.

sOzdemir BC,et al.Ann Oncol 2020;12:1775-1778.

t Due to an increased risk of GI perforation with IL-6 inhibitors (tocilizumab), assess for history of clinically active diverticular disease prior to initiating therapy and use with caution in those patients.

Note: All recommendations are category 2A unless otherwise indicated.

National NCCN pressed be to medIVE TE NCCN Guidelines Version 1.2026

NCCN Guidelines Index Table of Contents Discussion

![National\nNCCN\nManagement Checkpoint Inhibitor-Related\nHEMATOLOGIC ADVERSE EVENT(S)\nASSESSMENT\nGRADING\nGrade 1\nGrade 2\n·Consider increased CBC monitoring\n·Peripheral blood marced \n Reticulocyte count\nPT/INR, partial thromboplastin time (PTT),\nfibrinogen\nAbdominal ultrasound\nInfection panel: HIV,hepatitis C virus (HCV), H.\nplotoria\n·Underd 1275,000/mm3\n·Grade 75,000/00m3\nGrad 2\n·Continue immunotherapy\n·Monitor for signs of bleeding\n75,000/mm3\n·Add 2020-1.2024\nGrade 2\n50,000/mm3\n·Hold Immunotherapy\n·Hold immunotherapy\n·Considerne bone marrow results are not conclusive or other cell lines affected and aplastic anemia suspected\n·Evaluate for and rule out other non-ICI-related etiologies of thrombocytopenia\n·Examples include medication-related causes, infection,thrombotic therapy (TTP) rehomotic purpura (TTP), hemolytic uremic syndrome (HUS),and HLH\n](2/aj0YEe4oUhYkBdfpda0fYP/figurebc765d9748204a99bf2c3896206d2c13_0_3.png) 9 Principles of Immunotherapy Rechallenge(IMMUNO-C).

IVIG 2 g/kg divided in equal doses given over 2-5 consecutive days. Refer to the FDA-approved package insert for important safety information.

uThrombocytopenia induced by ICI is usually mild, may resolve spontaneously, and appears to respond to standard treatment algorithms for immune-related thrombocytopenia.Thus, standard institutional protocols may be appropriate for management.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Index

National SUNN cnsed to MEDELIVE TE NCCN Guidelines Version 1:2026

Conprehensive Management of Immune Checkpoint Inhibitor-Related Toxicities

![MUSCULOSKELETAL ASSESSMENT/GRADING ADVERSE EVENT(S)\n.\Number of joints\ndirectly involved\n\nConsider involved\nConsider the macrogenesis (cell count, gram stain and culture, crystal)\n.\Functional assessment\nAssessment\n●Consider\nMRI with or without contrast if diagnosis of synovitis is unclear\n●Consider joint x-ray to rule out other causes.\n●Disease markers\n(Anti-cyclic citrullinated peptide [anti-CCP] and rheumatoid factor [RF])\n●Disease activity 2024\nNCCN\nNational Cancer Network\n.\1:2023\n\nAssection\n■Continue immunotherapy if active measure below effective;otherwise hold immunotherapyh if NSAIDs and ineffective, consider prednisone 10-20 mg/day;if not already done) and increase prednisone to 30 mg/day.j,k\n●If unable to taper after 1 week, hold immunotherapyh if not already done) and increase prednisone to 30 mg/day j,k\n●If unable to taper prednisone from 30 mg/day after 1 week,\n●Can I I I I I I I I I I I I I I\nMCCN\n§Section 1\nInflammatory as REcentis as 2024\n●Disease markers can cause causes\n●Disease markers\n●Anti-cyclic citrullinated peptide [anti-CCP] and rheumatoid factor[RF])\n●Disease activity\n●Disease ngel\n●Rheumatology consultation\n·Consider holding immunotherapyh if NSAIDs are harrropes analysis\n·Nonether to taper after 1 week,\n●Rheumatology consultation\n·Prednisone 10-20 mg/day\n●Fulne to taper after 1 week,\n●If unable to taper differ ones from 30 mg/day after 1 week,\n●or sarilumab),p or tumor necrosis factor (TNF) inhibitors1,q,r\n](2/aj0YEe4oUhYkBdfpda0fYP/figure78bf96ec26594d198bb8158dd2118361_0_4.png) Version 1.2026, 10/23/2025 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

ICI_MS-1A

a Signs of inflammation include: joint swelling, morning stiffness (>1 hour), stiffness after inactivity, improvement in stiffness with activity, elevated CRP and/or ESR, or signs of synovitis on imaging.

b ICI IA can be seen with PMR-like manifestations.c Such as gout, infection, or pseudogout.d Mild in severity; only 1 or 2 joints involved. Consider aspiration to rule out septic joint if infection is suspected.e At least one joint with severe inflammation. f Limits ADLs, several joints involved.g Principles of Immunosuppression (IMMUNO-A).h Principles of Immunotherapy Rechallenge (IMMUNO-C).i Consider other non-opioid medications (eg, COX2 inhibitors or gabapentin/pregabalin). j Treat until symptoms improve to mild, then taper over 4–6 weeks. k If patients need to be on steroids long-term, see IMMUNO-A.l Perform the following screening tests prior to initiation of DMARDs: hepatitis serologies, CBC, TB, and liver tests.m csDMARDs include: methotrexate 15–20 mg (PO or SQ) every 7 days with folic acid 1 mg/day to reduce side effects. If methotrexate is contraindicated (including but not limited to: renal dysfunction, hepatic dysfunction, etc.), consider sulfasalazine starting at 500 mg PO BID (contraindicated in those with a sulfa allergy and requires assessment of glucose-6-phosphate dehydrogenase (G6PD) level prior to starting), leflunomide 10–20 mg/day PO, or hydroxychloroquine 200 mg PO daily or BID

based on weight (contraindicated in those with retinopathy).

n Consider intra-articular steroids in affected joint(s), depending on joint location and number involved and joint aspiration and fluid analysis. o For patients with significant concomitant inflammatory axial (spine and sacroiliac joint) inflammatory symptoms, TNF inhibitors should be preferred over csDMARDs.p Due to an increased risk of GI perforation with IL-6 inhibitors (tocilizumab or sarilumab), assess for history of clinically active diverticular disease prior to initiating

therapy and use with caution in those patients.

q TNF inhibitors include etanercept, adalimumab, infliximab, golimumab, or certolizumab. There is a slight increased risk of relapse.r In inflammatory arthropathies that have symptoms suggestive of psoriatic arthritis or spondyloarthropathies, consider agents that are approved for these indications

such as apremilast, IL-17, IL-12, or IL-23 inhibitors.

s Consider discontinuing immunotherapy if arthritis worsens, with repeated dosing, to the point where daily activities are limited or patient’s quality of life is severely

impaired.

t Consider ESR and CRP to monitor response if elevated at the onset of therapy. Inflammatory arthritis may become a chronic process requiring long-term management.

FOOTNOTES

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NCCN Guidelines Index Table of Contents Discussion

NCCN Consolidments Version 1:2026 NCCN Guidelines Department Inhibitor-Related Toxicities

|MUSCULOSKELETAL ADVERSE EVENT(S)|ASSESSMENT/GRADING|MANAGEMENT9| |---|---|---| |Polymyalgia rheumatica (PMR)4,v|●Assess for bilateral shoulder and hip girdle pain, and morning stiffness Screen for GCA symptoms (see below) ●Screen for GCA symptoms (see below) ● If visual symptoms or loss, see GCA Assessment/Grading and Management below ●ESR and CRP|●Continue immunotherapy If vision changes or loss present, hold immunotherapy until evaluated for GCAh ●Start prednisone 10-20 mg/day with slow taper over 6-8 weeksw If no resolution, consider holding immunotherapyh and increasing prednisone to 30-40 mgx ●If unable to taper prednisone or no improvement in symptoms, consider: ▶dsMARDs such as methotrexate ●IL-6 inhibitors (tocilizumab or sarilumab)p|

|Giant cell arteritis (GCA) (visual symptoms, headache, scalp levels, scalp claudication, often associated with fevers, night sweats, and weight loss)|●Screen for GCA symptoms ●If symptoms present, initiate prednisone 1 mg/kg/day with urgent referral to vascular surgery or ophthalmology for temporal artery biopsy± ultrasound due to risk of vision loss ●If available, refer to rheumatology|●Hold immunotherapyh ●If not already started, initiate prednisone 1 mg/kg/day taper over 8-12 weeks,x,y longer taper may be required ●Urgent referral to rheumatology even in mild cases for consideration of IL-6 inhibitors (tocilizumab or sarilumab) p| |---|---|---| |Giant cell arteritis (GCA) (visual symptoms, headache, scalp claudication, often associated with fevers, night sweats, and weight loss)|●Screen for GCA symptoms ●If symptoms present, initiate|●Hold immunotherapy 0 ●If not already started, initiate prednisone 1 mg/kg/day taper over 8-12 weeks,x,y longer taper may be required ●Urgent referral to rheumatology even in mild cases for consideration of IL-6 inhibitors (tocilizumab or sarilumab) p|

gPrinciples of Immunosuppression(IMMUNO-A).

hPrinciples of Immunotherapy Rechallenge(IMMUNO-C).

w If improving in 4 weeks, taper by 2.5 mg every 2-4 weeks.

p Due to an increased risk of GI perforation with IL-6 inhibitors (tocilizumab or sarilumab), assess for history of clinically active diverticular disease prior to initiating therapy and use with caution in those patients.

x Pneumocystis jirovecii pneumonia (PJP) prophylaxis if it is anticipated that patient will be treated with >20 mg prednisone for >4 weeks.

u Pain and/or stiffness in the morning usually involving bilateral shoulders and hip girdle region that limits instrumental or self-care ADLs.

y GCA requires a slower taper. Goldstein BL, et al. Arthritis Rheumatol 2014;66:768-769; Micaily I,et al.Ann Oncol 2017;28:2621-2622; Calabrese LH,et al.Nat Rev Rheumatol 2018;14:569-579.

vICI PMR can be seen with peripheral arthritis.

NCCN Guidelines Index Table of Contents Discussion

National NCCD to MEDIVE TE NCCN Guidelines: Version 1:2026

Comprehensive Network®

Management of Immune Checkpoint Inhibitor-Related Toxicities

MUSCULOSKELETAL ASSESSMENT/GRADING ADVERSE EVENT(S)

Myositisz(proximal muscle weakness, neck flexor weakness,with or without myalgias)

● Muscle strength testing(proximal muscles,including neck flexors, and distal muscles)

●Consider MRI without contrast, electromyography (EMG), muscle biopsy,and myositis antibodies if clinically indicated

MANAGEMENT9

•Consider holding or discontinuing immunotherapyh,ff

•Prednisone 0.5-1 mg/kg99,hh

•Monitor serial CK/aldolaseii

●If no response to therapy, consider re-evaluating for myasthenia gravis/myasthenia gravis-like syndrome(ICI NEURO-1) and myocarditis(ICI CARDIO-1), and escalate to management for severe or life-threatening myositis

•Hold immunotherapy; consider permanent discontinuation in select patientsh

•Inpatient care for severe or life-threatening myositis

Rheumatology or neurology consultation

Cardiology and/or neurology consultation if myocarditis and/or myasthenia gravis/myasthenia gravis-like syndrome is involved

•Consider IV methylprednisolone 500 mg to 1 g/day x 3 days followed by prednisone 1 mg/kg/day. After 4 weeks, taper prednisone by 10 mg every 2 weeks to 0.5 mg/kg/day and then 10 mg/month as clinical status allows

If no improvement after 2-4 weeks, consider the addition of a csDMARDhh

●If significant dysphagia, life-threatening situations,or refractory to steroids with minimal improvement after 1 week, consider IVIG ${}^{4}$ , methotrexate," mycophenolate mofetil, or rituximab

Abatacept with ruxolitinib has been used in concomitant myositis and myocarditismm

●Monitor serial aldolase/CK until symptoms have resolved and tapered off steroids

NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

ICI_MS-3A

g Principles of Immunosuppression (IMMUNO-A).

h Principles of Immunotherapy Rechallenge (IMMUNO-C).

z Myositis is a disorder characterized by inflammation and/or weakness involving the skeletal muscles with elevated muscle enzymes. aa Myocarditis symptoms are nonspecific (eg, chest pain, dyspnea, fatigue, palpitations [arrhythmia: heart block or ventricular ectopic beats], syncope, generalized

ejection fraction was preserved.

bb These concomitant irAEs can occur within the first month of therapy (median onset of 28–30 days).cc CK elevation <1000 mcg/L, mild weakness, and minimal impairment of ADLs; no myasthenia gravis/myasthenia gravis-like syndrome and/or myocarditis coexisting

with myositis.

dd Moderate pain associated with objective weakness and/or elevation of muscle enzymes (CK or aldolase) limiting self-care ADLs.ee Urgent intervention is indicated.ff Would not recommend holding ICI if no elevation in CK or evidence of active myositis.gg If improving after 2–4 weeks, begin slow prednisone taper by 5 mg/week. If unable to taper, or no response, add csDMARD.hh Methotrexate (with folic acid) as a steroid-sparing agent to speed up taper. If contraindication to methotrexate, consider mycophenolate mofetil or azathioprine.ii Do not need to trend aldolase unless aldolase elevation is the only evidence of myositis (CK normal). Aldolase can be falsely elevated if blood sample is hemolyzed.jj There have been case reports of a life-threatening triad of myositis, myocarditis, and myasthenia gravis/myasthenia gravis-like syndrome. kk IVIG 2 g/kg divided in equal doses given over 2–5 consecutive days. Refer to the FDA-approved package insert for important safety information.ll Methotrexate 15–25 mg weekly by oral or subcutaneous route.mm Salem JE, et al. Cancer Discov 2023;13:1100-1115.

FOOTNOTES

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National SUNN cns to MEDIVE TO THE NCCN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN CnN

NCCN Guidelines Index Table of Contents Discussion

NCCN Comprehensive Cancer Network®

Management of Immune Checkpoint Inhibitor-Related Toxicities

NEROUS ASYSTANb myasthenia gravis/ASSESSMENT/GRADING

● Neurology consultation

●AChR antibodies, anti-muscle-specific tyrosine kinase antibodies, and anti-striational antibodies in blood (not needed for diagnosis)

●Pulmonary function assessment with negative inspiratory force (NIF) and vital capacity (VC)

●EMG/nerve conduction study(NCS)with repetitive nerve stimulation and, if available, single-fiber EMG

●Consider MRI of the brain with and without contrast to rule out metastasis/leptomeningeal disease if there is facial/ocular/bulbar weakness

MANAGEMENT

· Discontinue immunotherapyf

•Consider inpatient care (even for initially mild cases, which can progress rapidly with a high mortality rate)

•Low-dose oral prednisone 20 mg daily 9

If no symptom improvement on low dose

◆ Increase every 3-5 days to a target dose of 1 mg/kg/day but not>100 mg daily

○Taper steroid based on symptom improvement

●Pyridostigmine 30 mg 3 times a day and gradually increase to maximum of 120 mg orally 4 times a day as tolerated and based on symptoms

•Permanently discontinue immunotherapyf

●Inpatient care (may need ICU-level monitoring)

●IV methylprednisolone 1-2 mg/kg/day gster/aperta based on symptom improvement)

•Initiate plasmapheres or IVIGh

Consider adding rituximab(375 mg/m2 weekly for 4 treatments or 500 mg/m2 every 2 weeks for 2 doses) if refractory to plasmapheresis or IVIG

●Frequent pulmonary function assessment

● Daily neurologic evaluation

●Avoid medications that can worsen myasthenia9.

aProgressive or fluctuating muscle weakness, generally proximal to distal. May have bulbar involvement (ie, ptosis, extraocular movement abnormalities resulting in double vision, dysphagia,facial muscle weakness) and/or respiratory muscle weakness. May occur with myositis and myocarditis. Respiratory symptoms may require evaluation to rule out pneumonitis. Miller Fisher variant of GBS has overlapping symptoms (ophthalmoplegia and ascending weakness).

b Myocarditis symptoms are nonspecific(eg, chest pain, dyspnea, fatigue, pallitations/ arrhythmia:heart block or ventricular ectopic beats], syncope, generalized weakness) and may occur as early as days to weeks after 1-2 doses of ICI. Although rare, myocarditis is often severe and associated with myositis/myasthenia gravis/myasthenia gravis-like syndrome(3 M's), and more common with combination therapy. In most fatal cases, conduction abnormalities were the cause of death, and ejection fraction was preserved.

c Some symptoms interfering with ADLs. Myasthenia Gravis Foundation of America(MGFA)severity class I(ocular symptoms and findings only) and MGFA severity class II(mild generalized weakness).

d Limiting self-care and aids warranted, weakness limiting walking, any dysphagia,facial weakness, respiratory muscle weakness, or rapidly progressive symptoms or MGFA severity class III-IV moderate to severe generalized weakness to myasthenic crisis.

e Principles of Immunosuppression (IMMUNO-A).

Principles of Immunotherapy Rechallenge(IMMUNO-C).

9 High-dose steroids(≥2 mg/kg/day) may exacerbate symptoms.

h IVIG 2 g/kg divided in equal doses given over 2-5 consecutive days. Refer to the FDA-approved package insert for important safety information.

${}^{i}$ Examples include, but are not limited to, beta-blockers, fluoroquinolones, and IV magnesium.

National NCCN Published to MEDIVE TE NCCN Guidelines Version 1:2026

1.2026 NCCN Guidelines Version 1:2026

NCCN Comprehensive Cancer Network®

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

NERVOUS SYSTEM ASSESSMENT/GRADING

![Guillain-Barré syndrome (GBS)^j\rightarrow\nabla_{\text {V}}(P_{1},P_{2})=\frac{\text { Inpatient care with access to ICU-level }}{\text { Inuteri level }} \cdot{MRI}\text { of the spine with and without }\\ 2.1333-23.333-24.33\text { contrast (rule out compressive lesion) } \end{array} \begin{aligned}& \text { |Inpatient care with access to ICU-level } \\ \text { CR16 } \end{aligned} \right. \begin{aligned}& \text {. Neurology consultation \\ \\ \end{aligned} \right. \text { - MRI of the spine with and without \\ \end{aligned} \n$\text { contrast (rule out compressive lesion) } \end{aligned} \t$ $\begin{aligned} \\ \text { CR16 } \end{aligned}$ \begin{aligned} \text {. Neurology consultation \\ \\ \text { CR16 } \end{aligned} \end{aligned} \t$ $\begin{aligned} \text { MRI of the spine with and without \\ \text { contrast (rule out compressive lesion) } \end{aligned} \right.$ $\begin{aligned} \text { CR16 } \end{aligned}$ \begin{aligned} \text {. Neurology consultation \\ \text { CR16 } \end{aligned} \end{aligned} \t$ $\begin{aligned} \text { - } \\ \text { Serum glioside antibody tests for \text { GBS } \text { variants (GQ1b for Miller Fisher } \\ \text { variant associated with ataxia and } \\ \text { ophthalmoplegia) } \end{aligned}$ $\begin{aligned} \text { + } \\ \text { Severe (G3-4)" } \end{aligned} \begin{aligned} \text { Moderate (G2)m } \\ \text { or } \\ \text { Severe (G3-4)" } \end{aligned} \end{aligned} \begin{aligned} \text { "Stance in1M3M}\\ \text { Moderate (G2)m } \\ \text { Severe (G3-4)" } \end{aligned} \end{aligned} \begin{aligned} \text {.1} \text { Inpatient care with capability of rapid transfer \\ \text { to ICU-level monitoring} \\ \text { to ICU-I level monitoring} \\ \text { - Start IVIGh or plasmapheresis in addition to IV} \\ \text { methylprednisolone 1 gram daily for 5 dayso}\\ \text { then taper over 4 weeks } \\ \end{aligned} \end{aligned} </td>\n <td>●Discontinue immunotherapyf</td>\n <td>of rapid transfer to ICU-level monitoring</td>\n <td>●Start IVIGh or plasmapheresis in addition to IV methylprednisolone 1 gram daily for 5 dayso</td>\n <td>to ICU-Lhgh or plasmapheresis in addition to IV 4 week</td>\n <td>●Stive IVIGh or plasmapheresis in addition to IV 4 methylprednisolone 1 gram daily for 5 dayso</td>\n <td>●Stive (G3-4)" </td>\n <td>then taper over 4 weeks</td>\n <td>●Frequent neurologic evaluation and pulmonary function monitoring</td>\n <td>5.2 function monitoring</td>\n <td>5.2 function monitoring</td>\n <td>5.2 function monitoring</td>\n <td>5.2 function monitoring</td>\n <td>5.2 function monitoring</td>\n <td>5.2 function monitoring</td>\n <td>5.2 function monitoring</td>\n <td>5.2 function monitoring</td>\n <td>5.2 function monitoring</td>\n <td>5.2 function monitoring</td>\n <td>5.2 function monitoring</td>\n <td>5.2 function monitoring</td>\n <td>5.2 function monitoring</td>\n <td>5.2 function monitoring</td>\n <td>5.2 function monitoring</td>\n <td>5.2 function monitoring</td>\n <td>5.2 function monitoring</td>\n <td>5.2 function monitoring</td>\n <t\n](2/aj0YEe4oUhYkBdfpda0fYP/figure739b12ecdbb941dc9d6a818fa32e29a2_0_7.png) ePrinciples of Immunosuppression(IMMUNO-A).

Principles of Immunotherapy Rechallenge(IMMUNO-C).

hIVIG 2 g/kg divided in equal doses given over 2-5 consecutive days. Refer to the FDA-approved package insert for important safety information.

Progressive, most often symmetrical muscle weakness with absent or reduced deep tendon reflexes. May involve extremities, facial, respiratory, and bulbar and oculomotor nerves. May have dysregulation of autonomic nerves. Often starts with pain in lower back and thighs.

${ }^{k}$ Early EMG/NCS findings may assess potential severity of GBS (Sejvar JJ, et al.Vaccine 2011;29:599-612; Leonhard SE,et al. Nat Rev Neurol 2019;15:671-683)and rule out sensory ganglionopathy, which may have a different prognosis.

${}^{1}$ Cerebrospinal fluid (CSF) typically has elevated protein and often elevated white blood cell(WBC) count; while cytology is negative in typical GBS, it is important to send given the risk of leptomeningeal carcinomatosis. Consider ID consult.ID workup: Measure opening pressure and check cell count, protein glucose,Gram stain, culture, PCR for HSV, and other viral PCRs depending on suspicion and cytology. May see normal glucose, normal culture, and Gram stain. May see reactive lymphocytes or histiocytes on cytology.

${}^{m}$ Some interference with ADLs, symptoms concerning to patient.

^Limiting self-care and aids warranted, weakness limiting walking, any dysphagia,facial weakness, respiratory muscle weakness, or rapidly progressive symptoms.

° Steroids are not usually recommended for idiopathic GBS; however, in immunotherapy-related forms, a trial is reasonable in addition to IVIG or plasmapheresis.

National SUNN Cancer Methods Version 1:2026

NCCN Guidelines Index

NCCN http://smy.yst/2025/10/28,21:14在医脉通平台下载，仅供个人使用，严禁分发。2025美国国家综合癌症网络版权所有。NCCN Guidelines Version 1:2026

![NERVOUS SYSTEM ADVERSE EVENT(S)\nMild (G1)^r and Moderate (G2)^s\nMild (G2)^s\nMild (G1)^r\nModerate (G2)^s\nSevere (G3-4)^t\nGBS (ICI)\nConsider B12, HbA1c, serum protein electrophoresis (SPEP) with immunofixation, HIV, and antineutrophil cytoplasmic antibody (ANCA)\n●Consider have3609.05\n·B12, HbA1c, SPEP with immunofixation, HIV, and ANCA\n●Consider EMG/NCS\n●Consider EMG/NCS\n●Consider neurology consultation\n·For progress, a result by using a general model by using the following potential to investigate using E2004.0\nMerg (G2)^t\nPeripheral neuropathyp,q\nModerate (G2)^s\nMerg (G1)^r\n01, H12, HbA1c, SPEP with immunofixation, HIV, and ANCA\n●Neuraxial imaging as per neurology\n●Consider EMG/NCS\n●Consider neurology consultation\n●Gabapentin, pregabalin, or duloxetine for pain\n\nSevere (G3-4)^t\nGBS (ICI)\nI1, NCCN\n●Consider interference with ADLs, symptoms concerning to the patient (ie, pain but no weakness or gait limitation).\nS Some interference with ADLs, symptoms concerning to the patient (ie, pain but no weakness or gait limitation).\nThe limiting self-care and aids warranted, weakness limiting walking or respiratory problems (ie, leg weakness, foot drop, rapidly ascending sensory changes).\nThe is a low threshold to hold ICls in mild cases of peripheral neuropathy. Sereve peripheral neuropathy and sensory ganglionopathy are not necessarily GBS but the management can be similar.\nThere is a low threshold to hold ICls in mild cases of peripheral neuropathy.\nSereve echnology (CI I) NEURO-2)\nI1, NCCN\n●Consider interference with E2004.0\nM M O\nSour (CI I) NEURO-2)\n1, NCCN\n●Consider interference with E2004.0\n·B12, HbA1c, SPEP with immunofixation, HIV, and ANCA\n●Initial observation or initiate prednisone\n0.5-1 mg/kg orally (if progressing from mild)\n·If progression, initiate IV methylprednisolone\n2-4 mg/kg/day " and see GBS (ICI NEURO-2)\n·Gabapentin, pregabalin, or duloxetine for pain\n](2/aj0YEe4oUhYkBdfpda0fYP/figure68da4bb0b5b64faaa6cc51aeba52ad3b_0_4.png) ePrinciples of Immunosuppression(IMMUNO-A).

Principles of Immunotherapy Rechallenge(IMMUNO-C).

p The presence of painful, asymmetric sensory/motor deficits should raise concern for mononeuritis multiplex and prompt evaluation for vasculitis or potentially life-threatening autonomic(eg, myenteric plexus) dysfunction. Hypo- or areflexia.Isolated sensory deficit or sensory plus lower motor neuron deficit.

g GI tract paresis due to myenteric neuritis is a rare toxicity associated with ICI therapy. The presentation may be fulminant with profound ileus. Early institution of high-dose steroids in concert with multidisciplinary management is recommended.

「No interference with function and symptoms not concerning to patient. Note: Any cranial nerve problem should be managed as moderate.

${}^{s}$ Some interference with ADLs, symptoms concerning to the patient (ie, pain but no weakness or gait limitation).

${}^{1}$ Limiting self-care and aids warranted, weakness limiting walking or respiratory problems(ie, leg weakness, foot drop, rapidly ascending sensory changes).Severe peripheral neuropathy and sensory ganglionopathy are not necessarily GBS but the management can be similar.

u There is a low threshold to hold ICLs in mild cases of peripheral neuropathy.

${}^{v}$ Specifically monitor for new interference with iADLs from either pain or weakness,gait difficulty,ataxia,or autonomic changes.

w Treat until symptoms improve to grade $\leq $1, then taper over 4-6 weeks.

Note: All recommendations are category 2A unless otherwise indicated.

PLEASE NOTE that use of the NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.

NCCN Guidelines Index

National NCC and MEDIVE TO NCCN Guidelines Version 1:2026

NCCN Comprehensive Management of Immune Checkpoint Inhibitor-Related Discussion Network®

|NEROUS ADVERSE EVENT(S)|ASSESSMENT|MANAGEMENT°|●Hold immunotherapyf if mild/moderate ●Consider discontinuing immunotherapy if severe ●Inpatient care (G3-4cc) ●Consider IV acyclovirdd until HSV and varicella zoster virus(VZV) PCR results obtained ●Add bacterial coverage until cultures/panel results are back ●Rule out bacterial and viral infection, then closely monitor off steroids| |---|---|---|---| |Aseptic meningitis|if abnormal neurologic exam of extremities, or unable to obtain exam ●Lumbar puncture(to exclude leptomeningeal disease)aa ●Consider neurology consultation|●Add bacterial coverage until cultures/panel results are back ●Rule out bacterial and viral infection, then closely monitor off steroids ●Start prednisone 0.5-1 mg/kg/day. For severe symptoms may start IV methylprednisolone 1-2 mg/kg/dayee|●Start prednisone 0.5-1 mg/kg/day. For severe symptoms may start IV methylprednisolone 1-2 mg/kg/dayee|

●Start prednisone 0.5-1 mg/kg/day. For severe symptoms may start IV methylprednisolone 1-2 mg/kg/dayee

||● MRI of the brain with and without contrastbb| |---|---| ||● Consider MRI of the spine with and without contrast, especially if abnormal neurologic exam of extremities, or unable to obtain exam| |Encephalitisy|● Lumbar punctureaa| ||● Electroencephalogram (EEG) to evaluate for non-convulsive seizure ● ESR, CRP, ANCA (if vasculitic process suspected)|

●Hold immunotherapyf if mild

•Discontinue immunotherapy if moderate/severe

●Inpatient care (G3-4cc)

•Consider IV acyclovirdd until HSV and VZV PCR results are obtained

•Add bacterial coverage until cultures/panel results are back;manage in consultation with ID team

●Trial of IV methylprednisolone 1-2 mg/kg/dayee

●If severe or progressing symptoms over 24 h, strongly consider IV methylprednisone 1 g daily for 3-5 days plus IVIGh or plasmapheresis

●If positive for autoimmune encephalopathy antibody or limited or no improvement after 7-14 days, consider rituximab

Principles of Immunosuppression(IMMUNO-A).

Principles of Immunotherapy Rechallenge(IMMUNO-C).

h IVIG 2 g/kg divided in equal doses given over 2-5 consecutive days. Refer to the FDA-approved package insert for important safety information.

Ⅹ May present with headache, photophobia, and neck stiffness, often afebrile but may be febrile.There may be nausea/vomiting. Mental status should be normal(distinguishing from encephalitis).

y Confusion, altered behavior, headaches, seizures, short-term memory loss, depressed level of consciousness, focal weakness, and speech abnormality.

z May reveal leptomeningeal enhancement that can resemble leptomeningeal metastasis.CSF sampling for cytology evaluation is needed to differentiate.

a8a Measure opening pressure and check cell count, protein glucose, Gram stain, culture, PCR for HSV, VZV, CMV, and other viral PCRs depending on suspicion, cytology, flow cytometry,and oligoclonal bands. If the patient is encephalopathic, check autoimmune encephalopathy panel. May see elevated WBC with normal glucose, normal culture, Gram stain, and elevated protein. May see reactive lymphocytes or histiocytes on cytology.

bb reveal T2/FLAIR changes typical of what is seen in autoimmune encephalopathies or limbic encephalitis or may be normal.

Limiting self-care and aids warranted.

dd 10 mg/kg IV every 8 hours.

Taper steroids over 4 weeks once symptoms resolve.

![NCCN\nNational\n\n](2/aj0YEe4oUhYkBdfpda0fYP/figure5ae2f7e0c8be4065a64203a99fec42d3_0_1.png) National SUNED to MEDIVEIVE 3NCC Cancer Network®

NCCN Guidelines Version 1:2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NEROUS SYSTEM ADVERSE EVENT(S)

ASSESSMENT

MANAGEMENT

Demyelinating and diseaseff (optic neururitis, 99 transverse myelitis, hh ADEMii [acute demyelinating) encephalomyelitis])

● Neurology consultation

● MRI of the spine and brain with and without contrastij

● Lumbar puncturekk

●B12, copper,HIV, syphilis serologies,antinuclear antibody(ANA),anti-Ro/La antibodies,aquaporin-4 IgG,myelin oligodendrocyte glycoprotein(MOG) IgG,autoimmuneence encephalopathy panel, and paraneoplastic panel

· Evaluation for constipation and urinary

· Discontinue immunotherapyf

•Inpatient care

•IV methylprednisolone 1 g/dayee for 3-5 days

● If there is no response or worsening after 48 hours on high-dose IV methylprednisolone, consider IVIGh or plasmapheresis

●For management of optic neuritis, see ICI_OCUL-3

ePrinciples of Immunosuppression(IMMUNO-A).

Principles of Immunosuppression(IMMUNO-A).

h IVIG 2 g/kg divided in equal doses given over 2-5 consecutive days. Refer to the FDA-approved package insert for important safety information.

ee Taper steroids over 4 weeks once symptoms resolve.

ff Guidon AC, et al. J Immunother Cancer 2021;9:e0028890.

99 Vision loss, eye pain, decreased visual acuity, visual field loss, dyschromatopsia, relative afferent pupillary defect, optic disc edema.

hh Acute or subacute weakness or sensory changes bilaterally, often with bowel/bladder changes and spinal level to pinprick, hyperreflexia, positive Babinski.

$^{\dagger}$ May present with headache, confusion, seizures, depressed level of consciousness, speech abnormality, focal weakness, sensory change (numbness or tingling), ataxia/loss of balance, or vision loss.

${}^{i}$ In patients with suspected optic neuritis, MRI of the orbits with and without contrast is recommended.

kk Cell count,protein,glucose,oligoclonal bands,viral PCRs,flow cytometry and cytology,and paraneoplastic panel.

NCCN Guidelines Index

National SUNN Cancer Medical Sciences: Version 1:2026

Conprehensive Management of Immune Checkpoint Inhibitor-Related Toxicities

![OULAR ADVERSE EVENT(S)\nACERSE EVENT(S)\nOphthalmology evaluation and management essential with vision testing to include:Visual acuity in each eye\nColor vision\nPupil size, shape,and reactivity\nVision or ocular ocular layer (RNFL)\nAsSESSMENT/GRADING\nVueitis\nPosterior or panuveitis (G3)\n20/200 or worse vision\nPupil size, shape,and reactivity\nVision or ocularly in intracularular pressure (IOP)Retinal nerve fiber layer (RNFL)\nMacula optical coherence (OCT) no tomography (OCT)\nDilated and visco evaluation:Visual acuity in each eye\nColor vision\nPupil size, including color and reactivity and reactivity\nVision or ocular ocular changes a,b\nMacula optical coherence (OCT)\nEpiscleritis\nMild (G1)\n·Moderate decrease (worse than than 20/20 but better than 20/20 or 3 lines decreased vision from baseline) (G2)\nMeadate decrease (worse than 20/40, or≤3 lines decreased 20/40 or >3 lines of decreased vision from baseline, up to 20/200) or worse vision (G4)\nEDI CLOUC-2 for sclritis, or sinrular and reactivity\nVuneitis\n·Hold immunotherapy\n·Amperular or panveitis (G3)\n·Posterior or panveitis (G4)\nVuneitis\n●Hold immunotherapy\n·Treatment guided by ophthalmology\n·Holdimmotherapy\n·Treatment guided by ophthalmology\n·Treatment guided by ophthalmology\n·Treatment guided by ophthalmology\n·Treatment guided by ophthalmology\nMaldone decrease (worse than 20/20 but better than 20/40, or 3 lines decreased\n20/40 or >3 lines of decreased vision from baseline, up to 20/200) or worse vision (G4)\n](2/aj0YEe4oUhYkBdfpda0fYP/figuredbbc84e99a91445a8e8a2b501af6f17c_0_4.png) NCCN授权医师脉通提供NCCN指南全文下载。wmIyys于2025/10/28,21:14在医脉通平台下载，仅供个人使用，严禁分发。2025美国国家综合癌症网络版权所有。

National pensed to MEDIVE TE NCCN Guidelines Version 1:2026

NCCN Guidelines Index Table of Contents Discussion

NCCN Comprehensive Cancer Network®

Management of Immune Checkpoint Inhibitor-Related Toxicities

![OULAR ADVERSE EVENT(S)\nASSESSMENT/GRADING\nScleritis\n\varnothing\n- Mild (G1)\n Oral NSAIDs (eg, flurbiprofen, indomethacin)\n● Moderate decrease (worse than 20/20\nbut better than 20/40, or $\le3$ lines\nDecreased decrease (worse than 20/40\n-20/GHER\n- Maxed decrease (worse than 20/40\nor>3 lines of decreased vision from baseline\nbaseline, baseline, up to 20/200 (G3)\n20/200 or worse vision\n- Continue immunotherapy\n●Artificial tears\nPupil size, shape, and reactivity\nVisual field\nRNFL\nOIP\nDilated容易 with vision\neq\nexamination\nSlit lamp examination\novate for other common causes\n(HLA-B27),including IDC\nIDC\nMild (G1)\nModerate decrease (worse than 20/20\n- Not better than 20/40\nbut better than 20/40, or $\le3$ lines\npermost and lower vision\nMarked decrease (worse than 20/40\n-20/GHER\nor>3 lines of decreased vision from baseline\nAIl\nOop\nLIP\nRNFL\nOIP\n-Marked decrease (worse than 20/40\nor>3 lines of decreased vision from baseline\nPlypl size, shape, and reactivity\nMudery field\nRNFL\nOIP\nModerate decrease (worse than 20/20\nbut better than 20/40\nor>3 lines decreased vision from baseline)\n20/200 or worse vision\nHold (G1)\nMild (G1)\n● Moderate decrease (worse than 20/20\nbut better than 20/40, or $\le3$ lines\nper most and decreased vision from baseline)\nMild\r\nor>3 lines of decreased vision from baseline, up to 20/200) (G3)\nNote: All recommendations are category 2A unless otherwise indicated.\n](2/aj0YEe4oUhYkBdfpda0fYP/figurec9507e1e09e84f25b33da8538a89372c_0_5.png) Note: All recommendations are category 2A unless otherwise indicated.

Footnotes on ICI_OCUL-3A

National SNe to MEDIVETENCN Guidelines Version 1:2026

NCCN Guidelines Index Table of Contents Discussion

NCCN Comprehensive Cancer Network®

Management of Immune Checkpoint Inhibitor-Related Toxicities

![OULAR ADVERSE EVENT(S)\nASSESSMENT\n Build(G1)\n Moderate decrease ( worse than 20/20 but better than 20/40, or $\simeq 3$ lines decreased vision from baseline) (G2)\n Vision or ocular changes a,b\n Ocular ADVERSE EVENT(S)\n Ophthalmology evaluation and management essential with vision testing to include: Visual acuity in each eye\n Color vision Pupil size, shape,and reactivity\n Vision field IOP RNFL\n Macula OCT\n Dilated\n NCCN\n Medical decrease (worse than 20/40\n endroly like eye disease/cranial\n or >3 lines of decreased vision from baseline) (G3)\n 20/200 or worse vision (G4)\n Irbital\n Mild (G1)\n Moderate decrease (worse than 20/20 but better than 20/40, or $\simeq 3$ lines decreased vision from baseline) (G2)\n Stilt lamp examination\n Evaluate for other common causes (HLA-B27), including ID°C\n Optic neuritis/neuropathy\n Mild (G1)\n Moderate decrease (worse than 20/20 or 3 lines of decreased vision from baseline) (G3)\n Mild (G1)\n Moderate decrease (worse than 20/40 but better than 20/200 or worse vision (G4)\n | Hold (G1)\n Mild (G1)\n Moderate decrease (worse than 20/20 or 3 lines of decreased vision from baseline) (G3)\n T - Ad 00/200 (G3)\n Mild (G1)\n Moderate decrease (worse than 20/20 but better than 20/40 or 3 lines of decreased vision from baseline) (G4)\n Vision or ocular changes in or $\n Vision or ocular changes in or \n 49 53 67 18 19 20\n Mild (G1)\n Mild (G1)\n Moderate decrease (worse than 20/20 but better than 20/40 or worse vision from baseline) (G4)\n V 20 20/200 or worse vision (G4)\nestortable (G1)\n Mild (G1)\n Moderate decrease (worse than 20/20 but better than 20/40 or 20/200 or worse vision (G4)\nNccN (G1)\n Moderate decrease (worse than 20/20 but better than 20/40 or 20/200 or worse vision (G4)\nNccN (G1)\n Mild (G1)\n Moderate decrease (worse than 20/20 but better than 20/40 or 20/200 or worse vision (G4)\nNccN (G1)\n Hold immunotherapy)\n Treatment guided by ophthalmology to include systemic prednisone/\n IV methylprednisolonef\n](2/aj0YEe4oUhYkBdfpda0fYP/figureebe0cd05ac164d17ad6fe83f9f3d7276_0_5.png) Note: All recommendations are category 2A unless otherwise indicated.

Footnotes on ICI_OCUL-3A

NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

ICI_OCUL-3A

FOOTNOTES

a Patients experiencing ocular AEs may present with any of the following symptoms: blurred/distorted vision, blind spots, change in color vision, diplopia, photophobia, tenderness/pain, eyelid swelling, and proptosis. Both uveitis and episcleritis can be associated with eye redness but slit lamp examination is essential to rule out

anterior chamber inflammation.

b See ICI_MS-2 for management of GCA.c Etiologies such as syphilis, toxoplasmosis, and TB can cause uveitis and therefore should be evaluated for and ruled out prior to stopping ICI therapy and/or initiating other local therapies.

d Principles of Immunosuppression (IMMUNO-A).e Principles of Immunotherapy Rechallenge (IMMUNO-C).f Treat with 1 mg/kg/day, not to exceed 60 mg/day until symptoms improve to grade ≤1, then taper over 4–6 weeks.g If refractory to high-dose systemic steroids, consider adding infliximab, or antimetabolites (eg, methotrexate) for panuveitis.

PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.

NCCN Guidelines Index

NCCN ismed to MEDIVE TE NCCN Guidelines Version 1:2026

Table of Contents

Discussion

|PulMONARY ADVERSE EVENT(S)|GRADING|MANAGEMENTf · Consider holding immunotherapyg ·Reassess in 1-2 weeks ·History and physical (H&P) ·Pulse oximetry (resting and with ambulation) ·Consider chest CT with contrasth, i ●Consider repeat chest CT in 4-6 weeks or as clinically indicated if patient develops symptoms| |---|---|---| |Pneumonitis|Mild (G1)b|●Consider chest CT with contrasth, i ●Consider repeat chest CT in 4-6 weeks or as clinically indicated if patient develops symptoms| |Pneumonitis|Moderate (G2)c,d|●Hold immunotherapyg ·Consider pulmonary consultation ·Minimally invasive evaluation ·Consider infectious workup: ▶ Nasal swab for potential viral pathogens ∞ Sputum culture (including bacterial, fungal, and acid-fast bacilli [AFB]), blood culture, and urine antigen test (eg, pneumococcus, legionella) ●Chest CT with contrasth, i and repeat chest CT in 3-4 weeks| |Pneumonitis|Moderate (G2)c,d|●Invasive evaluation ·Consider early bronchoscopy with BAL (send for institutional immunocompromised panelk) and consider transbronchial lung biopsy if clinically feasible to evaluate for progressive malignancy, fungal infections, or steroid responsive ILD ●Consider empiric broad-spectrum antibiotics (including coverage for atypical pathogens) if infection has not yet been fully excluded ·Prednisone/IV methylprednisolone 1-2 mg/kg/day ·Consider mycophenolate mofetil as a steroid-sparing immunosuppressant for steroid-dependent pneumonitis at the time of steroid taperingm ●Monitor every 3-7 days with n: H&P and pulse oximetry (resting and with ambulation) ●If no improvement after 48-72 hours of steroids,° treat as grade 3| |Severe (G3-4)e|ICI_PULM-2||

NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

ICI_PULM-2

ASSESSMENT/GRADING

MANAGEMENTf

Severe (G3–4)e pneumonitisa

• Hold immunotherapyg

• Inpatient care

• Pulmonary and ID consultation

• Minimally invasive evaluation

Infectious workup:

Consider that the patient may be immunocompromised

◊ Nasal swab for potential viral pathogensj

◊ Sputum culture (including bacterial, fungal, and AFB), blood culture, and urine antigen test (eg, pneumococcus, legionella)

◊ Consider cardiac evaluation to exclude cardiac causes for clinical presentation

• Invasive evaluation

Bronchoscopy with BAL (send for institutional immunocompromised panelk) if feasible to rule out infection,

malignant lung infiltration, or steroid responsive ILD and consider transbronchial lung biopsy if feasible and

clinically indicated

• Consider empiric broad-spectrum antibiotics (including coverage for atypical pathogens) if infection has not yet been fully excluded

• IV methylprednisolone 1–2 mg/kg/day. Assess response within 48 hours and plan taper over ≥6 weeksf

• Consider adding any of the following if no improvement after 48 hours:

Preferred:

◊ IVIGp

◊ Tocilizumabq

Other recommended:

◊ Mycophenolate mofetil 1–1.5 g BID then taper in consultation with pulmonary servicem

– Consider mycophenolate mofetil as a steroid-sparing immunosuppressant for steroid-dependent

pneumonitis at the time of steroid taperingm

◊ Infliximabr 5 mg/kg, a second dose may be repeated 14 days later at the discretion of the treating provider

Footnotes on ICI_PULM-2A

Note: All recommendations are category 2A unless otherwise indicated.

PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.

NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

ICI_PULM-2A

FOOTNOTES

a Focal or diffuse inflammation of the lung parenchyma (typically identified on CT imaging). Symptoms may include dry cough, shortness of breath, fever, chest pain,

and increased oxygen requirement. The imaging features of pneumonitis are known to be variable and may include ground-glass opacities, organizing pneumonia,

hypersensitivity, reticulonodular changes, or a mixture of all these appearances.

b Asymptomatic; confined to one lobe of the lung or <25% of lung parenchyma.c Presence of new/worsening symptoms. d Consider cardiac etiologies. e G3-severe symptoms involve all lung lobes or >50% of lung parenchyma, limiting self-care ADLs, oxygen indicated; G4–life-threatening respiratory compromise. f Principles of Immunosuppression (IMMUNO-A).g Principles of Immunotherapy Rechallenge (IMMUNO-C).h CT with contrast to rule out other etiologies if not contraindicated.i See Pre-Therapy Assessment: Pulmonary on IMMUNO-2.j Viral pathogen assessment should include influenza, COVID-19, and respiratory syncytial virus (RSV).k Immunocompromised panel may include CBC with differential, bacterial culture, and Gram stain; AFB culture and stain; fungal immunoassay, culture, and silver stain; and/or CMV, HSV, PJP, and respiratory virus PCR.

l Treat until symptoms improve to grade ≤1, then taper over 4–6 weeks.m Mycophenolate mofetil is unlikely to improve steroid-unresponsive pneumonitis immediately but may have clinical benefit to avoid steroid dependence.n If clinically indicated and appropriate, monitoring can be done with telemedicine.o In people with pre-existing/underlying lung compromise, greater clinical suspicion and caution should be taken.p IVIG 2 g/kg divided in equal doses given over 2–5 consecutive days. Refer to the FDA-approved package insert for important safety information.q Khanna D, et al. Lancet 2016;387:2630-2640; Khanna D, et al. Lancet Respir Med 2020;8:963-974; Manfredi A, et al. Intern Med J 2020;50:1085-1090. Due to an

increased risk of GI perforation with IL-6 inhibitors (tocilizumab), assess for history of clinically active diverticular disease prior to initiating therapy and use with caution in those patients.

r Data for infliximab demonstrate mixed response for treatment of ICI-pneumonitis and use of this agent should be considered carefully.

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National SUNN CERdensed to MEDIVE TO BECCN 2025.14:2026

NCCN Guidelines Index

![NCCN\nNational\nNCCN\nControl\nSSESSMENT\nGRADING\nNational\n\nComprehensive\nNot i\n2026\nNCCN\nNational\n\n\n\n\nRENAL ADVERSE EVENT(S)\nASSESSMENT\nGeneral:1\n\nStage 1, 2, 1\nA|K\n\n\n\n\n\n\nACK\n2\n\n\n\n\nA DERSE EVENT(S)\nCheck BUN, spot urine protein/creatinine ratio, urine microalbumin/creatinine ratio, urine electrolytes (sodium, creatinine),b and urinalysis(c) =\n\n\n\n\n1\n$NCCN\nGuiding\nStage 1\nA|K I^{-}\n$\nConsidering immunotherapy\nConcluding immunotherapy? \n$\nNCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\nHigh \n$NCCN\n\n](2/aj0YEe4oUhYkBdfpda0fYP/figuref36091aba5284ec6b99ff97db892e715_0_3.png) ![#####Elevated serum serum recine and aruruline rule, rule out acute glomerulonephritise\n2018\nGeneral:Stage 1,2, and 3AKI\nManagement Humpoire-Related\nGRADING\nGeneral:Stage 1,1,2, and 3 AKI\nLimit/discontinue nephrotoxic medications and dose adjust to creatinine clearance\nAvoid PPIs; use H2 blockers for Gl prophylaxis if initiating corticosteroids\n●Consider increased oral/IV hydration and reassess\n●Check sCR every 3-7 days\n●End my methodapyj\n●Consider holding immunotherapyy\n●Consider nephrology consult is still sustained elevations in creatinine\n●Hold immunotherapyj\n●Hold immunotherapyj\n●Consider nephrology consult is in a study of computer 2018/1.066777\nMethalprynodisone 1-2 mg/kg/day\nStage 2 AKI$|\n●Hold immunotherapyj\n●Consider inpatient care\n●Nephrology consultation\n●Prednisone/IV methyl prednisolone 1-2 mg/kg/day\nStage 3 AKI$|\n●Renal biopsyl\ntive\n●Prednisone/IV methyl prednisolone 1-2 mg/kg/day\nStage 3 AKI$|\n●Based on biopsy results, consider adding one of the following if kidney injury remains> stage 2 after 4-6 weeks of steroids or if creatinine increases during steroid taper (or once off steroids) (in alphabetical order)m:\n#######Aethioprine\nInfliximab\nMycophenolate mofetil\nRituximab\n#####Note: All recommendations are category 2A unless otherwise indicated.\n](2/aj0YEe4oUhYkBdfpda0fYP/figureabf8ed1decd5485e8d75038e7cd6e1fe_0_4.png) Version 1.2026, 10/23/2025 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

ICI_RENAL-1A

FOOTNOTES

a Azotemia, creatinine elevation, and inability to maintain acid/base or electrolyte balance.b Rule out pre-renal volume depletion and/or acute tubular necrosis.c Frequency and additional lab tests to be determined in consultation with nephrology to inform treatment.d General medical review and testing as warranted for prerenal and postrenal causes. Include medication review for nephrotoxic agents such as NSAIDs and PPIs, and consider obstruction, cardiomyopathy/heart failure, pulmonary hypertension, diuretics, hypovolemia due to primary GI cause, stones, and infection.

e For proteinuria >1 g/24-hour with no other etiology for proteinuria present such as diabetes or hypertension and/or gross or microscopic hematuria, check ANA; RF;

ANCA; anti-double-stranded DNA (dsDNA); serum C3, C4, and CH50; hepatitis B and C reflexive panels; SPEP; and urine protein electrophoresis (UPEP). For ICIinduced etiologies such as vasculitis and glomerulonephritis, check the following serologies, in addition to obtaining a kidney biopsy: ANA, dsDNA, RF, C3, C4, ANCA, anti-glomerular basement membrane (GBM), hepatitis B and C, HIV, rapid plasma reagin (RPR), SPEP, UPEP, and immunofixation electrophoresis (IFE). Consider

24-hour urine collection.

f 1.5 to <2x baseline or increase of ≥0.3 mg/dL over 48 hours.g 2 to <3x baseline.h ≥3.0x baseline; 4.0 mg/dL or need for renal replacement therapy (RRT); dialysis as indicated.i Principles of Immunosuppression (IMMUNO-A).j Principles of Immunotherapy Rechallenge (IMMUNO-C).k Treat until symptoms improve to grade ≤1, then taper over 4–6 weeks. Gupta S, et al. J Immunother Cancer 2022;10:e005646; Lee MD, et al. J Immunother Cancer

2021;9:e002292.

l Renal biopsy may help distinguish between ICI versus non-ICI–related toxicities; however, initiation of steroids should not be delayed while waiting for biopsy.m Data supporting use of these agents are limited.n Lin JS, et al. Oncoimmunology 2021;10:1877415.

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Note: All recommendations are category 2A unless otherwise indicated.

IMMUNO-A 1 OF 3

General Principles

• Close consultation with disease-specific subspecialties is encouraged.

Referral to a tertiary care center may be required for management of complex cases or multi-system irAEs.

• Selected irAEs including hypothyroidism and other endocrine irAEs may be treated with hormonal supplementation, without the need for

steroid therapy. See Endocrine Toxicities section.

• Vaccines that are inactivated or killed preparations are permissible during a course of immunotherapy. Due to the lack of clarity regarding

live vaccine use, it is not recommended during ICI therapy.

• Combination therapies with non-ICI agents (eg, vascular endothelial growth factor [VEGF] inhibitors) may complicate irAE workup due to

overlapping toxicity. If low suspicion of irAE, consider holding non-ICI therapy and monitoring before use of immunosuppression.

• An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.

Principles of Steroid Use in the Management of irAEs

• We recommend early intervention with steroids for the general management of immune-related toxicity.

• If unable to taper steroids, steroid-sparing measures with secondary agents may be appropriate to minimize steroid exposure and expedite resumption of ICI therapy.

• In the absence of specific indications such as prior infusion reaction or concurrent chemotherapy, routine premedication with steroids is not recommended given the potential mitigation of immunotherapeutic effectiveness in the prophylactic setting.

• Steroid Dosing

See individual toxicity pages for specific recommendations on steroid dose by grade. Where immunotherapy rechallenge is indicated, see

the Principles of Immunotherapy Rechallenge (IMMUNO-C) for guidance by organ site.

Higher potency (eg, Class 2 or 3) topical steroids are preferred for short-term use for immune-related dermatitis, compared to longer term

use of lower potency steroids.

Prednisone is the preferred oral steroid due to ease of dosing and wide availability. IV methylprednisolone is the preferred IV steroid.

• Steroid Taper

Longer steroid tapers (>4 weeks, sometimes 6–8 weeks or longer) may be required to prevent recurrent irAE events, particularly

pneumonitis, hepatitis, and neuromuscular toxicities.

Patients who are initiated on longer steroid tapers should have close follow-up with oncologist or co-managing disease-specific

subspecialist team to monitor for side effects of steroid use, and to evaluate any need for modifying immunosuppressant regimen as

appropriate based on clinical improvement of irAE.

Continued PRINCIPLES OF IMMUNOSUPPRESSION FOR PATIENTS RECEIVING IMMUNE CHECKPOINT INHIBITOR IMMUNOTHERAPY

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IMMUNO-A 2 OF 3

• Prophylaxis

Infection

◊ Pneumocystis jirovecii pneumonia (PJP) prophylaxis is recommended for patients expected to receive ≥20 mg daily prednisone

equivalent for ≥4 weeks. Consider starting PJP prophylaxis if still steroid-dependent by the end of 2 weeks. Sulfamethoxazoletrimethoprim is preferred. For patients with a sulfa allergy, consider aerosolized/IV pentamidine. Consider avoiding atovaquone due

to risk of diarrhea particularly in patients with colitis, and avoid dapsone due to risk of hemolytic anemia. Check glucose-6-phosphate

dehydrogenase (G6PD) screen prior to dapsone use. See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.

◊ Other fungal infections are rare, and the utility of prophylaxis for these infections is unclear. Patients receiving extended

immunosuppression may be at higher risk of an invasive fungal infection.

◊ Prophylaxis against HSV or VZV reactivation can be considered. See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.

Gastritis

◊ PPI therapy or H2 blockers can be considered for patients at higher risk of gastritis (eg, NSAID use, anticoagulation) for the duration of steroid therapy. Consider prescribing full-dose PPI when the patient is taking high-dose steroids.

Osteoporosis

◊ If patients need to be on steroids long-term, they are at risk for developing osteoporosis. Vitamin D and calcium supplementation

should be provided to prevent osteoporosis. Refer patient to physical therapy and to endocrinology; weight-bearing exercises are

recommended.

◊ Steroid use of >30 mg for >30 days puts patients at high risk for vertebral fractures. Depending on clinical context, consider use of

agents to maintain bone mineral density.

Pathogen Reactivation

• There is a risk for hepatitis B virus (HBV) reactivation with anti-TNFα agents, rituximab, or other immunosuppressive agents (eg, steroids). Test for HIV, hepatitis B (surface antigen and core antibodies), and hepatitis C prior to TNF inhibition and monitor HBV/HCV carriers during and for several months after therapy.

• There is a risk for TB activation. Test for latent/active TB prior to TNF inhibition. TB testing should not delay initiation of anti-TNFα agents for the management of irAEs.

Results of TB testing need not be finalized prior to dosing anti-TNFα agents in the acute setting.

Interferon-gamma release assays for TB testing are preferred.

• For individuals starting on steroids who were born or who have lived for >3 months in areas endemic for Strongyloides such as Central or

South America, Southeast Asia, and Africa, would send Strongyloides IgG serology and either treat for positive serology, or treat empirically with ivermectin 0.2 mg/kg daily x 2 days and repeat in 2 weeks for total of 4 doses.

PRINCIPLES OF IMMUNOSUPPRESSION FOR PATIENTS RECEIVING IMMUNE CHECKPOINT INHIBITOR IMMUNOTHERAPY

Continued

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Principles of Immune Checkpoint Blockade in Patients with Pre-Existing Autoimmune/Viral Conditions or Organ Transplant Recipients

Note: All recommendations are category 2A unless otherwise indicated.

IMMUNO-A 3 OF 3

1 Portuguese AJ, et al. J Natl Compr Canc Netw 2022;20:406-416.

PRINCIPLES OF IMMUNOSUPPRESSION FOR PATIENTS RECEIVING IMMUNE CHECKPOINT INHIBITOR IMMUNOTHERAPY

• Patients with a history of HIV or viral hepatitis may be candidates for immunotherapy. See the NCCN Guidelines for Cancer in People with HIV.

• Patients with pre-existing autoimmune conditions or organ transplant recipients may be candidates for immune checkpoint blockade.

• Patients with autoimmune neurologic conditions or life-threatening autoimmune disorders, particularly if not controlled with

immunosuppressive medications or requiring high doses of immunosuppression, are unlikely to be suitable candidates for cancer

immunotherapy.

• Patients with prior allogeneic hematopoietic cell transplant (HCT) may be candidates for immunotherapy.

Considerations for Patients with Pre-existing Autoimmune Conditions

• Anti–cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)-based therapy has a higher incidence of exacerbating baseline autoimmune conditions relative to anti-programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1)–based approaches.

• Optimization of immunosuppression for pre-existing autoimmune conditions, including close follow-up with pertinent subspecialists, is

recommended.

Goal of immunosuppressive regimen allowing for dose of prednisone <10 mg daily or equivalent prior to initiating cancer immunotherapy.

Considerations for Organ Transplant Recipients1

• Graft failure while on cancer immunotherapy has been reported. Transplant organ loss may be an outcome of treatment with cancer

immunotherapy and should be discussed with patient and organ transplant team. The risks and benefits of ICI therapy in patients with organ

transplantation are very complex. Please refer to transplant team prior to starting immunotherapy in such patients.

Patients with solid organ transplantation who have a viable option for alternative therapy if there is graft rejection (eg, kidney) may

be candidates for immunotherapy, particularly if there is no prior evidence of graft rejection and if the patient is on maintenance

immunosuppression.

Consideration for Patients with Prior Allogeneic HCT

• There is an increased risk of transplant-related complications, including potentially fatal graft-versus-host disease (GVHD).

• Careful discussion with patient and allogeneic HCT physicians should precede initiation of immunotherapy.

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NCCN Guidelines Version 1.2026

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Note: All recommendations are category 2A unless otherwise indicated.

IMMUNO-B 1 OF 3

HEALTH CARE PROVIDER (HCP) INFORMATION

Prior to Starting Immune Checkpoint Inhibitor (ICI) Therapya:

• Assess patient’s understanding of disease and recommendations for treatment.

• Educate patients about mechanism of action and rationale for use of ICIs.

• Document any underlying medical conditions affecting any organ system (eg, pulmonary, cardiac, neurologic, musculoskeletal).

• It is important to take a history of any autoimmune diseases.

• Record all medications, including over-the-counter medications and herbal supplements.

• Patients of childbearing potential should be advised to use effective birth control during and for at least 5 months after the final dose of

immunotherapy.

The effect of immunotherapy on human reproductive function is unknown. Consider fertility preservation and reproductive endocrinology

referral for all patients starting therapy who have not yet completed family planning.

• Breastfeeding is contraindicated during and for at least 5 months after the final dose of immunotherapy.

• Provide patients with and instruct them to carry a wallet card that outlines the type of immunotherapy they are receiving, potential irAEs, and contact numbers for their oncology health care team.

• Assess patient’s ability to monitor and report potential irAEs. Engagement of caregiver may be necessary.

• Assess patient for potential for home care support service needs during therapy.

• Educate patient about the potential toxicity profile of ICI therapy, including presenting symptoms and timing.

• Inform patient of existing educational resources:

NCCN Guidelines for Patients

Understanding Immunotherapy Side Effects

Oncology Nursing Society: Immunotherapy Wallet Cards

Instruct Patients to Notify the Oncology Health Care Team if:

• Any new signs or symptoms develop, including severe fatigue, headache, rash, cough, shortness of breath, chest pain, abdominal bloating, change in bowel pattern, weight loss, vision changes or eye pain, severe muscle weakness, severe muscle or joint pains, and/or mood

changes.

irAEs can occur after completion of therapy. Patients should monitor symptoms for at least 2 years following the conclusion of

immunotherapy.

• Patient is evaluated by other HCPs or admitted to the hospital.

• Any new medications are prescribed, or prior to receiving any immunizations or vaccinations.

Vaccines that are inactivated or killed, or mRNA (eg, COVID vaccines) preparations are permissible during a course of immunotherapy. Due

to the lack of clarity regarding live vaccine use, it is not recommended during ICI therapy.

• Patients are experiencing ICI-T1DM and/or ICI-hypophysitis with adrenal insufficiency. These patients are recommended to wear a medical

alert bracelet, ensure adequate supply of medications if traveling, and notify their oncologist or endocrinologist in advance of scheduled

procedures or in case of acute illness as medication doses may need to be adjusted. See ENDO-3 for recommendations on stress dose

steroids.

PRINCIPLES OF IMMUNOTHERAPY PATIENT EDUCATION

Continued

a Principles of Routine Monitoring for Immune Checkpoint Inhibitors (IMMUNO-1).

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NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

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HEALTH CARE PROVIDER (HCP) INFORMATION

Toxicity Managementa:

• Review patient medications for potential drug interactions (eg, QT prolongation) when administering agents to manage ICI-related toxicity.

• Mild to moderate AEs:

Provide symptomatic management.

Delay in immunotherapy may be recommended if unclear if irAE is developing or until AEs resolve to grade 1 or pre-treatment baseline.

Steroids may be required if AE does not improve. If hormone replacement is required, it is usually for lifetime and may continue beyond the

completion of therapy with ICIs.

• Severe AEs:

Discontinue immunotherapy.

Initiate steroid therapy immediately. IV methylprednisolone should be considered until there is evidence of improvement in toxicity.

Additional immunosuppressant therapy may be required for steroid-unresponsive AEs.

Inpatient care and additional supportive care may be required.

Ensure appropriately timed follow-up visits with oncologist or co-managing disease-specific subspecialist team for patients who required

hospitalization for severe AEs. Close monitoring is encouraged as these patients are likely to have been started on new medications such

as immunosuppressive agents and hormone replacement therapy that may require further adjustment or re-evaluation after hospitalization.

• Supportive care during immunosuppressant therapy may include the following:

Monitoring of blood glucose levels

PPIs or H2 blockers to prevent gastritis

Antimicrobial and antifungal prophylaxis to prevent opportunistic infections

Vitamin D and calcium supplementation to prevent osteoporosis

Note: All recommendations are category 2A unless otherwise indicated.

IMMUNO-B 2 OF 3

PRINCIPLES OF IMMUNOTHERAPY PATIENT EDUCATION

Continued

a Principles of Routine Monitoring for Immune Checkpoint Inhibitors (IMMUNO-1).

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NCCN Guidelines Version 1.2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

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• Educational efforts must consider the patient’s primary language and literacy level.

• Education should be provided at the start of therapy and at regular intervals as the trajectory of irAEs is variable. Reinforcement of

educational concepts is essential.

Immunotherapy Background:

• One of the functions of the immune system is to distinguish healthy cells from abnormal cells. Tumor cells have proteins on their surface

that bind to immune cells, blocking the ability of the immune cell to recognize them as foreign.

• ICIs are a class of medications that prevent tumors from “hiding” or “evading” the body’s natural immune system. ICIs block the proteins

referred to above, “releasing the brakes” on the immune system’s white blood cells (WBCs).

• ICI therapy may be given in combination with other ICIs, chemotherapy, or targeted therapy.

Side Effects (AEs):

• AEs from immunotherapy differ from those of other types of cancer treatment and can affect one or several different organ systems.

• Amplifying the immune system can cause T cells to attack healthy cells in the body, causing inflammatory conditions that mimic a range of autoimmune conditions, some of which can be serious. These are known as irAEs.

• irAEs can occur at any time during treatment or after treatment is completed. irAE rebound during steroid taper can also occur, which may impact steroid taper.

• The severity of AEs can range from asymptomatic to severe or life-threatening. They may be cumulative over the course of therapy.

• Combination therapy may increase the severity of AEs. This can occur when immunotherapy is combined with chemotherapy, targeted

agents, radiation therapy, or other types of immunotherapy.

• Some immune-related toxicities (eg, inflammatory arthritis, pneumonitis) may become chronic/require long-term management (Braaten TJ, et al. Ann Rheum Dis 2020;79:332-338; Johnson DB, et al. Cancer Immunol Res 2019;7:1755-1759; Naidoo J, et al. J Immunother Cancer 2020;8: e000840).

Monitoring and Treatment Responsea:

• Therapy with ICIs requires close communications between patient/family and the treating center. Symptoms that patients may think are

unrelated (eg, diarrhea or nausea) are often signs of ICI toxicity.

• Educate patients to notify all HCPs (especially primary care physicians [PCPs]) that they are receiving/have received immunotherapy.

• Regular monitoring will be conducted to detect any potential irAEs and to assess treatment response.

• Laboratory tests should be obtained prior to each treatment and at regular intervals after completion of immune checkpoint blockade to

assess for organ function (eg, CMP; kidney, liver, thyroid, pancreas).

• Physical exams will include monitoring of organ function (eg, cardiac, pulmonary, neurologic, skin).

• Assess for significant shifts in weight, as they may be indicative of fluid balance disorders.

• Treatment response time differs from standard cancer therapy; it may take longer to see a response than with other types of cancer therapy.

• Most irAEs can be managed effectively if detected and treated early.

PRINCIPLES OF IMMUNOTHERAPY PATIENT EDUCATION

Note: All recommendations are category 2A unless otherwise indicated.

IMMUNO-B 3 OF 3

a Principles of Routine Monitoring for Immune Checkpoint Inhibitors (IMMUNO-1).

PATIENT EDUCATION CONCEPTS

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National NCCD to medLOVIVE TNCN Cndelines: Version 1:2026

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NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF IMMUNOTHERPARY RECHALLENGE

General Principles

●Discuss the risks/benefits of restarting immunotherapy with the patient.

●About 1 in 3 patients may have recurrence of the same irAE after rechallenge.a Exercise caution when considering resumption of immunotherapy after significant irAEs. With some exceptions, resumption of immunotherapy following grade 2-3 irAEs can be considered on resolution to $\leq$ grade 1. Monitor closely for recurrent symptoms.

If re-challenged and toxicity returns, permanently discontinue class of immunotherapy.

If an objective response (complete or partial) to ICI therapy was achieved, resumption of immunotherapy may not be necessary. The risk of toxicity on resumption may outweigh benefit.

●IrAEs that respond to immunosuppressive therapies may pose a lower risk for rechallenge.

●Permanent discontinuation of a given class of immunotherapy may be warranted for severe irAEs or for some moderate irAEs with high risk of morbidity/mortality. For example, if a patient experiences grade 3 or 4 toxicity from an ipilimumab-containing regimen, consideration may be given to later therapy with a PD-1 or PD-L1 monotherapy after resolution of the earlier toxicity.

●Consult with organ-specific specialists prior to resumption of immunotherapy as appropriate following an immunotherapy hold due to irAEs.

Organ-Specific Considerations for Immunotherapy Rechallenge After a Hold

|Cardio- vascular|· Permanent discontinuation is warranted in the setting of grade 2-4 myocarditis.| |---|---| |Endocrine|● Thyroid: No discontinuation required for hypothyroidism. For symptomatic hyperthyroidism resembling Graves-like disease, consider holding immunotherapy and resuming after workup is complete and there is evidence for improvement in symptoms and TFTs. ● Hypophysitis manifested by deficiency of ACTH, TSH, and/or gonad-stimulating hormones, but without symptomatic pituitary swelling: Immunotherapy may continue while replacement endocrine therapy is regulated. ● Hypophysitis accompanied by symptoms of pituitary swelling(eg, headache, vision disturbance, and/or neurologic dysfunction): Hold immunotherapy until resolution of symptoms after steroid therapy and hormone replacement is initiated; consider resumption of immunotherapy after symptoms related to mass effect are resolved.| |1|• T1DM with DKA: Consider resuming once DKA has been corrected and glucose level has stabilized. ● Primary adrenal insufficiency: After appropriate replacement endocrine therapy is instituted, immunotherapy may continue.| |Eye|● Hold immunotherapy per guideline; consider resumption of immunotherapy in consultation with ophthalmology.|

a Dolladille C,et al. JAMA Oncol 2020;6:865-871.

Note: All recommendations are category 2A unless otherwise indicated.

Continued

IMMUNO-C 1 OF 3

![NCCN\nNCCan\nAcer\n](2/aj0YEe4oUhYkBdfpda0fYP/figure3bf8ae409ea74c7c987feab516e1533c_0_1.png)

NCCN doped 1921:2026

Conprehensive Management

Management of Immune Checkpoint Inhibitor-Related

Toxicities

NCCN Guidelines Index

Table of Contents

Discussion

PRINCIPLES OF IMMUNOTHERPARY RECHALLENGE

Organ-Specific Considerations for Immunotherapy Rechallenge After a Hold

|GI|•After grade 2 colitis, may consider resumption of immunotherapy after symptoms have resolved to ≤ grade 1. For grade 3 colitis, if combination ICI therapy was used previously, consider resumption of monotherapy with anti-PD-1 or anti-PD-L1. The risk of recurrent colitis is dependent on agent and/or combination resumed(ie,CTLA-4+/-PD-1>PD-1+ LAG-3>PD-1). In rare circumstances in which the patient cannot completely taper off steroids, immunotherapy may be resumed while patient is still on≤10 mg predisneol equivalent daily. Consider concurrent vedolizumab on immunotherapy resumption. ●Esophagitis/gastritis/duodentities: Once symptom remission on medical management has been achieved, immunotherapy rechallenge can also be considered with the same strategy as colitis, although high-level evidence is still lacking. ●Discontinue if irAE is serious or life-threatening. Do not make up doses missed due to irAE and/or required steroid treatment.| |---|---| |Hematologic|●Hemolytic anemia,HLH-like syndrome: Consider resumption of immunotherapy in consultation with hematology. ●Aplastic anemia: For severe or very severe, discontinue. For non-severe, consider resumption of immunotherapy in consultation with hematology. ●Thrombocytopenia: Rechallenge upon resolution of platelet count to ≤ grade 1 (or prior baseline), and treatment for thrombocytopenia has been discontinued.| |Kidney|●Hold immunotherapy per guidelines; on resolution to ≤ stage 1, consider resumption concomitant with or without steroid if creatine is stable. ●After restarting immunotherapy, monitor creatinine every 2-3 weeks or more frequently as clinically indicated. If creatinine remains stable, consider longer durations between creatinine checks. Gupta S et al. J Immunoher Cancer 2022;10:e005646. ●Consider permanent discontinuation in the setting of severe (grade 3-4) proteinuria(Discussion). ●For resolved stage 2 and/or stage 3 renal irAE, consider permanent discontinuation if possible; may consider re-challenge if clinically indicated, at least after≥2 months of holding ICI therapy. ●If the patient has partial or complete recovery after AKI, consider rechallenge after discussion with nephrology.| |Liver|●Transaminitis without synthetic liver dysfunction: Following a grade 2 irAE, may consider resumption of immunotherapy after ALT/AST return to baseline and steroids, if used, have been tapered to≤10 mg prednisone equivalent daily. ●Permanently discontinue immunotherapy in the setting of G4 synthetic liver dysfunction and/or permanent biliary strictures requiring endoscopic retrograde cholangiopreatatography(ERCP).| |Lung|●Progressive grade 1 pneumoniais requiring a hold: Consider resumption on radiographic evidence of improvement. ●Grade 2/3: Consider resuming once pneumonitis has resolved to≤ grade 1 and patient is off steroids. ●Permanent discontinuation is warranted in the setting of severe (grade 4) pneumonitis.| |Musculo- skeletal|●Inflammatory arthritis,myositis,PMR,GCA(moderate to severe irAE requiring hold):Resume and stabilization,or adequate management of symptoms. Permanent discontinuation may be warranted for severe inflammatory arthritis,PMR,or GCA that significantly impairs ADLs and quality of life. ●Severe or life-threatening myositis (with or without myocarditis): Consider permanent discontinuation in select patients due to high risk of morbidity/mortality.|

Continued

Note: All recommendations are category 2A unless otherwise indicated.

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NCCN Guidelines Index

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Management of Immune Checkpoint Inhibitor-Related

Table of Contents

Discussion

Toxicities

PRINCIPLES OF IMMUNOTHERAPY RECHALLENGE

Organ-Specific Considerations for Immunotherapy Rechallenge After a Hold

|Nervous System|●Myasthenia gravis/myasthenia gravis-like syndrome: Permanently discontinue immunotherapy after grade 3-4 AE. ●GBS: Discontinue immunotherapy for severe(grade 3-4) GBS. ●Peripheral neuropathy: Following hold for grade 1-2 AE, consider resuming if symptoms resolve to≤ grade 1 or if patient has well-controlled isolated painful sensory neuropathy. ●Aseptic meningitis: Consider resuming following mild to moderate AE if symptoms resolve to grade 0. ●Encephalitis: Discontinuation is warranted in the setting of severe encephalitis. ●Demyelinating disease: Discontinuation of immunotherapy following any-grade AE.| |---|---| |Oral Mucosa|●Consider rechallenge after symptoms become grade 1, or mild in the case of oral dyesthesia. ●Discuss risks of potential worsening symptoms compared with benefits for patients with moderate to severe Sicca or dyestesthesia symptoms.| |Pancreas|●Symptomatic grade≤3 pancreatitis: Consider resumption of immunotherapy if no clinical/radiologic evidence of pancreatitis± improvement in lipase. Consider consultation with relevant pancreatic specialist regarding resumption. ●Permanent discontinuation is warranted for severe(grade 4) pancreatitis and other related complications(eg, abscess, fistula)| |Skin|● Maculapopular rash and/or pruritis: Consider resuming after symptoms have resolved to≤ grade 1(ie, once skin condition is mild/localized with only topical intervention indicated). ●Discontinuation of immunotherapy in the setting of severe or life-threatening bullous disease(grade 3-4), including all cases of SJS and TEN. ● Psoriasis and lichen planus: Rechallenge may be considered if symptoms are controlled and extent of BSA is<30%, especially if the patient is on targeted biologic.|

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Concomprehensive Management of Immune Checkpoint Inhibitor-Related Toxicities

ABBREVIATIONS

|AChR|acetylcholine receptor| |---|---| |ACTH|adrenocorticotropic hormone| |ADEM|acute demyelinating encephalomyelitis| |ADL|activities of daily living| |AE|adverse event| |AFB|acid-fast bacilli| |AKI|acute kidney injury| |ALT|alanine aminotransferase| |ANA|antinuclear antibody| |ANC|absolute neutrophil count| |ANCA|antineutrophil cytoplasmic antibody| |AST|aspartate aminotransferase| |ATG|antithymocyte globulin| |BAL|bronchoalveolar lavage| |BNP|b-type natriuretic peptide| |BRAT|bananas,rice,apple sauce,toast| |BSA|body surface area| |BUN|blood urea nitrogen| |CAR|chimeric antigen receptor| |CBC|complete blood count| |CCP|cyclic citrullinated peptide| |CGM|continuous glucose monitoring| |CK|reatine kinase| |CMP|comprehensive metabolic panel| |CMV|cytomegalovirus| |COPD|chronic obstructive pulmonary disease|

|CRS|cytokine release syndrome| |---|---| |csDMARD|conventional synthetic disease-modifying antirheumatic drug| |CSF|cerebrospinal fluid| |CTLA-4|cytotoxic T-lymphocyte-associated antigen 4| |DAT|direct antiglobulin test| |DKA|diabetic ketoacidosis| |DM|diabetes mellitus| |DRESS|drug reaction with eosinophilia and systemic symptoms| |dsDNA|double-stranded DNA| |ECG|electrocardiogram| |EEG|electroencephalogram| |EGD|esophagogastroduodenoscopy| |EMG|electromyogram| |ENT|ear,nose, and throat| |ERCP|endoscopic retrograde cholangiopancreatography| |ESR|erythrocyte sedimentation rate| |FSH|follicle-stimulating hormone| |FT4|free thyroxine| |G6PD|glucose-6-phosphate dehydrogenase| |GBM|glomerular basement membrane| |GBS|Guillain-Barré syndrome| |GCA|giant cell arteritis| |G-CSF|granulocyte colony-stimulating factor| |CGV|gamma-glutamyl transferase| |GI|gastrointestinal|

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Comprehensive Management of Immune Checkpoint Inhibitor-Related Toxicities

|GVHD|graft-versus-host disease|ILD|interstitial lung disease| |---|---|---|---| |H&P|history and physical|INR|international normalized| |HBsAg|hepatitis B surface antigen|IO|immuno-oncology| |HBV|hepatitis B virus|IOP|intraocular pressure| |HCP|health care provider|irAE|immune-related adverse event| |HCT|hematopoietic cell transplant|IVIG|intravenous immunoglobulin| |HCV|hepatitis C virus|LDH|lactate dehydrogenase| |Hb|hemoglobin|LFT|liver function test| |HIV|human immunodeficiency virus|LH|luteinizing hormone| |HLA|human leukocyte antigen|LLN|lower limit of normal| |HLH|hemophagocytic lymphohistiocytosis|LV|left ventricular| |HSV|herpes simplex virus|LVEF|left ventricular ejection fraction| |HUS|hemolytic uremic syndrome|MAS|macrophage activation syndrome| |iADL|instrumental activities of daily living|MGFA|Myasthenia Gravis Foundation of America| |ICI|immune checkpoint inhibitor|MOG|myelin oligodendrocyte glycoprotein| |ICI-T1DM|immune checkpoint inhibitor-associated type 1 diabetes mellitus|MRCP|magnetic resonance cholangiopreatography| |ICU|intensive care unit|NAAT|nucleic acid amplification test| |ID|infectious disease|NCS|nerve conduction study| |IEC|immune effector cell|NIF|negative inspiratory force| |IEC-HS|immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome|NK|natural killer| |IEF|immunofixation electrophoresis|NT-|nonsteroidal anti-inflammatory drug| |Ig|immunofixation electrophoresis|proBNP|N-terminal prohormone B-type natriuretic peptide| |IgE|immunoglobulin|OCT|optical coherence tomography| |IgG|immunoglobulin G|PCP|primary care physician| |IL|interleukin|PCR|polymerase chain reaction| |Version 1.2026,10/23/2025|©2025 National Comprehensive Cancer Network® (NCCN®),All rights reserved. NCCN|interleukin|Continued|

|ABBREVIATIONS|| |---|---| |ILD|interstitial lung disease| |INR|international normalized ratio| |IO|immuno-oncology| |IOP|intraocular pressure| |iRAE|immune-related adverse event| |IVIG|intravenous immunoglobulin| |LDH|lactate dehydrogenase| |LFT|liver function test| |LH|luteinizing hormone| |LLN|lower limit of normal| |LV|left ventricular| |LVEF|left ventricular ejection fraction| |MAS|macrophage activation syndrome| |MGFA|Myasthenia Gravis Foundation of America| |MOG|myelin oligodendrocyte glycoprotein| |MRCP|magnetic resonance cholangiopreatography| |NAAT|nucleic acid amplification test| |NCS|nerve conduction study| |NIF|negative inspiratory force| |NK|natural killer| |NSAID|nonsteroidal anti-inflammatory drug| |NT-|N-terminal prohormone B-type natriuretic peptide| |OCT|optical coherence tomography| |PCP|primary care physician| |PCR|polymerase chain reaction| |PD-1|programmed cell death protein 1|

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National NCCD ised to MEDIVETE NCCN Guidelines Version 1:2026 NCCN Guidelines Version 1:2026 Comprehensive Management of Immune Checkpoint Inhibitor-Related

|NCCN|National Cancer Network®|NCCN Guidelines Version 1:2026|NCCN Guidelines Index Table of Contents Discussion||| |---|---|---|---|---|---| |NCCN|National Cancer Network®|Management of Immune Checkpoint Inhibitor-Related|NCCN Guidelines Index Table of Contents Discussion|Keckpoint Inhibitor-Related|| ||||||| |PD-L1|programmed death ligand 1|TPO|thyroid peroxidase||| |PE|pulmonary embolism|TRAb|TSH receptor antibody||| |PFT|pulmonary function test|TSH|thyroid-stimulating hormone||| |PJP|Pneumocystis jirovecii pneumonia|TSI|thyroid-stimulating immunoglobulin||| |PMR|polymyalgia rheumatic|TTE|transthoracic echocardiogram||| |PNH|paroxysmal nocturnal hemoglobinuria|TTP|thrombotic thrombocytopenic purpura||| |PPI|proton pump inhibitor|ULN|upper limit of normal||| |PT/INR|prothrombin time/international normalized ratio|UPEP|urine protein electrophoresis||| |PTT|partial thromboplastin time|UTI|urinary tract infection||| |PUD|peptic ulcer disease|UVB|ultraviolet B||| |RBC|red blood cell|VC|vital capacity||| |RF|rheumatoid factor|VEGF|vascular endothelial growth factor||| |RNFL|retinal nerve fiber layer|VZV|varicella zoster virus||| |RPR|rapid plasma reagin|WBC|white blood cell||| |RR|respiratory rate||||| |RRT|renal replacement therapy||||| |RSV|respiratory syncytial virus||||| |sCR|serum creatinine||||| |SJS|serum creatinine||||| |SPEP|serum protein electrophoresis||||| |TB|tuberculosis||||| |TEN|toxic epidermal necrolysis||||| |TFT|thyroid function test||||| |Tg|thyroglobulin||||| |TNF|tumor necrosis factor||||| |TPN|total parenteral nutrition|||||

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National NCC and MEDIVE TE NCCN Guidelines Version 1:2026

NCCN Guidelines Index Table of Contents Discussion

Concomprehensive Network®

Management of Immune Checkpoint Inhibitor-Related Toxicities

|NCCN Categories of Evidence and Consensus|| |---|---| |Category 1|Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.| |Category 2A|Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.| |Category 2B|Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the intervention is appropriate.| |Category 3|Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.|

All recommendations are category 2A unless otherwise indicated.

Discussion

Table of Contents

Overview ...................................................................................................... MS-2

Guidelines Update Methodology .................................................................. MS-2

Literature Search Criteria ............................................................................. MS-2

Sensitive/Inclusive Language Usage ........................................................... MS-3

The Role of the Immune System in Cancer ................................................. MS-3

Immune Checkpoint Inhibitors ..................................................................... MS-4

Management of ICI-Related Toxicity .......................................................... MS-10

General Principles of Immunosuppression ............................................. MS-10

Managing irAEs in Special Patient Populations...................................... MS-12

Specific irAE Management ..................................................................... MS-15

Infusion-Related Reactions ................................................................ MS-15

Dermatologic Toxicity ......................................................................... MS-16

Gastrointestinal (GI) Toxicity .............................................................. MS-21

Hepatic Toxicity .................................................................................. MS-22

Pancreatic Toxicity ............................................................................. MS-23

Endocrine Toxicity .............................................................................. MS-24

Pulmonary Toxicity ............................................................................. MS-27

Renal Toxicity .................................................................................... MS-29

Ocular Toxicity ................................................................................... MS-30

Nervous System Toxicity .................................................................... MS-30

Cardiovascular Toxicity ...................................................................... MS-33

Musculoskeletal Toxicity .................................................................... MS-34

Hematologic Toxicity .......................................................................... MS-36

References ................................................................................................ MS-37

This discussion corresponds to the NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities. MS-2,

MS-3, and MS-17 to MS-21 were updated on October 25, 2024. All other sections were last updated on April 8, 2019.

PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.

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Management of Immune Checkpoint Inhibitor-Related Toxicities

Overview

The aim of the NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities is to provide oncology practitioners with recommendations on how to manage immune-related adverse events (irAEs) related to immune checkpoint inhibitors. Recommendations for the management of irAEs related to immune checkpoint inhibitors (ICIs)are included in the current version of the guidelines. The Guidelines are updated by the NCCN Management of Immunotherapy-Related Toxicities Panel, a multidisciplinary group of representatives from NCCN Member Institutions consisting of medical oncologists and hematologic oncologists with expertise in a wide array of disease sites, as well as experts from the fields of cardiology, dermatology, endocrinology,gastroenterology, hepatology, neurooncology,nephrology,ophthalmology, pulmonary rheology,heumatology,oncology nursing,and oncology pharmacy. The NCCN Management of Immunotherapy-Related Toxicities Panel also updates the NCCN Guidelines for Management of CAR T-Cell Therapy and Lymphocyte Engager-Related Toxicities, which includes recommendations for the management of toxicities related to chimeric antigen receptor (CAR) T-cell therapy and the emerging class of lymphocyte engages (including T-cell-engaging bispecific antibodies).

The patient population eligible to receive cancer immunotherapy is expanding. Initially approved for the treatment of primarily advanced or metastatic disease, data indicate that ICIs may also provide clinical benefit in earlier settings for multiple cancer types.1-9

Clinicians should be aware that toxicities related to cancer immunotherapy are autoimmune in nature and can impact essentially any organ system.10 The toxicity profiles of cancer immunotherapy and management strategies for irAEs are distinct from those of traditional chemotherapy.10,11 Early recognition and prompt intervention are key goals for the management of toxicities related to cancer immunotherapy.

In general, a multidisciplinary approach is recommended, and consultation with an appropriate specialist for evaluation and treatment is encouraged to ensure optimal patient outcomes. Unfortunately, obtaining a specialist consultation within an urgent timeframe can be challenging.Therefore, the guidelines provide initial steps for oncology clinicians to assess and manage a patient's irAE while minimizing disruption to cancer treatment, particularly in situations when access to a specialist is limited. The guidelines also provide guidance on when inpatient care is needed.

These guidelines will be updated at least annually by the collaborative efforts of the panel members based on their clinical experience and available scientific evidence.

Guidelines Update Methodology

The complete details of the Development and Update of the NCCN Guidelines are available at www.NCCN.org.

Literature Search Criteria

Prior to the update of the NCCN Guidelines for the Management of Immune Checkpoint-Inhibitor-Related Toxicities, an electronic search of the PubMed database was performed to obtain key literature in the management of immune checkpoint inhibitor-related toxicities published since the previous Guidelines update, using the search terms:checkpoint inhibitor or immune checkpoint, in combination with the terms toxicity,adverse, or safety.The PubMed database was chosen because it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.12

The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types:Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV;

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Guideline; Practice Guideline, Randomized Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation Studies. The data from key PubMed articles as well as articles from additional sources deemed as relevant to these guidelines as discussed by the Panel during the Guidelines update have been included in this version of the Discussion section. Recommendations for which high-level evidence is lacking are based on the Panel's review of lower-level evidence and expert opinion.

present on cancer cells. Various mechanisms are in place to closely regulate the activation and function of immune system effectors. However,malignant cells can also modulate immune cell activity, thus evading recognition and destruction by the immune system. This section provides a brief overview of the relationship between the immune system and tumors, and how immunotherapy targets effector cells in the immune system to activate and enhance the antitumor response.

Sensitive/Inclusive Language Usage

NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation.13 NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; anti-racist, anti-classist, anti-misogynist, anti-ageist, anti-ableist, and anti-weight biased;and inclusive of individuals of all sexual orientations and gender focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.

Immunosveillance refers to the process by which the immune system can screen for, recognize, and respond to foreign pathogens or abnormal(ie, precancerous, cancerous) cells within the body. The theory of cancer immunosurveillance has been incorporated into the larger concept of cancer immunoediting, which details several phases of the interaction between cancer and the immune system: elimination, equilibrium, and escape. In the elimination phase, a strong response to an immunogenic tumor leads to successful elimination of tumor cells. When the immune system is unable to completely eliminate the tumor, a phase of equilibrium occurs whereby the tumor remains present without progression or metastasis. Persistent equilibrium can lead to the selection of cells that have mutated to resist or avoid the antitumor immune response. This is described as the escape phase, when tumor cells"escape" the antitumor immune response, leading to tumor growth and progression to cancer.14-18

Conditions or events that compromise the immune system can lead to cancer cells escaping immunosurveillance.15,19,20 Once cancer cells have escaped immunosurveillance and have begun to proliferate, their genetic and phenotypic plasticity enable them to develop additional mechanisms by which the tumor can evade, thwart, or even exploit the immune system.15,19,20

The Role of the Immune System in Cancer

The immune system is capable of mobilizing immune effector cells in response to cancer cells. Immunotherapies harness the immune system to attack and destroy tumors by regulating molecules involved in immune cell

Dynamic interactions take place between the immune system and cancer cells, whereby immune cells can detect genetic and cellular abnormalities

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activation. In doing so, immunotherapy seeks to activate or reactivate the antitumor immune response to overcome or circumvent the immune evasion or“escape” mechanisms employed by cancer cells and tumors.

and tumors deficient in DNA mismatch repair mechanisms. ICIs, which were initially indicated for pretreated advanced disease, have moved into earlier treatment settings. ${ }^{26}$

Evolution of Cancer Immunotherapy

Immune Checkpoint Inhibitors

Initial approaches to immunotherapy for cancer are focused on enhancing the immune system's antitumor response by targeting cytokines and other molecules responsible for regulating immune cell activity. Some examples of earlier-generation cancer immunotherapy include interleukin-2(IL-2)and interferon(IFN) alfa-2b, which have been used to treat malignancies such as melanoma and renal cell carcinoma(RCC). However, a low therapeutic index and suboptimal efficacy limit the use and impact of these agents.21,22 Lenalidomide and pomalidomide, immunomodulatory agents used for treating multiple myeloma, represent another prior approach to cancer immunotherapy.23,24 These agents have a complex mechanism of action that results in the costimulation of T cells and NK (natural killer)cells, increased IL-2 and IFN gamma production, and decreased IL-6 and tumor necrosis factor(TNF)-alpha levels, among other effects.23-25 However, the landscape of cancer care has undergone a dramatic shift with the recent approval of a new generation of cancer immunotherapies during the past 8 years.

Some of the most effective immunotherapies to date target immune checkpoints exploited by cancers to decrease immune activity.This section will provide a general overview of the mechanism of action of ICIs and discuss what is known regarding ICI-mediated immune dysfunction.For a discussion of the efficacy data for ICIs, please see the NCCN Guidelines for Treatment of Cancer by Site at www.NCCN.org.

Mechanism of Action

T-cell activation is an essential component of antitumor immunity,requiring costimulation through more than one mechanism. Binding of antigen-specific T-cell receptor (TCR) to major histocompatibility complex (MHC) on antigen-presenting cells (APCs) must be accompanied by costimulatory signals. CD28 is a well-characterized costimulatory factor expressed on T cells. Adequate CD28 binding to B7 family of costimulatory factors (CD80 [B7-1] or CD86 [B7-2]) on APCs is required for T-cell proliferation and full activation. The presence of growth factors such as IL-2 promotes T-cell differentiation and survival.32,33

Notable new treatments that have recently received FDA approval include ICIs and CAR T-cell therapies. ICIs comprise a novel class of agents that target immune cell“checkpoints,” such as programmed cell death-1(PD-1;eg,nivolumab, pembrolizumab26,27) and PD-1 ligand(PD-L1; eg,atezolizumab, avelumab, durvalumab28-30), as well as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; eg, ipilimumab,31 tremelimumab [under investigation]). Indications for ICIs have expanded dramatically and now include patients with lung (non-small cell and small cell cancers), head and neck, bladder, kidney, gastric, ovarian, and liver cancers, as well as melanoma, Hodgkin lymphoma, Merkel cell carcinoma,

Since unopposed immune activation can lead to a number of tissue-damaging consequences, the immune system has evolved to have complex self-regulatory mechanisms to control or dampen immune responses. This immunologic tolerance is maintained through a variety of mechanisms that include regulatory immune cells, immunosuppressive cytokines and chemokines, and immune checkpoint signaling. Immune checkpoint proteins such as CTLA-4 and PD-1 are closely regulated by immune cells to modulate T-cell activity. When bound by endogenous ligands, these receptors initiate a signaling cascade that suppresses T-cell

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activation, limiting the immune response. Cancer cells to evade various mechanisms of immune tolerance, including immune checkpoints to evade recognition by the immune system. Antibodies have been designed to bind these receptors to prevent receptor-ligand interaction, thus removing inhibition of T-cell activation. In doing so, the inhibitory interactions between tumor cells and infiltrating T cells are blocked, reversing T-cell tolerance. This process“releases the brake” on the immune response,promoting the immune system to mount an antitumor response.34-43

restricted to hematopoietic cells. PD-1 signaling exerts an inhibitory effect during the effector phase through inhibition of previously activated T cells primarily in the peripheral tissues. It decreases T-cell proliferation through reduced production of IFN-gamma, TNF alpha, and IL-2. In addition to blocking tumor cell apoptosis, PD-1 interaction with PD-L1/2 can lead to the progressive loss of T-cell functions (ie, T-cell exhaustion) and drive the conversion of T effector cells to Treg cells with immunosuppressive properties.33,51-56 Studies have implicated PD-1 signaling in the antitumor response.57 Blockade of the PD-1/PD-L1 interaction can lead to the reactivation of T-cell populations that have become exhausted following prolonged antigen exposure, such as quiescent antitumor T cells.33,52,58

CTLA-4 Inhibitors

CTLA-4 is expressed by CD4+ (helper), CD8+ (cytotoxic) T cells, as well as regulatory T cells (Tregs). CTLA-4 functions as an early inhibitory signal during the priming phase for T-cell activation, typically within the lymph nodes. CTLA-4 cell surface expression is upregulated by several factors including TCR activation and certain cytokines. Early studies identified CTLA-4 as a negative regulator of T-cell activation through its high-affinity binding to costimulatory factors of the B7 family (ie, CD80 and CD86) at the surface of APCs. CTLA-4 outcompetes CD28 for binding to costimulatory factors on APCs, acting as a brake on this mechanism for T-cell activation by reducing IL-2 production and T-cell proliferation and survival. The relative degree of signaling through CD28/B7 versus CD28/CTLA-4 determines activation versus anergy of T cells.32,33,44-47

ICI-mediated Immune Dysfunction

The pharmacodynamics and pharmacokinetics of ICI immunotherapy differ greatly from that of cytotoxic chemotherapy or targeted anti-cancer therapy.59 Similarly,anti-CTLA-4 and anti-PD-1/PD-L1 immunotherapies are associated with toxicity profiles that are distinct from those observed with conventional anti-cancer therapies, though their presentation may at times be similar.60-66 Whereas traditional cytotoxic chemotherapy often results in acute-onset emetic and myelosuppressive effects, irAEs tend to be relatively delayed-onset and inflammatory or autoimmune in nature.67-70

Although the pathophysiology of ICI-related irAEs is not yet fully elucidated, knowledge regarding the role of immune checkpoint pathways in autoimmune disease provides some clues. Many autoimmune diseases are related to failure of T-cell tolerance and uncontrolled activation of immune effector cells. Alterations in the genes encoding immune checkpoint proteins have been implicated in autoimmune disease. CTLA-4 and PD-1 polymorphisms have been linked to human autoimmune diseases including Celiac disease, diabetes mellitus, lupus, rheumatoid arthritis, and autoimmune thyroid disease. The spectra of irAEs associated with blockade of immune checkpoints falls in line with the phenotypes

Subsequent studies revealed the potential role of CTLA-4 blockade in the antitumor response. ${ }^{48}$ CTLA-4 blockade results in greater numbers of effector T-cell clones becoming active and proliferating while reducing the immunosuppressive activity of Tregs. ${ }^{33,49,50}$

PD-1/PD-L1 Inhibitors

PD-1 receptor is present on the cell surface of various immune cells such as T cells, B cells, and NK cells. Its ligands, PD-L1 and PD-L2, have differential tissue expression. PD-L1 is expressed by a wide variety of tissues types, including tumor cells, whereas PD-L2 expression is mainly

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observed as a result of mutations in the genes encoding CTLA-4 and PD-1 and has considerable overlap across the various ICIs.71-74

The precise pathophysiology of ICI-mediated irAEs is currently unknown.Translational research provides some evidence that irAEs may result from some combination of autoreactive T cells, autoantibodies, and/or proinflammatory cytokines (eg, interleukin-17). $^{73,75}$ One potential mechanism is T-cell activity directed at antigens present in both tumor cells and healthy tissue. $^{76,77}$ Inflammation in otherwise normal tissues could result from elevated levels of inflammatory cytokines as a downstream effect of T-cell activation. $^{78-81}$ Additionally, direct binding of immune checkpoint antibodies to targets expressed in normal tissues (eg,CTLA expression in the pituitary) could lead to complement-mediated inflammation. $^{82,83}$ Finally, immunotherapy might increase the levels of preexisting autoreactive antibodies. $^{84}$

Early- and later-onset irAEs may result from distinct mechanisms that have yet to be elucidated. Typical earlier-onset, common irAEs appear to involve generalized epithelial inflammation and may be observed in the form of rash, colitis, and pneumonitis. These irAEs typically involve recruitment of neutrophils into normal tissues. Later-onset irAEs, which are typically less common, can include neurologic events and hypophysitis,among others. These tend to be more localized, organ-specific reactions.Research is ongoing into the specific mechanisms underlying irAEs associated with specific ICIs.

Incidence and Prevalence of irAEs

The incidence and prevalence of ICl-related toxicity is still being fully elucidated; much of the existing figures are based on trials of ipilimumab,pembrolizumab, and nivolumab. Comprehensive irAE data on newer agents are still being collected and analyzed. Due to the nature of irAEs and inconsistent reporting, it is likely that reported rates underestimate the

actual incidence of these events. The reported incidence of any-grade irAEs associated with single-agent ICI treatment ranges widely across agents and trials, from approximately 15% to 90%.85,86 Severe irAEs requiring immunosuppression and hold or discontinuation of treatment are estimated between 0.5% and 13% for monotherapy.85 Analysis of pooled trial data found that 43% of patients discontinued combination therapy(nivolumab/ipilimumab) due to AEs, with gastrointestinal(GI) events being the most commonly reported reason for discontinuation.87 ICI immunotherapies have been associated with rare AEs that are still in the process of being identified and studied at high-volume centers.

Single-Agent Therapy

CTLA-4 A 2015 meta-analysis by Bertrand et al examined data from 1265 patients across 22 clinical trials of anti-CTLA-4 antibodies(ipilimumab [n = 1132]and tremelimumab [n = 133]), reporting an overall incidence of 72% for any-grade irAEs and 24% for high-grade irAEs.88 The most commonly observed AEs were dermatologic and Gl, followed by endocrine and hepatic events. A randomized, double-blind, phase III trial in patients with unresectable or metastatic melanoma revealed a dose-dependent effect in treatment-related AEs for patients receiving ipilimumab at a dose of 3 mg/kg(n = 362) or 10 mg/kg(n = 364).89 High-grade irAEs were reported in 18% and 30% of the 3 mg/kg and 10 mg/kg treatment groups, with 2 and 4 treatment-related deaths, respectively. The most common high-grade AEs, including diarrhea, colitis, elevated liver enzymes, and hypophysitis, were all more common at the higher dose of ipilimumab.89 Adjuvant use of ipilimumab (10 mg/kg) for resected stage III melanoma appears to be associated with a higher incidence of AEs. Based on phase III data in patients receiving adjuvant ipilimumab (n = 475), the incidence of high-grade irAEs was 41.6% with 5 fatalities (1.1%).90,91

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PD-1/PD-L1

For PD-1/PD-L1 inhibitors, the reported overall incidence of any-grade irAEs was up to 30% based on patients in phase III trials.86,92-94 To date,the incidence of high-grade AEs associated with PD-1/PD-L1 inhibitors appears to be somewhat less dose-dependent than ipilimumab and to vary by disease site.85 In a recent meta-analysis of anti-PD-1/PD-L1 agents,any-grade and severe-grade irAEs occurred in about 26.8% and 6.1% of patients, respectively.95 Rates of high-grade irAEs were similar across pembrolizumab, nivolumab, and atezolizumab, ranging from 5% to 8%.95

De Velasco and colleagues recently reported on the incidence of the most common ICI-associated irAEs in a meta-analysis of 21 randomized phase II/III trials conducted from 1996 to 2016, which included a total of 6528 patients who received monotonically(atelyzolizumab, n= 751; ipilimumab, n= 721; nivolumab, n= 1534; pembrolizumab, n= 1522) and 4926 patients in placebo or standard therapy control arms using chemotherapy or biologic agents.96 Due to inconsistent recognition and reporting of less-common irAEs in the clinical trial data, this meta-analysis was limited to examination of 5 common and well-documented types of irAEs: colitis,liver toxicity (AST elevation), rash, hypothyroidism, and pneumonitis. When compared to patients in trial control arms, patients receiving ICLs were found to be at greater risk for any-grade immune-related colitis, AST elevation, rash, hypothyroidism, and pneumonitis. Within this cohort,across all ICls, the incidence of grade 3/4 events was 1.5% for colitis,1.5% for liver toxicity, 1.1% for rash, 0.3% for hypothyroidism, and 1.1%for pneumonitis. High-grade colitis and rash were significantly more common among patients on ipilimumab than in those receiving PD-1/PD-L1 inhibitor. ${ }^{96}$ In a separate review of the data, Kumar and colleagues also compared the risk of developing certain irAEs with different classes of ICls.85 While ipilimumab was associated with higher rates of colitis, pruritus, rash, and hypophysitis, PD-1/PD-L1 inhibitors resulted in a higher risk for developing vitiligo (typically observed in

patients with melanoma), thyroid dysfunction, hepatotoxicity, and pneumonitis.85

De Velasco et al compared the risk of developing specific irAEs by tumor type(melanoma, lung, and other), reporting no significant differences for all-grade or high-grade irAEs.96 Khgoa et al also conducted a systematic review of irAEs by ICI class and tumor type in 6869 patients from 48 trials between 2003 and 2015,97 with probable considerable overlap in patient population from the De Velasco study. Although most findings were similar, Khoja and colleagues' findings deviated slightly when analyzing irAE incidence according to tumor histology in patients treated with PD-1 inhibitors. They found that patients with melanoma experienced higher incidence of Gl and skin irAEs but a lower incidence of pneumonitis compared with NSCLC. Patients with melanoma experienced arthritis and myalgia more commonly than those with RCC, but patients with RCC experienced higher frequency of pneumonitis and dyspnea. However,comparisons of irAE incidence across disease type were not adjusted for patient factors such as smoking history and age. Similar comparisons were not possible for CTLA-4 blockade since the majority of available data was on patients with melanoma.97

The safety data for PD-L1 inhibitors are still maturing and data collection is ongoing. Comparison of irAE incidence for PD-1 versus PD-L1 inhibitors have been calculated primarily from data published on patients with non-small cell lung cancer(NSCLC). A 2018 meta-analysis compared the data on toxicity profiles of PD-1 and PD-L1 inhibitors from 23 studies that occurred between 2013 and 2016(PD-1: n=3284; PD-L1: n=2460).98 A near-significant trend revealed irAEs to be more common with PD-1 versus PD-L1 blockade(16% vs.11%;P=.07). However, the incidence of severe irAEs was not significantly different between PD-L1 and PD-1 inhibitors,(5% vs.3%,P= 0.4). Pneumonitis occurred twice as often with PD-1 inhibitors(4% vs.2%;P=.01) and hypothyroidism was also more

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common with PD-1 inhibitors(6.7% vs. 4.2%; P=.07).98 Similar findings were reported in a 2017 meta-analysis of data on pneumonitis incidence with PD-1 inhibitors (12 trials, n = 3323) and PD-L1 inhibitors (7 trials, n = 1806).99 For PD-1 versus PD-L1 inhibitors, the incidence for any-grade pneumonitis was 3.6% versus 1.3% (P=.001) and 1.1% versus 0.4% for high-grade pneumonitis (P=.02).99

single-agent nivolumab(21%) and ipilimumab(28%). The percentages of patients discontinuing treatment due to any-grade treatment-related AEs were 39%,12%, and 16% for patients receiving combination therapy,nivolumab, and ipilimumab, respectively. Preliminary findings suggest that early discontinuation due to irAEs(after a median of 3 doses) may not compromise the survival benefit, as evidenced by a 3-year survival rate of 67%.102

Combination Therapy

Numerous ongoing studies are examining regimens that include ICLs given in combination with another ICI, chemotherapy, or targeted agent. While combination regimens offer the potential for enhanced efficacy, in general,observed toxicity with ICI-based combination regimens is greater than that for ICI monotherapy. Combined PD-1 plus CTLA-4 blockade triggers substantially more irAEs than anti-PD-1 agents alone, with high-grade events reported for 55% to 60% of individuals receiving combination therapy versus 10% to 20% of individuals receiving anti-PD-1 monotherapy.100-102 Studies have begun to investigate the extent to which combination therapies pose clinical safety and tolerability challenges, and whether these challenges will limit their usefulness as anticancer therapy.103-106

The KEYNOTE-029 trial began to investigate whether standard-dose pembrolizumab in combination with reduced-dose ipilimumab may be more tolerable than full-dose ICI combinations.108 Dose-modified nivolumab plus ipilimumab regimens are also under investigation for NSCLC and small cell lung cancer(SCLC),109,110 and nivolumab plus ipilimumab is recommended by the NCCN Guidelines for Small Cell Lung Cancer.

Safety data have also been published for early-phase investigations of ICI therapy in combination with additional targeted agents or chemotherapeutics.111-113 Immune checkpoint blockade given in combination with radiation therapy is also the subject of investigation.114,115

ICI Therapy-Related Fatal irAEs

The only current FDA-approved regimen using combined ICI therapy is nivolumab plus ipilimumab for treating advanced melanoma, RCC, or microsatellite-unstable tumors. ${ }^{27,31}$ Nivolumab plus ipilimumab resulted in enhanced survival outcomes compared with ipilimumab monotherapy in advanced melanoma. ${ }^{102,107}$ In the phase III CheckMate 067 trial of nivolumab plus ipilimumab versus ipilimumab or nivolumab monotherapy $(n=945, randomized in a 1:1:1 ratio), treatment-related AEs occurred in $96 \%$ of patients receiving combination therapy and $86 \%$ of those treated with monotherapy. Although no unique toxicities were identified in patients receiving ICI combination therapy, the incidence of high-grade irAEs for combination therapy (59%) was more than twice the incidence for

A recently published systematic review and meta-analysis examined fatal irAEs from ICI therapy using data from multiple sources. ${ }^{101}$ Meta-analysis of data from 112 published trials(n $=19,217$ ) compared the rate of fatal irAEs by agent. Similar rates of fatal irAEs were reported for anti-PD-1(0.36%) and anti-PD-L1 agents(0.38%), with significantly higher rates of fatal irAEs reported for anti-CTLA-4 monotherapy(1.08%) and anti-PD-1/PD-L1 + anti-CTLA-4 combination regimens(1.23%). For ipilimumab monotherapy, significantly fewer fatal irAEs occurred at the 3 mg/kg dose than 10 mg/kg dose. However, when used in combination with

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anti-PD-1 therapy, no significant difference in fatal irAE rate was observed for ipilimumab at $1mg/kg$ versus $3mg/kg$ dose.101

Examination of 613 cases of fatal ICI-related irAEs reported in the WHO pharmacovigilance database revealed that certain ICI agents were associated with a different spectrum of fatal irAEs.101 The majority of fatal irAEs associated with ipilimumab monotherapy were due to colitis (70%),with smaller proportions of hepatitis and pneumonitis-related deaths.However, fatal irAEs with anti-PD-1/PD-L1 therapy were distributed more broadly: pneumonitis (35%), hepatitis (22%), colitis (17%), neurologic events (15%), and myocarditis (8%). Among the fatal irAEs reported for combination regimens (ipilimumab plus anti-PD-1/PD-L1), colitis was most common (37%), followed by myocarditis (25%), hepatitis (22%),pneumonitis (14%), and myositis (13%). When fatality rates were assessed across different types of irAEs, myocarditis was associated with the highest risk of death (52/131 cases, 39.7%). Fatality rates for patients with hepatitis, pneumonitis, nephritis, and neurologic events ranged between 10% and 17%, while ≤5% of hypophysitis, adrenal insufficiency,and colitis cases proved fatal. 101

Finally, temporal patterns of fatal irAEs were examined using combined pharmacovigilance case reports and multicenter retrospective data review.101 For irAEs that eventually proved fatal, symptom presentation occurred a median of 40 days after onset of monotherapy with ipilimumab or an anti-PD-1/PD-L1 agent, and 14.5 days after initiation of combination regimens. Median time to death after initiation of ipilimumab monotherapy,anti-PD-1/PD-L1 monotherapy, or combination regimen was 64,43, and 35 days, respectively.101

IrAEs as a Biomarker of Treatment Response

Investigators have begun to examine whether developing certain ICI-mediated irAEs may be linked to improved treatment response and

survival outcomes. An overview of the preliminary findings related to irAEs and treatment outcomes is provided below. Further research into this phenomenon is needed to explore potential patterns.

Historically, induction of cutaneous irAEs was suggested as a positive prognostic factor in patients with melanoma who received various types of immunotherapy.116 A retrospective review found that cutaneous irAEs,particularly vitiligo, may be associated with improved treatment response with pembrolizumab.117-119 In patients with melanoma who received nivolumab, rash and vitiligo were both associated with improved overall survival(OS).120 The potential relationship between development of Gl irAEs and survival outcomes has also been investigated. A retrospective analysis of 327 patients found an association between Gl irAEs and OS,with diarrhea being an independent predictor of OS regardless of whether immunosuppressive therapy was required to manage this irAE.121

In a prospective cohort of 524 patients receiving ICI therapy, patients who developed rheutologic irAEs had a higher tumor response rate compared with patients who experienced no irAEs(85.7% vs.35.3%; P<.0001).122 Additionally, early data suggest a possible association between the development of neurologic irAEs and favorable disease response.Durable disease response has been reported in the setting of neurologic irAEs despite early discontinuation of ICI.123

However, in a retrospective review of 298 patients who received ipilimumab for metastatic melanoma, the occurrence of any-grade irAEs was not associated with OS or time to treatment failure(TTF).124 The authors also found no association between systemic corticosteroid therapy to manage irAEs and OS or TTF. Along similar lines, investigators have also questioned the impact of early discontinuation of ICI due to toxicity on antitumor efficacy and safety. Schadendorf et al examined pooled data from randomized phase II/III trials in which patients received combination nivolumab plus ipilimumab therapy (n = 409).87 Therapy was discontinued MS-9

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due to AEs in 176 patients, including 96 patients who discontinued therapy during the induction phase (in which the majority of high-grade AEs occurred). Overall response rate (ORR) was 58.3% for patients who discontinued therapy due to AEs during induction, versus 50.2% for those who did not discontinue therapy. Although similar, median OS was not reached for either group.87

irAEs may be treated with hormonal supplementation without the need for immunosuppression.

Immunomodulators

In these guidelines, recommendation for use of specific immune-modulating agents to manage irAEs are typically extrapolated from evidence for treating autoimmune conditions of the relevant organ system(s). Several commonly used immunosuppressants for managing steroid-refractory or severe irAEs are discussed below.

Management of ICI-Related Toxicity

The primary facets of irAE management include recognition and grading of toxicity, immunosuppression, and individualized modification to ICI administration. Early recognition of symptoms and prompt intervention are key goals for the management of immunotherapy-related toxicity.Significant irAEs often necessitate holding immunotherapy, with permanent discontinuation of the class of agent associated with the toxicity in the setting of certain severe irAEs.

TNF inhibitors are a class of drugs widely used to block the inflammatory effects of TNF in autoimmune diseases.125 Inflixab is a monoclonal anti-TNF-α antibody used for treating various autoimmune diseases,including Crohn's disease, ulcerative colitis, rheumatoid and psoriatic arthritis, and psoriasis.125-127 Inflixab blocks the interaction of TNFa with its receptors, inhibiting induction of pro-inflammatory cytokines(IL-1, IL-6)and modulating the activity of immune effectors such as leukocytes,neutrophils, and eosinophils.127,128 Inflixab has become a commonly used agent for treating steroid-refractory irAEs that develop during ICI therapy.73,129 For patients with severe irAEs not responsive to steroids within 48 to 72 hours, early initiation of anti-TNFa theory(ie, at 72 hours)may be warranted in consultation with the relevant medical specialist.Duration of therapy with TNF-alpha blockers for irAEs is not clearly defined, but is typically a single dose. A second dose of anti-TNFa therapy may be required, and can be administered 2 weeks after initial dose of infliximab. Anti-TNFa agents(eg, infliximab) are particularly effective in management of immune-related colitis and inflammatory arthritis(IA).

General Principles of Immunosuppression

Corticosteroids are the mainstay of treatment for most high-grade irAEs.Importantly, short-term use of corticosteroids to treat irAEs has not been shown to reduce anti-tumor efficacy. Appropriate duration and careful taper of corticosteroid therapy is important to prevent the recurrence of irAEs. Severe or steroid-refractory irAEs may require administration of additional immunosuppressive agents. For patients with severe irAEs not responsive to steroids within 48 to 72 hours, initiation of an additional immunosuppressant agent may be warranted in consultation with the relevant medical specialist. Close monitoring and follow-up should be performed to assess for response to corticosteroids and other immunosuppressants in the setting of ICI-related toxicity.

Vedolizumab is an integrin antagonist that binds to a4β7 integrin, blocking its interaction with mucosal addressin cell adhesion molecule-1(MAdCAM-1), inhibiting the migration of T cells across the endothelium into inflamed Gl tissues. Vedolizumab is currently indicated for treating Gl inflammation due to ulcerative colitis and Crohn's disease. ${}^{130,131}$ Case

Tailored recommendations regarding the use of non-steroid immunosuppressants can be found in the individual irAE treatment algorithms and corresponding discussion sections. Selected endocrine

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reports have described the use of vedolizumab for treating ICI-induced enterocolitis. ${ }^{ 131,132}$ Vedolizumab may provide more specific immune suppression for the inflamed Gl mucosa, hence theoretically sparing systemic immune suppression and anti-tumor immune responses.

Plasmapheresis is a type of therapy that may be indicated when a substance in the plasma, such as immunoglobulin, becomes acutely toxic,as can occur during certain autoimmune reactions. During plasmapheresis, the blood contents are separated extracorporeally,resulting in removal of the plasma and subsequent therapeutic plasma exchange via infusion. Indications for which this procedure is a first-line therapy include neurologic conditions such as myasthenia gravis and GBS, but it is also indicated for various other autoimmune conditions.153 Plasmapheresis(and IVIG) is often indicated as a second-line therapy for managing neurologic irAEs after limited or non-response to initial high-dose corticosteroid.154 However, success in treating severe and often rapidly progressive neurologic irAEs has been mixed.154-156

Mycophenolate-containing medicines are immunosuppressive agents used for preventing organ rejection after transplant(ie, kidney, heart,liver). It is available as mycophenolic acid(MPA) or as mycephonolate mofetil(MMF), a prodrug of MPA.133,134 These agents have multiple immunosuppressive actions, which result in decreased B- and T-cell proliferation, T-cell apoptosis, and suppression of dendritic cells and IL-1.135,136 Published studies also support the clinical efficacy of these mycophenolate in various inflammatory or autoimmune conditions, such as autoimmune hepatitis, myositis, bullous disease, interstitial lung disease, and lupus nephritis, among others.137-142 Retrospective analyses and case reports describe the use of myophenolate in the management of steroid-refractory irAEs, including those involving the liver, kidney,pancreas, and eyes.100,143-146

Additional agents that have been used less frequently as part of advanced lines of immunosuppressive therapy include rituximab, tacrolimus,tocilizumab,cyclosporine,cyclophosphamide,methotrexate,and antirheumatic agents(eg, sulfasalazine, leflunomide).

Considerations for Patients on Immunosupppressants

Intravenous immunoglobulin(IVIG) has been used to suppress a wide array of autoimmune and chronic inflammatory conditions. 147,148 It is comprised of pooled IgG immunoglobulins harvested from the plasma of healthy blood donors and prepared for intravenous (IV) administration.The immunomodulatory mechanisms of IVIG are not fully understood, but it is known to modulate the activity and effector functions of B and T lymphocytes, impacting antigen presentation, pathogenic autoantibodies,complement system, and cytokines.148-150 Efficacy has been demonstrated in neurologic inflammatory or autoimmune conditions such as Guillain-Barré syndrome (GBS), myasthenia gravis, neuropathies,rheumatologic conditions, blistering disorders, immune hematologic conditions, and many others.151,152

Additional supportive care measures are needed for patients receiving an immunosuppressive regimen. Hyperglycemia, gastritis, opportunistic bacterial or fungal infections, and osteoporosis can occur with a longer-term systemic corticosteroid.157-162 The panel recommends blood glucose monitoring and various prophylactic measures. For patients at higher risk of developing gastritis (ie, those taking nonsteroidal anti-inflammatory drugs [NSAIDS] or anticoagulants), histamine 2 (H2)blockers or proton pump inhibitors can be given during steroid therapy.Consider prophylactic antimicrobial and antifungal agents. Prophylaxis against Pneumocystis jirovecii pneumonia (PJP) should be considered in patients receiving a prednisone equivalent of $\geq 20 mg$ /day for 4 or more weeks, with general prophylaxis against fungal infections (ie, fluconazole)for patients receiving a prednisone equivalent of $\geq 20 mg$ /day for 6 or more

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weeks. Consider prophylaxis against zoster reactivation. Lastly, vitamin D and calcium supplementation is recommended to reduce the risk of osteoporosis.

Anti-TNF-α therapy may pose a risk of reactivating viral infections such as viral hepatitis or tuberculosis(TB).163-166 The panel recommends testing for hepatitis B and C virus prior to TNF inhibition, and carriers should be monitored during and for several months after immunosuppressive therapy. Additionally, testing for latent/active TB is recommended prior to initiation of infliximab therapy; IFN-gamma release assays are preferred.However, TB testing should not delay initiation of anti-TNFa agents for the management of acute severe or refractory irAEs.

Impact of Immunosuppressive Agents on Immunotherapy Efficacy}$$\text{Although no prospective data exist, retrospective data generally suggest}$$

appear to decrease ICI efficacy. Results were recently published from a pooled analysis of 4 studies enrolling 576 patients who received nivolumab for advanced melanoma.167 When adjusting for the number of nivolumab doses, ORR was higher among patients who experienced all-grade irAEs compared with those who did not. Among the 474 phase III trial participants, 114 (24%) received systemic corticosteroids for managing irAEs. ORR was not significantly different between patients who required corticosteroids and those who did not.167 Similar findings were reported by an earlier retrospective analysis of 298 patients with metastatic melanoma who were treated with ipilimumab.124 Within this cohort, 103 (35%) required corticosteroid therapy to manage irAEs, and 29 of these patients (10%) also required anti-TNF alpha therapy to address unresolved symptoms. OS and TTF were not impacted by the development of irAEs or the need for corticosteroid therapy to manage them.124 Similarly, among a pooled group of 409 patients who received nivolumab plus ipilimumab combination therapy as part of CheckMate 067

and 069, ORR was not reduced among patients who required corticosteroid therapy to manage irAEs relative to the rest of the cohort.87,168

Investigators have also analyzed whether immunosuppression via TNF antagonist had a negative impact on combination ICI therapy response.Based on retrospective analysis of data from CheckMate 067 and 069,using inflixibam to manage colitis did not appear to alter the kinetics of tumor response or durability.87 Another analysis of pooled data from these trials demonstrated similar survival outcomes between patients with GI irAEs who received corticosteroid therapy± inflixibam and patients with GI irAEs who did not receive immunosuppressive agents.168

Due to clinical trial exclusion criteria, less is known about the impact of immunosuppressants on ICI efficacy when given prior to ICI therapy. A recent retrospective study identified 90 individuals who were on baseline corticosteroid therapy(≥10 prednisone equivalent daily) from a cohort of 640 patients with NSCLC on anti-PD-1/PD-L1 monotherapy. Baseline corticosteroid therapy was associated with poorer outcomes from ICI therapy, as indicated by decreased ORR, progression-free survival(PFS),and OS.169 Additional research will be needed to better understand the potential impact of corticosteroid exposure prior to or during ICI therapy initiation, especially as it pertains to premedication with corticosteroid prior to ICI infusion.

Managing irAEs in Special Patient Populations

Patients with Prior irAEs or Pre-existing Autoimmune Conditions

In patients with pre-existing autoimmune disease, exacerbation of autoimmunity is a concern with the administration of immune-activating agents.Similarly,ICI therapy must be approached cautiously among patients who have experienced a prior irAE while receiving immunotherapy. Data on the toxicity of ICLs in patients with preexisting

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autoimmune disease or irAEs is generally lacking due to exclusion of these populations from clinical trials leading to FDA approval. Based on limited data from smaller retrospective studies, ICIs appear to be similarly effective in these patient groups with response rates of 20% to 40%.170-172 Based on the available data, most autoimmune disease flares and irAEs in this patient population have been managed with corticosteroid or additional immunosuppressive therapy; however, fatal AEs have been reported.173 Preliminary data on safety and toxicity are described below.

In the largest series to date, ipilimumab therapy was provided to a cohort of 30 patients with advanced melanoma and pre-existing autoimmune disorders including inflammatory bowel disease(n= 6), rheumatoid arthritis(n=6), psoriasis(n=5), systemic,lupus erythematosus(n=2),multiple sclerosis(n=2),autoimmune thyroiditis(n=2),and various others.172 Thirteen of 30 patients were taking immunosuppressive therapy to manage their conditions. While on ipilimumab, 27% of patients experienced exacerbation of their autoimmune condition, typically in the form of recurrent or enhanced preexisting symptoms. Most were managed successfully using corticosteroid, with 2 patients requiring infliximab. Ten patients(33%) experienced conventional high-grade irAEs considered unrelated to their baseline autoimmune condition(including one fatality due to colitis in a patient with skin-limited psoriasis). Three patients experienced concurrent autoimmune condition flares and conventional irAEs requiring high-dose corticosteroid. However, half of the cohort experienced no irAEs or autoimmune condition flare.172

Studies have also examined the effects of PD-1 inhibitors for advanced melanoma in patients with pre-existing autoimmune disease.170,171 Among a subset of 19 patients with prior autoimmune disease, PD-1 inhibition led to autoimmune flare in 42%, and onset of a new irAE in 16%.170 In a separate study of 52 patients with significant autoimmune conditions(eg,rheumatoid arthritis, polymyalgia rheumatica, Sjogren's syndrome,

immune thrombocytopenic purpura, psoriasis), 38% had an autoimmune condition flare requiring immunosuppression, and 29% developed a new irAE.171 Interestingly, no members of that cohort with Gl or neurologic autoimmune conditions(n= 11) experienced a flare.171 In both studies of PD-1 inhibitors, most flares of preexisting autoimmune conditions were adequately managed using immunosuppressive and symptomatic therapy.170,171 However, onset of new irAEs led to discontinuation of PD-1 inhibitor in about 10% of patients in one study.171

Reviews of the data have also probed the impact of PD-1 inhibitor therapy for treating melanoma in patients who developed prior treatment-related irAEs during ipilimumab monotherapy or combination CTLA-4/PD-1 blockade.170,171,174 Among the 22 patients with ipilimumab-related irAEs described by Gutzmer et al., treatment with a PD-1 inhibitor led to a flare of the prior irAE in 4.5% of patients, while 23% developed a new irAE. In another study of 67 patients with prior ipilimumab-related irAEs requiring immunosuppression, flare was reported in 3% of patients, and 34%developed new irAEs.171

Nivolumab or pembrolizumab monotherapy was resumed in a cohort of 80 patients who had previously discontinued combination ICI therapy due to irAEs.174 Upon resumption of PD-1 inhibitor, 14 patients(18%)experienced a recurrence of the same irAE and 17 patients(21%)experienced clinically significant“distinct” or de novo irAEs. Half of the cohort(n= 40) experienced any-grade irAE, with high-grade toxicity in 18%(n= 14).Twenty-four patients(30%) discontinued PD-1 monotherapy due to irAE. Colitis and neurologic toxicities were found to be least likely to recur, whereas hepatitis, pancreatitis, nephritis, and pneumonitis recurred more commonly. Symptomatic hypophysitis and rash were assessed as intermediate risk for recurrence; however, 1 fatality occurred due to recurrent and worsening rash and bullous disease. Due to the relatively high rate of severe but distinct irAEs that were observed during anti-PD-1

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agent rechallenge (21%),the authors posited two potential explanations.First, patients could be predisposed to subsequent toxicity due to immune priming by ICI combination therapy, and second, delayed presentation of irAEs due to combination therapy-related toxicity could have occurred.174 Additional research is needed to understand the safety of ICI therapy in this population and others at a potentially greater risk for developing irAEs.

In the setting of most severe(and some moderate) irAEs, permanent discontinuation of that given class of immunotherapy is typically warranted. For example, if a patient experiences grade 3 or 4 toxicity from an ipilimumab-containing regimen, consideration may be given to later therapy with anti-PD-1/PD-L1 monotherapy upon full resolution of any earlier toxicity.

NCCN Recommendations

Optimization of immunosuppression for pre-existing autoimmune conditions and close cooperation with pertinent subspecialists is recommended. These guidelines suggest a goal of immunosuppressive regimen allowing for prednisone dose of <10 mg daily (or equivalent) prior to initiating cancer immunotherapy. However, patients with autoimmune neurologic conditions or life-threatening autoimmune disorders are unlikely to be suitable candidates for ICI immunotherapy. Additionally, ICI therapy may not be appropriate for patients whose autoimmune conditions are inadequately controlled using immunosuppressive medications, or for those who require high doses of immunosuppressive agents to manage their condition.

Organ Transplant Recipients

Concerns regarding graft rejection in transplant recipients has led to the exclusion of this patient population from many clinical trials of ICI therapy.175 Safety and efficacy data on ICI therapy in patients who have received a prior organ transplant are limited to a small number of case reports. Safe ipilimumab use has been reported in several patients who received kidney or liver transplants.175-178 A 2017 review of 12 case reports on ICI use in transplant recipients identified 4 patients who experienced kidney graft rejection after combination CTLA-4/PD-1 blockade or anti-PD-1 monotherapy.175 PD-1 inhibition appears to be more commonly associated with graft rejection, suggesting that this pathway may play a more critical role in allograft immune tolerance.175,179 Other factors to consider in organ transplant recipients who may be candidates for ICI therapy may include elapsed time between transplant and initiation of immunotherapy, the strength of maintenance immunosuppressive therapy required to prevent graft rejection, and the immunogenicity of the transplanted organ.175,176

Caution should be exercised when considering resumption of ICI therapy for patients who have experienced a previous treatment-related irAE. A key consideration is the patient's tumor response. In patients with responding or stable disease, it may be prudent to continue close surveillance and to re-introduce ICI therapy if the patient develops evidence of progression of cancer. As appropriate, consult with organ-specific specialists prior to resumption. With some exceptions,resumption of ICI therapy after a grade 2 irAE can be considered once signs and symptoms have resolved to grade 1 or below. Perform close follow-up to monitor for any signs or symptoms of irAE recurrence. If toxicity returns upon ICI rechallenge, permanently discontinue that class of ICI.

Research is underway to explore alternative immunosuppressive regimens in an effort to reduce allograft rejection during ICI therapy.176,179 The safety and utility of immunotherapy is also being investigated in patients with multiple myeloma who may be unable to mount an adequate immune response. In KEYNOTE 183 and KEYNOTE 185, more deaths were observed for treatment arms in which pembrolizumab was added to lenalidomide/dexamethasone or pomalidomide/dexamethasone.180

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NCCN Recommendations

Consideration of ICI therapy in organ transplant recipients is very complex and requires multidisciplinary involvement. Graft failure while on ICI immunotherapy has been reported, and transplant organ loss may be an outcome of treatment. Patients with solid organ transplantation who have a viable option for alternative therapy if graft rejection occurs (ie, kidney and dialysis) may be candidates for immunotherapy, particularly if there is no prior evidence of graft rejection and patients are on a stable maintenance immunosuppression regimen. The possible consequences of ICI therapy should be discussed with the patient and organ transplant team and there should be a plan in place to seamlessly manage the patient if graft loss occurs. Although patients with prior allogeneic stem cell transplant may be candidates for immunotherapy, there is an increased risk of transplant-related complications, including potentially fatal graft-versus-host disease (GVHD). Careful discussion with the patient and stem cell transplant physicians should precede initiation of immunotherapy.

Specific irAE Management

In general, close consultation with disease-specific subspecialists is encouraged during irAE management. Referral to a tertiary care center may be required for management of complex cases or multi-system irAEs.Due to the kinetics of the immune response, the onset of irAEs can occur at any point during treatment or even after completion of therapy.181,182 irAE rebound during steroid taper has also been reported. The typical timing and presentation of specific irAEs are discussed below. Please see the corresponding algorithm pages in the guidelines for detailed recommendations on assessing and treating particular irAEs by grade/severity.

Caution and careful judgment are required when considering whether to resume immunotherapy following significant toxicity. Clinicians should

assess patient's tumor status prior to rechallenge. If an objective response(complete or partial) to ICI therapy was achieved, resumption of immunotherapy may not be advisable due to risk of toxicity recurrence.The NCCN Panel recommends that clinicians discuss the risks/benefits of restarting immunotherapy with the patient.

Infusion-Related Reactions

Infusion reactions have been reported most commonly with the PD-L1 inhibitor avelumab. Pooled safety data on avelumab reported that 25% of patients experienced any-grade infusion reactions(439/1738) with high-grade events in 0.7%(12/1738); the majority occurred during the first infusion, with nearly all reactions occurring within the first 4 treatment cycles.28,183 Premedication appeared to decrease the rate of severe infusion-related reactions(IRRs).183 The U.S. prescribing instructions for avelumab include acetaminophen and diphenhydramine prior to infusion during the first 4 treatment cycles.28

Most infusion reactions associated with ICls are mild and associated with low-grade fever, chills, headache, or nausea. Severe or high-grade reactions occurred in <1% of patients across all other ICls. Incidence of any-grade infusion reactions for the remaining ICls include atezolizumab at 1.3%, durvalumab at 2.2%,<10% for PD-1 inhibitors, and <1% for ipilimumab monotherapy.26,27,29-31,86

NCCN Recommendations

The panel refers clinicians to the prescribing information for each individual immunotherapy agent for recommendations regarding premedication to prevent infusion reactions. In the absence of specific indications such as prior IRR or concurrent chemotherapy, routine premedication with corticosteroids prior to receiving ICI therapy is not recommended given the potential mitigation of immunotherapeutic effectiveness in the prophylactic setting.

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In patients having a possible IRR, perform a physical examination, monitor vital signs, monitor pulse oximetry, and perform an ECG if the patient is experiencing chest pain or sustained tachycardia. Symptoms of IRRs can include fever, chills, rigors; urticaria/pruritus; angioedema; flushing;headache; hypertension or hypotension; and/or shortness of breath,cough, or wheezing. Hypoxemia, dizziness/syncope, sweating, and arthralgia or myalgia may also occur.

Mild (G1) reactions are typically transient and do not require immunotherapy infusion interruption or other intervention. For moderate (G2) reactions, hold or slow the rate of infusion and treat per institutional guidelines.Antihistamines, acetaminophen, NSAIDS, narcotics, or IV fluids may be required. Moderate reactions typically respond promptly to symptomatic treatment and require medication for≤24 hours. Consider premedication with acetaminophen and diphenhydramine with future infusions. For severe (3/4) IRRs, treat urgently according to institutional guidelines. Permanently discontinue the immune checkpoint drug(s)associated with the toxicity. Severe reactions are often more prolonged with limited responsiveness to intervention or infusion interruption.Symptoms can reocur following initial improvement. Inpatient care and urgent intervention may be needed to prevent life-threatening consequences.

Dermatologic Toxicity

Dermatologic toxicities are the most prevalent irAEs associated with ICI therapy. Inflammatory skin conditions typically present within the first 2 cycles of treatment (ie, within several weeks).60,93,96,184,185 Ipilimumab has been consistently associated with higher rates of all-grade dermatologic irAEs than PD-1/PD-L1 inhibitors; reported incidences of all grade dermatologic toxicity range from 37%-70% for ipilimumab and 17%-40%for PD-1/PD-L1 inhibitors. The rates of high-grade dermatologic irAEs are similar across ICI classes and range from 1%-3% for ipilimumab and

PD-1/PD-L1 inhibitors.85,93,186,187 Generally, regimens combining CTLA-4 blockade with an anti-PD-1/PD-L1 agent led to more frequent, severe, and earlier presentation of dermatologic toxicity.188

Maculopapular rash, with or without pruritus, is the most common presentation. Vilitigo is also a fairly common observation in patients with melanoma on PD-1 inhibitors, typically presenting later in the course of treatment. Observed inflammatory skin conditions reported with ICI therapy include eczematous, lichenoid, and psoriasisiform manifestations,as well as bullous dermatitis.60,184,188,189 Alopeia and hair regipmentation have also been reported.188,190,191 The majority of dermatologic irAEs are low grade and manageable with appropriate care without requiring interruption of ICI. However, rare cases of severe cutaneous reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis(SJS/TEN)and drug rash with eosinophilia and systemic symptoms (DRESS) have been reported. 189,192,193 Although serious conditions typically required hospitalization, resolution was achievable via systemic immunosuppressive therapy and ICI discontinuation.

NCCN Recommendations

To assess potential dermatologic irAEs, the guidelines recommend total body skin exam, including mucosa, and patient history of any prior inflammatory dermatologic disease. Routine examination of skin and mucosa is recommended for patients with a history of immune-related skin disorders. Clinicians should monitor the lesion type and affected body surface area(BSA); photographic documentation may be helpful. Biopsy can be considered for rash with unusual features. Treatment recommendations are subdivided by presentation. In general, short-term use of higher potency topical corticosteroids(eg, Class 2 or 3) is preferred over longer-term use of a lower-potency agent.

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Toxicities

Bullous Dermatitis and SJS/TEN

Maculopapular rash is characterized by the presence of macules (flat) and papules (elevated). Also known as morbiliform rash, it is one of the most common cutaneous AEs, frequently affecting the upper trunk, spreading centripetally, and may be associated with pruritus. Oral antihistamine and topical emollient are recommended. Mild (G1) maculopapular rash should be treated with moderate-potency topical cortical corticosteroid while ICI therapy continues. For moderate rash (G2), treatment with high-potency topical corticosteroids and/or 0.5-1 mg/kg/day prednisone is indicated. Consider holding immunotherapy. For severe rash (G3/4), hold immunotherapy and treat with high-potency topical corticosteroids and 0.5-1 mg/kg/day prednisone (with dose increase up to 2 mg/kg/day if no improvement).Urgent dermatology consultation is recommended; consider inpatient care.Following immunotherapy hold, consider resuming once symptoms have resolved to $\leq G1$ and only topical interventions are indicated.

Bullous dermatitis and other forms of blistering skin reactions are characterized by skin inflammation and fluid-filled bullae. For mild to moderate bullous dermatitis, hold immunotherapy until resolution.High-potency topical corticosteroid(G1) or 0.5-1 mg/kg/day prednisone/methylprednisolone(G2) is indicated. For severe or life-threatening bullous dermatitis and all cases of SJS/TEN,hospitalization and permanent discontinuation of immunotherapy are required. Seek urgent consultation from dermatology, ophthalmology, and urology. Methylprednisolone/prednisone should be initiated at 1-2 mg/kg/day.

In cases for which systemic corticosteroid is indicated, treatment should be continued until symptoms improve to ≤ G1, followed by dose taper over 4 to 6 weeks.

Pruritus

Pruritus is an intense itching sensation that may occur with or without rash. Mild pruritus(G1) can be treated with oral antihistamines and moderate-potency topical corticosteroid while immunotherapy is continued. Consult dermatology and continue immunotherapy with intensified antipuritic therapy for moderate pruritus(G2). Immunotherapy hold can be considered in select cases. Oral antihistamines are recommended in addition to high-potency topical steroid. For severe pruritus, hold immunotherapy and obtain urgent dermatology consultation.In addition to antihistamines, oral or IV prednisone/methylprednisolone(0.5-1 mg/kg/day) should be administered. Consider a GABA antagonist such as gabapentin or pregabalin, and aprepitant oromalizumab for refractory cases. Following immunotherapy hold, consider resuming once symptoms have resolved to≤ G1 and only topical intervention is required.

Lichen Planus and Lichenoid Diseases

ICI-related lichen planus and lichenoid disease are characterized by violaceous (dark red/purple) papules and plaques without scale over the trunk and extremities, and significant pruritis. ${ }^{194,195}$ Erosions and striae (white lines intersecting) in the oral and valvucosa may also occur. ${ }^{194,196}$ The mean time to onset is approximately 6 to 12 weeks after initiation of ICI treatment. ${ }^{194}$ Up to 6% of patients who received ICI treatment have been reported to experience lichen planus or lichenoid disease. ${ }^{197}$

A single-center retrospective cohort study characterized the management of ICI-related lichenoid eruptions in 119 patients with various types of cancers.196 Patients included 108 with lichenoid dermatitis,15 with lichenoid mucositis, and 2 with lichenoid dermatoses.Topical steroids were the most frequently used treatments for the management of lichenoid dermatitis (81%). Other treatments included

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oral antihistamines, oral steroids, acitretin, intralesional triamcinolone,narrow-band ultraviolet B (UVB), and other unspecified nonsteroidal treatment. Treatments used for lichenoid mucositis included topical steroids, unspecified nonsteroidal treatments, oral steroids, and acitretin.

Another single-center retrospective study assessed lichenoid mucocutaneous eruptions in 20 patients with advanced cancer who received programmed cell death protein 1(PD-1) or programmed death ligand 1(PD-L1) inhibitors.195 Eruptions on the trunk, extremities, and/or mouth were reported. Topical steroids were used most frequently,although some patients were also treated with oral steroids or phototherapy.

Other documented treatments used for lichen planus and lichenoid reactions (either ICI-related or idiopathic) included steroids (topical,intralesional, or oral), tacrolimus, narrow-band UVB phototherapy,cyclosporine, doxycycline, acitretin, apremilast, and other nonsteroidal immunomodulators such as hydroxychloroquine, azathioprine,methotrexate, and mycophenolate mofetil.198-200

High-potency topical steroids (eg, clobetasol 0.05% or fluocinonide 0.05% [cream or ointment]) or tacrolimus(0.1% ointment) are recommended for all grades of lichen planus and lichenoid diseases. In general, gel can be considered for mucosal disease, solution for scalp disease, and cream/lotion/ointment for all other affected areas. Oral antihistamines, prednisone, and narrow-band UVB phototherapy(if available) are recommended for moderate lichen planus and lichenoid diseases. If severe, prednisone or intravenous (IV) methylprednisolone is recommended; other agents that can be considered include acitretin(if no childbearing potential), doxycycline in combination with nicotinamide,and other steroid-sparing immunosuppressants, such as azathioprine,cycloporine, hydroxychloroquine, methotrexate, and mycophenolate

mofetil. A referral to dermatology, if available, should also be considered for those with severe symptoms.

ICI treatment can be continued in patients experiencing mild lichen planus/lichenoid disease, while treatment should be held if the presentation is moderate or severe. Rechallenge with ICI can be considered when symptoms are controlled and if the extent of BSA is<30%, especially if the patient is receiving a targeted biologic.

Psoriasis and Psoriasis and Psoriasis

ICI-related psoriasis and psoriasisiform disease are characterized by thick,red,scaly plaques that are typically accentuated on extensor surfaces,scalp, umbilicus, and postauricular surfaces.194,197,201. The time of onset is typically within 3 weeks of ICI treatment.194 ICI-related psoriasis includes both de novo psoriasis and the exacerbation of existing psoriasis.197,201

A retrospective study characterized the treatments used for 115 patients with ICI-related psoriasis.201 Over half of the patients presented with grade 1 psoriasis. Many patients were treated with only topical measures(59.1%), while 40.9% received both topical and systemic agents.Systemic therapies used included acetitin, systemic steroids, apremilast,Methotrexate, and biologics specifically approved for psoriasis(eg,tumor necrosis factor[TNF]-alpha inhibitors, interleukin[IL]-23 inhibitors).Two patients received topical steroids in combination with narrow-band UVB phototherapy.

A separate systematic review of 60 published studies evaluated treatments used for the management of ICI-related psoriasis in 242 patients.202 Topical steroids were the most common treatment used(83%). Other treatments included acitretin, systemic steroids,phototherapy, methotrexate, and biologics approved for psoriasis.

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Systemic non-biologics recommended by the American Academy of Dermatology (AAD)/National Psoriasis Foundation (NPF) guidelines for idiopathic psoriasis include acitretin,apremilast, cyclosporine,methotrexate, and others.203 AAD/NPF also recommend a number of approved biologics for the treatment of idiopathic psoriasis.204 Of note,systemic steroids have historically not been used for the treatment of psoriasis due to risk of a pustular rebound flare and are not currently recommended by the AAD/NPF guidelines for the management of psoriasis.201,203,205

High-potency topical steroids (eg, clobetasol 0.05% or fluocinonide 0.05% [cream or ointment]) and topical vitamin D analogues are recommended for all grades of ICI-related psoriasis and psoriasisformise diseases. Narrow-band UVB phototherapy is recommended for moderate psoriasis, if available. Apremilast or acitretin (if no childbearing potential)can be considered if the irAE is deemed moderate or severe.Cyclosporine and methotrexate are recommended as additional treatment options for severe ICI-related psoriasis. The NCCN Panel also recommends referral to a dermatologist for consideration of biologics approved for the treatment of moderate or severe psoriasis. 204 Systemic steroids are not recommended for patients with ICI-related psoriasis/psoriasisform diseases.

While ICI treatment can be continued in patients experiencing mild psoriasis/psoriasisiform disease, the NCCN Panel recommends holding ICI treatment if the patient's condition is moderate or severe.Rechallenge with ICI can be considered if symptoms are controlled and extent of body surface area(BSA) is <30%, especially if the patient is receiving a psoriasis-targeted biologic.

Oral Mucosa Inflammation

Oral mucosa inflammation is characterized by irritated gums and/or oropharynx, including red/white lesions,erosions, and/or ulcers, striae,

or diffuse mucositis. The prevalence of ICI-related oral mucosal disorders is estimated to be approximately 3%.206

Data on the treatment of ICI-related oral mucosa inflammation are limited. A retrospective single-center study evaluated 152 patients with various types of cancer who experienced ICI-related oral mucositis.207 Grade 1 or 2 mucositis was reported in 91% of patients. Oral ulcers or aphthae were reported in 97% of patients. No medical treatment was given to 11% of patients and over half of patients were treated with only supportive medication, which consisted of viscous lidocaine, sucralate,proton pump inhibitors (PPls), and H2 blockers (also known as histamine H2 antagonists). The rest of the patients received topical and/or systemic immunosuppressants (23.7%), which included oral prednisone and IV methylprednisolone. None of the patients in the study received nonsteroidal systemic immunosuppressants.

A systematic review of published reports(primarily case studies) similarly identified topical measures and oral/IV steroids as the primary management strategies used to treat 42 patients with ICI-related oral mucositis.208

Good oral hygiene (such as twice-daily tooth brushing, chlorhexidine or fluoride oral rinse if tooth brushing is too painful) and dietary modifications(eg, avoidance of crunchly, spicy, or acidic foods;avoidance of hot food/drinks) are recommended by the NCCN Panel for all patients with oral mucosa inflammation. Referral to dermatology is recommended if available. A referral to dentistry should be considered for those with mild symptoms and strongly considered for those with moderate or severe inflammation to ensure adequate hygiene and to protect against the risk of dental caries. If available, a referral to an ear,nose, and throat(ENT) specialist is recommended to assist in the management of persistent mucositis or if there is oropharynx/larynx involvement.

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In general, ICIs should be held for patients with moderate or severe symptoms; a lip or oral biopsy is also recommended if not previously done. Rechallenge with ICI can be considered after symptoms improve to grade 1 or better. Topical steroids in the form of oral liquid or gel formulation are recommended as the first line of therapy for oral mucosa inflammation. Topical calcineinir inhibitor tacrolusim 2onment can be considered for moderate symptoms, while prednisone or IV methylprednisolone is an option for those with moderate or severe symptoms, including those who are unable to eat. Inpatient care is also recommended for patients with severe symptoms.

For the management of oral lichen planus, clinicians should follow the management recommendations for lichen planus and lichenoid disease described above.

Dry Mouth (Sicca Syndrome)

Dry mouth (sicca Syndrome) has been reported with ICI use.209-211 Patients with sicca syndrome present with an abrupt onset of dry mouth that can cause difficulty with speaking, eating, swallowing,and/or staying asleep. Some patients, but not all, may experience dry eye.211 Dry mouth (sicca syndrome) is estimated to occur in 2% to 11%of patients who receive ICI treatment.206,209

Data from a single-center study that included 20 patients who experienced ICI-related sicca syndrome showed that onset of the condition typically occurred within 3 months of treatment with ICIs.210 Supportive care measures(including hydration and use of systemic sialagogues),steroids(eg, prednisone), and holding ICI therapy were the primary management strategies reported in the study.

Another study described management strategies based on ImmunoCancer International Registry (ICIR) data derived from 26 patients with various cancer types who developed sicca syndrome

following ICI therapy.211 Topical measures were initially used for most patients, while systemic steroids were administered to those for whom topical measures were ineffective. Use of other immunosuppressants in the second-line setting was also reported for select patients.

Dietary modifications and topical measures(such as saliva substitutes and mouth rinses) are recommended by the NCCN Panel for all patients with dry mouth (sicca syndrome). Prednisone and systemic sialogagues (ie, cevimeline or pilocarpine, to increase flow of saliva) are options for those with moderate or severe symptoms. Dry mouth from sicca syndrome may be partially improved with steroids but usually will require chronic care for salivary dysfunction. Clinicians should be aware that severe sicca syndrome, if left untreated, can result in dental caries and eventually the loss of teeth. Referral to rheumatology and dentistry is also recommended; inpatient care can be considered for those with severe dry mouth. Holding immunotherapy is recommended for those symptoms become grade 1. When considering rechallenge, clinicians should have a discussion with patients regarding the risks of potential worsening symptoms compared with the benefits.

Oral Dyesthesia

Oral dyesthesia is generally described as oral pain with a "burning"sensation in the absence of, or disproportionate to, skin changes, oral sensitivity, dysgeusia, phantomgeusia, or other altered sensation with normal clinical findings. In the literature, multiple terms have been used to describe this condition, including burning mouth syndrome and stomatodynia.212 This irAE is often not an isolated event and may occur with other types of ICI-related oral toxicities, such as mucosal inflammation. The prevalence of ICI-related oral/oropharyngeal pain is estimated to be 4%.206

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Data on the management of ICI-related oral dysesthesia is limited. However, several studies have investigated treatment options for non-ICI-related oral dysesthesia. Data from a single-center study found that some, but not all, patients with burning mouth syndrome treated with steroids experienced an improvement in symptoms.213 Use of gabapentin has been evaluated within the context of a randomized, double-blind,placebo-controlled trial in patients with symptoms of burning in the mouth. ${ }^{214}$ Ten out of the 20 patients who received gabapentin alone experienced a reduction in burning sensation. Other topical agents,psychotropic medications, and psychological therapy have also been used to treat oral dysesthesia; ${ }^{212,213}$ however, high-quality data are needed, especially within the context of ICI treatment.

Dietary modifications are recommended by the NCCN Panel for all patients with oral dysesthesia. Topical steroids or viscous lidocaine are generally considered first-line treatment options for oral dysesthesia.gabapentin is an option for those with moderate or severe symptoms. ICI therapy should be held if symptoms interfere with oral intake(moderate/grade 2) or if patients are experiencing disabling pain and tube feeding or total parenteral nutrition is indicated(severe/grade 3).Rechallenge can be considered if symptoms become mild; however, the Panel recommends initiating a discussion with patients about the risks of potential worsening symptoms compared with benefits.

Gastrointestinal (GI) Toxicity

GI irAEs may present as diarrhea or symptoms of colitis, which include watery diarrhea, cramping, and urgency. Diarrhea and colitis are the second-most commonly reported AEs with ICIs, and symptoms typically develop within 6 to 8 weeks of starting treatment. ${ }^{215,216}$ GI irAEs have been reported more frequently with anti-CTLA-4 monotherapy than with PD-1/PD-L1 inhibitors. In studies of CTLA-4 blockade, diarrhea has been reported in up to half of patients, with incidence typically reported between

30% and 40%.85,217 The highest rates of ICI-mediated GI irAEs have been observed with the addition of a PD-1/PD-L1 inhibitor to CTLA-4 blockade.218-220 Retrospective case reviews suggest that symptom grade may not correlate with colitis severity as observed by endoscopy and histology.121,221

Systematic reviews and meta-analyses have examined the incidence of specific GI irAEs in patients with solid tumors who received ICI therapy. A meta-analysis of 34 studies enrolling 8863 patients with solid tumors examined the incidence of GI irAEs with various ICIs.220 The highest rates of GI irAEs were observed in patients receiving combination ipilimum but s nivolumab, with all-grade colitis, severe colitis, and severe diarrhea reported in 13.6%, 9.4%, and 9.2% of patients, respectively. Incidence of irAEs with ipilimumab monotherapy was 9.1% for all-grade colitis, 6.8% for severe colitis, and 7.9% for severe diarrhea. Monotherapy with a PD-1/PD-L1 inhibitor had the lowest GI irAE incidence, with 1.3% for all-grade colitis, 0.9% for severe colitis, and 1.2% for severe diarrhea. No significant differences in GI irAE incidence were observed by tumor type(eg, melanoma, NSCLC, RCC).220 Another meta-analysis compared the pooled incidence of diarrhea and colitis for different checkpoint inhibitors in patients with melanoma (CTLA-4: n = 3116; PD-1 inhibitors: n = 1537).PD-1 inhibitors were associated with a lower relative risk of all-grade diarrhea and colitis compared with anti-CTLA-4 agents, while combination therapy was associated with a higher relative risk of diarrhea and colitis than monotherapy. Rates of discontinuation were higher among patients taking anti-CTLA-4 agents.219

Corticosteroids are typically the first line of treatment for GI irAEs. In retrospective reviews of patients with ICI-related enterocolitis, symptoms resolved with corticosteroid treatment in approximately 40% to 60% of individuals.216,221,222 However, a recent retrospective analysis of patients found higher infection rates among patients treated with long-duration

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steroids (>30 days). Long-duration corticosteroid without infliximab was associated with increased infection risk compared to short-duration steroid plus infliximab, suggesting that earlier non-steroid immunosuppressive therapy may confer better outcomes.121

methylprednisolone, 2 mg/kg/day. If no response is detected in 2 days,continue steroids and consider adding infliximab. Consider vedolizumab for infliximab-refractory diarrhea and colitis or cases for which infliximab is contraindicated.

Endoscopy revealed colonic ulcerations more commonly in steroid-refractory cases.216,221,222 Case studies report on the successful use of infliximab for treating severe, steroid-refractory colitis associated with ipilimumab.222-224 Case series and reports have also documented successful treatment of ICI-mediated, steroid-dependent, or steroid-refractory enterocolitis with vedolizumab.131,225 Vedolizumab may be effective in the setting of infliximab-resistant inflammation of the small intestine and colon.132

For patients taking ipilimum, the panel recommends permanent discontinuation if a serious or life-threatening Gl irAE occurs. For patients receiving PD-1/PD-L1 inhibitors, therapy should be held for G2/3 irAEs,with consideration of rechallenge upon resolution of symptoms below G1.For rare circumstances in which the patient cannot completely taper off corticosteroids, immunotherapy may be resumed while the patient is still on ≤10 mg prednisone(or equivalent) daily. Permanly discontinue the immunotherapy agent(s) responsible for the toxicity after G4 irAEs. If a systemic corticosteroid is given, treatment should be continued until symptoms improve to ≤ G1, followed by dose taper over 4 to 6 weeks.Convert from IV methylprednisolone or oral prednisone when appropriate.

NCCN Recommendations

Determine the patient's baseline bowel habits. Blood in the stools and/or fever should prompt a more thorough workup for infection and for other causes of Gl bleeding, including peptic ulcer disease(PUD) and malignant bleeding. For patients presenting with mild diarrhea(G1), close monitoring is recommended with progressive symptoms indicating further workup.Loperamide or diphenoxylate/atropine and hydration are recommended,and consider holding immunotherapy. Moderate(G2) or severe(G3/4)diarrhea and colitis require stool evaluation to rule out infectious etiology.Consider abdominal/pelvic CT with contrast and Gl consultation for further evaluation(ie, colonoscopy or flexible sigmoidoscopy±esophagogastroduodenoscopy[EGD] with biopsy). Therapy for irAE can be initiated while awaiting test results.

Hepatic Toxicity

Although immune-related hepatotoxicity occurs at a lower rate than diarrhea/colitis, it is a well-documented ICI-mediated irAE that is typically mild but can be severe or even fatal in rare cases.74 Asymptomatic elevations in aspartate transaminase(AST) and alanine transaminase(ALT) are the most commonly observed hepatic AEs.66,186 The pooled incidence of immune-related hepatotoxicity is estimated at 3% to 9% for ipilimumab and between 0.7% and 1.8% for PD-1/PD-L1 inhibitors.226 Combination therapy is associated with a considerably higher incidence of hepatotoxicity with 29% and 17% experiencing any-grade and high-grade hepatotoxicity, respectively.226,227 Median time of onset is typically 5 to 6 weeks from start of treatment but irAEs can occur months later.226,228-230 Autoimmune hepatitis and drug-induced hepatitis can present in a similar fashion and be difficult to distinguish, but can often be differentiated by distinct histologic features and imaging.231,232 A recent study characterized

For moderate diarrhea/colitis (G2), hold immunotherapy and administer prednisone/methylprednisolone (1 mg/kg/day). If no improvement is noted within 2 to 3 days, increase corticosteroid dose to $2 mg /kg /day$ and consider adding infliximab. Consider inpatient care if needed to provide adequate supportive care for severe colitis (G3/4). Administer IV

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the distinct histologic patterns associated with hepatitis mediated by CTLA-4 versus PD-1/PD-L1 blockade.228

Corticosteroids are the most common method of treatment in most studies of ICI-mediated hepatotoxicity.226,228,229 In several cases, re-initiation of steroids after taper was needed based on worsening liver values.229 Mycophenolate has been used to treat severe persistent hepatitis despite corticosteroid therapy.146,226,233,234 Another study reported the use of cyclosporine as an additional immunosuppressant in the setting of steroid-refractory hepatotoxicity.229 Infliximab is not recommended given concerns for liver toxicity, although it has not been tested in this setting. Case report data also suggest that tacrolimus may be effective for treating refractory ICI-related hepatitis.235,236

(G3/4) requires permanent discontinuation of ICI therapy, hepatology consult, and LFT monitoring every 1 to 2 days. Provide inpatient care for G4 transaminitis and consider hospitalization for G3. Liver biopsy can be considered if there are no contraindications. Initiate prednisone at 1-2 mg/kg/day(G3) or 2 mg/kg/day(G4). For patients with persistent severe hepatitis despite high-dose corticosteroid for 3 days, consider adding MMF. Infliximab is not currently recommended for use in patients with hepatitis.

For $\ge$ G2 transaminitis with bilirubin levels above 1.5 ULN(excluding patients with Gilbert's syndrome), management is similar to that for high-grade hepatitis without bilirubin elevation. Permanently discontinue immunotherapy and initiate prednisone at 2 mg/kg/day. Monitor LFTs daily and consult with hepatology. Mycophenolate can be considered in addition to steroid for refractory cases after 3 days.

NCCN Recommendations

Liver damage may be indicated by elevated levels of the liver enzymes ALT and AST (ie, transaminitis). Patients experiencing hepatic irAEs may present with varying grades of transaminitis. The panel recommends ruling out other potential factors such as viral etiology, disease-related hepatic dysfunction, or drug-induced enzyme elevations. Specialist consultation should be considered and efforts should be made to limit or discontinue any hepatotoxic medications. Assess acetaminophen, dietary supplement,and alcohol use.

For all hepatitis cases requiring corticosteroid, initiate tapering when liver enzymes show sustained improvement or return to $\leq$ G1. Continue to taper dose over at least 1 month with re-escalation as needed for rebounding enzyme levels. In the setting of G2 hepatitis without elevated bilirubin, clinicians can consider resuming immunotherapy once liver enzymes return to baseline and prednisone(or equivalent) has been tapered to $\leq$ 10 mg daily. Do not rechallenge following high-grade (G3/4)irAEs.

Pancreatic Toxicity

Amylase and/or lipase elevations, although typically asymptomatic, can occur with ICI therapy. The potential significance of asymptomatic elevations remains unclear, but discontinuation of therapy is not usually recommended based on these findings alone.85,186,237 Although rare, acute pancreatitis has been observed in patients taking ICIs, 186,231,238 and radiologic features of immune-related pancreatitis have been described.239 Cases of recurrent pancreatitis have been reported upon resumption of

Treatment recommendations are separated based on the co-occurrence of elevated bilirubin. Management of transaminitis without elevated bilirubin is by grade, based on the degree to which enzymes exceed the upper limit of normal [ULN]). For mild transaminitis (G1), immunotherapy can be continued with increased frequency of transaminase and bilirubin monitoring. Consider holding immunotherapy for concerning laboratory value trends. Hold immunotherapy for moderate transaminitis (G2) and monitor liver function tests (LFTs) every 3 to 5 days and consider prednisone 0.5-1 mg/kg/day. Severe or life-threatening transaminitis

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PD-1 inhibitors following a hold for initial irAE.174 Toxic effects on the endocrine pancreas, such as hyperglycemia and diabetes, are addressed in the larger context of the endocrine system in the next section.

NCCN Recommendations

Baseline/routine amylase/lipase assessments and pancreatic imaging do not need to be performed outside of clinical suspicion of pancreatitis. For persistent moderate/severe elevations in amylase and/or lipase, the panel recommends evaluation for pancreatitis to include clinical assessment and imaging. Imaging may include abdominal CT with contrast or magnetic resonance cholangioparecatography (MRCP). Other potential causes for elevated pancreatic enzymes should be considered. For moderate/severe elevations in amylase and/or lipase, consider continuing immunotherapy if no evidence of pancreatitis is found.

Provide standard medical care for signs and symptoms of acute pancreatitis, including hospital admission, aggressive fluid resuscitation,and pain control. Gastroenterology consultation and immunosuppression are warranted if clinical assessment and/or imaging findings support moderate/severe acute pancreatitis. For moderate (G2) pancreatitis, hold immunotherapy and initiate methylprednisolone/prednisone at 0.5 to 1 mg/kg/day. Permanently discontinue ICI therapy for severe (G3/4)pancreatitis and administer corticosteroid at 1-2 mg/kg/day.

In cases for which systemic corticosteroid is indicated, treatment should be continued until symptoms improve to≤ G1, followed by dose taper over 4 to 6 weeks. If there is no evidence clinical/radiologic evidence of resuming immunotherapy after a hold for a symptomatic G2 irAE.Consider consulting with a pancreatic specialist regarding rechallenge.Resumption of immunotherapy is not recommended after G3/4 pancreatitis.

Endocrine Toxicity

ICI-related endocrine gland autoimmunity has resulted in dysfunction of the thyroid, pituitary, adrenal glands, and pancreas. Manifestations of immune-mediated endocrine gland dysfunction include hypothyroidism,hyperthyroidism, hypophysitis, type I diabetes, and primary adrenal insufficiency. The mechanisms of ICI-mediated endocrinopathies have been reviewed by Sznol et al and Byun et al.240,241 Because many symptoms of endocrine toxicity could be related to other acute illnesses or underlying malignancy, diagnosis can be challenging. Additionally,clinicians have to differentiate whether the source of endocrine dysfunction is central (ie, pituitary) or primary (eg, adrenal or thyroid) in order to tailor management appropriately.240,241 Due to this potential complexity,endocrinology specialists play an important role in the management of these irAEs, particularly for severe or complex cases. Alessandr et al have reviewed imaging features of endocrine irAEs at presentation and after treatment to assist in making a differential diagnosis.242

Different patterns of endocrine dysfunction have been observed with various ICI regimens. Hypophysitis is characteristic of ipilimumab, while thyroid dysfunction is seen more commonly with PD-1/PD-L1 inhibitors.Other types of endocrine irAEs such as primary adrenal insufficiency and type I diabetes are considerably more rare. Overall, combination ICI therapy was associated with highest incidence of endocrinopathy.86,240,241,243 Median time to onset of moderate to severe endocrinopathy has ranged between 1.75 and 5 months for ipilimumab.Median time to onset of endocrinopathy with PD-1 inhibitor monotherapy ranged from 1.4 to 4.9 months.215,241

A 2018 meta-analysis examined the incidence of endocrine dysfunction across 38 randomized trials enrolling 7551 patients who received monotherapy with PD-1 inhibitor, PD-L1 inhibitor, or CTLA-4 inhibitor; or combination anti-PD-1/CTLA-4 therapy.243 The estimated incidence of

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Management of Immune Checkpoint Inhibitor-Related Toxicities

hypothyroidism was 3.8% with ipilimumab, and up to 13.2% for combination therapy. Compared with ipilimumab, PD-1 inhibitors were associated with a significantly greater risk of hypothyroidism(OR, 1.89;95% CI, 1.17-3.05; P=.03). Interestingly, the risk of hyperthyroidism was higher with PD-1 versus PD-L1 inhibitors (OR, 5.36; 95% CI, 2.04-14.08;P=.002). Overall, the observed incidence of hypophysitis was 6.4% for combination therapy; 3.2% for CTLA-4 inhibitors; 0.4% for PD-1 inhibitors;and below 0.1% for PD-L1 inhibitors. Compared to PD-1 monotherapy,hypophysitis was a more common occurrence during ipilimumab monotherapy(OR,0.29;95% CI,0.18-0.49;P<.001) and combination therapy(OR, 2.2; 95% CI, 1.39-3.60; P=.001). The rarer nature of primary adrenal insufficiency and diabetes precluded statistical comparison of endocrine irAE incidence between different ICI regimens.243

A retrospective review identified 27 cases of new-onset insulin- dependent diabetes from a population of 2960 patients that received ICl therapy over 6 years at 2 academic medical centers (0.9% prevalence).244 All patients who developed or experienced a worsening of diabetes (ie, becoming insulin dependent) had received anti-PD-1/PD-L1 therapy. Median time to onset was 20 weeks after the first ICl cycle; 59% presented with ketoacidosis, 42% had evidence of pancreatitis, and 40% had one or more positive autoantibodies on testing. Additional concurrent irAEs were present among 70% of the individuals with ICl-related diabetes, many of whom experienced other endocrine AEs. Seventy-six percent of the individuals who developed ICI-related diabetes had the HLA-DR4 genotype, a significantly higher frequency than that reported for the general population, suggesting a possible high-risk allele for the development of this irAE.244 However, further research will be needed.

ICI-mediated endocrine toxicity often results in permanent organ damage and typically requires life-long hormonal supplementation.241,245-247 To date,evidence does not suggest that high-dose corticosteroid therapy mitigates

organ damage in most cases of ICI-mediated endocrinopathy; however,corticosteroids may help to mitigate symptoms of acute inflammation in the setting of hypophysitis, adrenalitis, or in some cases, thyrototoxicosis.Experts generally do not recommend corticosteroid therapy for managing hypothyroidism or type I diabetes.240,241,245,247,248

NCCN Recommendations

Thyroid Dysfunction

Thyroid function should be assessed by monitoring the levels of thyroid-stimulating hormone (TSH) and free thyroxine (T4). In the setting of thyroid abnormalities, routine monitoring is recommended every 4 to 6 weeks. This interval can be extended to every 12 to 18 weeks in patients who have normal thyroid function or who continue to be asymptomatic.Evaluation of total T3 is recommended in the setting of abnormal findings.

For asymptomatic or subclinical hypothyroidism, defined as elevated TSH with normal free T4, continue routine monitoring and proceed with immunotherapy. Levethyroxine can be considered for TSH levels above 10 mIU/L. Primary hypothyroidism is characterized by elevated TSH levels (>10 mIU/L) and low free T4 with clinical symptoms. Provide thyroid supplementation and consider endocrine consultation. Prior to starting thyroid replacement therapy, concomitant adrenal insufficiency should be ruled out by testing AM cortisol levels. Low or suppressed TSH with inappropriately low free T4 may present as a sequela of hypophysitis, in which other pituitary axes may be affected. Follow free T4 for thyroid replacement in the setting of hypophysitis-induced loss of TSH production.

Although rare, thyroiditis(often a painless, transient inflammatory process)can occur with ICI therapy. Thyrotoxicosis, observed as low or suppressed TSH (<0.01 mIU/L) with high free T4 and/or total triodothyronine (T3),may be symptomatic in the setting of high free T4. If symptomatic (eg,palpitations, anxiety, insomnia), consider endocrine consultation and propranolol to manage symptoms until resolution. Thyrotoxicosis often

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evolves to hypothyroidism. Repeat thyroid function testing should be performed in 4 to 6 weeks. Findings of persistent suppressed TSH with high free T4/total T3 should be followed by additional testing for true hyperthyroidism and Graves' disease-like etiology. Hypothyroidism usually ensues after an occurrence of ICI-induced thyrotoxicosis. If TSH becomes significantly elevated(>10 mlU/L), thyroid supplementation should be initiated.

methylprednisolone/prednisone at 1-2 mg/kg/day until acute symptoms resolve, typically 1 to 2 weeks. Then taper steroids rapidly to physiologic replacement levels upon improvement. Consider resumption of ICI therapy once symptoms related to mass effect have resolved.

The more common presentation for hypophysitis features deficiency of TSH/ACTH and/or gonad-stimulating hormones, but without symptomatic pituitary swelling. Patients may manifest a variety of symptoms related to deficiency of endogenous thyroid hormone, cortisol, or gonadal hormones.Immunotherapy can be continued while endocrine therapy is titrated to appropriate physiologic levels.

Immunotherapy may be continued in the setting of hypothyroidism or thyrotoxicosis. When appropriate, levothyroxine is given for thyroid hormone supplementation at approximately 1.6 mcg/kg with the intent of getting TSH levels to reference range or age-appropriate values.

Levothyroxine dose can be reduced by 10% to avoid hyperthyroidism in patient populations that may be sensitive to thyroid supplementation (ie,elderly or patients with comorbidities). The guidelines recommend TSH and T4 monitoring every 4 to 6 weeks during immunotherapy, with follow-up every 12 weeks thereafter, as indicated.

Physiologic hormone replacement will likely be required indefinitely(typically life-long), and should include steroid replacement, levothyroxine if accompanied by central hypothyroidism, and testosterone supplementation in males. Provide patient education regarding stress doses of hydrocortisone in the event of infection, trauma, or other medical event. Patients should wear a medical alert bracelet.

Hypophysitis

Acute symptoms of hypophysitis can include headache, photophobia,dizziness, nausea/emesis, fevers, anorexia, visual field cuts, or severe fatigue. Chronic symptoms can include fatigue and weight loss. Workup for hypophysitis should include assessment of adrenocorticotropic hormone(ACTH),AM cortisol, follicle-stimulating hormone(FSH),luteinizing hormone(LH),TSH,free T4, testosterone in men, and estrogen in premenopausal women. Test results indicative of hypophysitis may show low levels of the following: ACTH, AM cortisol, sodium, potassium,testosterone, and DHEA-S. If the patient is symptomatic, a brain MRI with pituitary/sellar cuts is recommended.

Primary Adrenal Insufficiency

Workup for primary adrenal insufficiencyial should include serum cortisol, as well as a comprehensive metabolic panel(CMP) and renin levels.Follow-up evaluation for abnormal findings should include ACTH, LH,FSH, and testosterone. Hallmarks of adrenal damage include low AM cortisol(<5) with ACTH above the reference range, with or without abnormal electrolytes and symptoms. Other abnormalities may include hypotension, orthostatic hypotension, low sodium, and high potassium.

Endocrinology should be consulted for these patients, with specialist evaluation prior to any surgery or procedure. Hold immunotherapy. If patients are hemodynamically unstable, inpatient care and high-dose/stress-dose corticosteroids are recommended. Patients with severe symptoms including hypotension may require additional fluids. It is

Consider consulting endocrinology if a diagnosis of hypophysitis is made.For acute, symptomatic hypophysitis(headache and symptoms that are caused by acute swelling of the pituitary), hold immunotherapy and initiate

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important to initiate corticosteroid replacement prior to other hormone replacement to avoid adrenal crisis. Steroid replacement will include hydrocortisone or prednisone, plus mineralocorticoid replacement(fludrocortisone). Immunotherapy can be resumed once endocrine replacement therapy has been established.

Physiologic hormone replacement will likely be required indefinitely(typically life-long). The goal for physiologic steroid replacement is to identify the lowest steroid dose needed to prevent symptoms of adrenal insufficiency. Provide patient education regarding stress doses of hydrocortisone in case of infection, trauma, or other medical event.Patients should wear a medical alert bracelet.

Hyperglycemia/Diabetes

Fasting glucose is preferred to assess potential hyperglycemia. Note that high-dose corticosteroids can induce or exacerbate hyperglycemia.Consider endocrinology referral and appropriate management if patients are symptomatic or hyperglycemia remains persistently uncontrolled.Management is guided by patient history of type II diabetes mellitus(T2DM), glucose levels, and concern for diabetic ketoacidosis(DKA).Symptoms of DKA may include excessive thirst, frequent urination,general weakness, vomiting, confusion, abdominal pain, dry skin, dry mouth, increased heart rate, and fruity odor on the breath.

For patients with new-onset hyperglycemia less than 200 mg/dL, and/or a history of T2DM with low suspicion for DKA, the observed hyperglycemia may be corticosteroid-related or due to preexisting diabetes.

Immunotherapy can be continued with serial blood glucose monitoring at each dose. Diet and lifestyle modifications are recommended as needed along with medical therapy per institutional guidelines.

Further workup is warranted for findings of 1) new-onset hyperglycemia>200 mg/dL; 2) random blood glucose>250 mg/dL; or 3) history of T2DM

with glucose levels $>250 ~m / d L$ . If any of the previous findings are noted,consider new-onset type I diabetes mellitus (T1DM) and evaluate for DKA.ICI-related development of T1DM is rare (1%-2%) but can be life-threatening if insulin therapy is not provided. Management and monitoring should be directed by endocrinology team. DKA requires hospitalization and immunotherapy hold. Management of DKA varies by institution and may include (but is not limited to) IV fluids with or without potassium supplementation, IV insulin, and hourly testing of glucose,serum ketones, blood pH, and anion gap. Corticosteroid therapy is not recommended for treating T1DM as there is insufficient evidence to suggest that it effectively reverses ICI-related T1DM, and it may further complicate glycemic control.

Pulmonary Toxicity

Pneumonitis has been associated with ICI therapy. Generally, rates of any-grade pneumonitis for PD-1/PD-L1 monotherapy have been reported at or below 5% for all-grade, and around 1% for high-grade pneumonitis. 249,250 Unlike the pattern with most other irAEs, ipilimumab monotherapy has a lower incidence of pneumonitis compared with PD-1/PD-L1 inhibitors, with reported rates of less than 1%.251,252 Observed rates for combination immunotherapy(PD-1/PD-L1 inhibitor plus anti-CTLA-4) are higher than for monotherapy with other ICIs.249,250,253 Although wide-ranging, median time to irAE onset from start of treatment has been reported at 2.5 months, with generally earlier onset for combination versus monotherapy. 249,253

A 2016 meta-analysis of 20 clinical trials of PD-1 inhibitors that enrolled 4496 patients with melanoma, lung, or renal cancer revealed an overall incidence of all-grade and high-grade pneumonitis of 2.7% and 0.8%, with a higher incidence in NSCLC than melanoma.250 Incidence was higher for combination therapy than for monotherapy(all-grade 6.6% vs.1.6%,P<.001;high-grade 1.5% vs.0.2%,P=.001).

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A pooled analysis of 916 patients analyzed pneumonitis among patients who received PD-1/PD-L1 inhibitors with or without anti-CTLA-4 therapy.Incidence of pneumonitis for PD-1/PD-L1 inhibitor monotherapy versus combination therapy(PD-1/PD-L1 inhibitor+ CTLA-4 inhibitor) was 3%versus 10%, respectively(P=.001). No significant differences were observed in rates of pneumonitis between PD-1 and PD-L1 inhibitors. A similar incidence of pneumonitis was observed among the largest disease cohorts, melanoma and NSCLC, for both monotherapy and combination therapy. Of the patients diagnosed with pneumonitis in this study, most low-grade cases were treated in the outpatient setting, but 19% of patients with G2 pneumonitis and all patients≥G3 required inpatient care. All mild pneumonitis(G1) cases were managed using ICI dose holds or oral corticosteroid, while all moderate and severe cases received oral or IV corticosteroid. Among patients with G3 or higher pneumonitis, 42%required additional immunosuppression with infliximab alone or infliximab with cyclophosphamide.249

parenchyma and is typically identified on CT imaging as ground-glass opacities.For mild to moderate pneumonitis(G1), consider holding immunotherapy and obtain chest CT, with repeat imaging in 4 weeks or sooner if clinically indicated for worsening symptoms. For mild pneumonitis, reassess in 1 to 2 weeks, including physical exam and pulse oximetry at rest and with ambulation. For moderate pneumonitis(G2),consult pulmonology and order infectious workup to include nasal swab for potential viral pathogens as well as sputum, blood, and urine cultures. The panel recommends infectious evaluation with institutional immunocompromised panel. Bronchoscopy with bronchoalveolar lavage(BAL) can be used to rule out infection and malignant lung infiltration.Consider chest CT with repeat imaging in 3 to 4 weeks. Consider empiric antibiotics if infection has not yet been fully excluded and begin methylprednisone/prednisolone at 1-2 mg/kg/day. Monitor every 3 to 7 days with physical examination and pulse oximetry. Treat with corticosteroid until symptoms improve to ≤ G1 and then taper over 4 to 6 weeks.The panel recommends treating per the algorithm for severe(G3)pneumonitis if no improvement is seen after 48 to 72 hours of corticosteroid therapy.

NCCN Recommendations

These guidelines characterize mild pneumonitis (G1) as asymptomatic,confined to less than 25% of the lung parenchyma or a single lobe.Moderate pneumonitis (G2) is characterized by the presence of new or worsening symptoms including shortness of breath, cough, chest pain,and fever. Severe pneumonitis (G3) involves all lobes of the lung or greater than 50% of the lung parenchyma. The symptoms typically limit self-care activities of daily living (ADLs). Life-threatening (G4) pneumonitis involves serious respiratory compromise.

Permanently discontinue immunotherapy for all cases of severe or life-threatening pneumonitis. Inpatient care is required. Complete infectious workup and bronchoscopy with BAL as per the G2 algorithm and consult with pulmonary and infectious disease specialists. Consider empiric antibiotics if infection has not yet been fully excluded and begin methylprednisone/prednisolone at 1-2 mg/kg/day. Assess response within 48 hours and plan a slow corticosteroid taper over≥6 weeks. If no improvement is observed after 48 hours of treatment, consider additional immunosuppression with any of the following agents: infliximab,MMF, or IVIG.

Baseline pulmonary function should be determined by measuring oxygen saturation(at rest and with ambulation), and pulmonary function tests are recommended for high-risk patients. Repeat oxygen saturation tests as symptoms indicate and evaluate for pneumonitis via chest CT.

Pneumonitis can present as focal or diffuse inflammation of the lung

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National PLEPPARE NOTED MEDIVE TEC NCCN Guidelines Version 1:2026

Management of Immune Checkpoint Inhibitor-Related Toxicities

Resumption of immunotherapy following mild emergence of improvement. Following G2 irAE, rechallenge can be considered upon resolution of pneumonitis to ≤G1 and no requirement for steroid.

Renal Toxicity

Based on initial studies, the estimated incidence of all-grade renal toxicity is approximately 2% for monotherapy, and up to 4.9% for ICI combination therapy.227,254 Based on a review of phase II and III clinical trials of ICls enrolling 3695 patients, the incidence of high-grade renal toxicity was 0.6%.254 However, reviews of emerging data suggest that incidence of renal toxicity could be considerably higher.255,256 For ipilimumab, time to onset of renal toxicity has been reported to be around 6 to 12 weeks for ipilimumab, but 3 to 12 months for PD-1 inhibitors.257

In the largest case series to date, time to onset of renal toxicity was around 3 months from initiation of ICI therapy, but varied from 3 weeks to approximately 8 months.254 Within the cohort of 13 patients, kidney injury was preceded by an extraren arIAE in 7 patients and pyuria(>5 white blood cells [WBC] per high-power field [HPF]) was present in 8 of 13 patients. Pathology revealed acute tubulointertistial nephritis in 12 of 13 patients. Among the 10 patients who were treated with corticosteroid, 9 patients showed recovery of renal function (complete recovery in 2, partial recovery in 7). Four patients required hemodialysis, and 2 remained dialysis-dependent.254 Other case reports/series have discussed similar approaches to diagnosis and management of ICI-related nephritis.258-260 Notably, there is conflicting evidence surrounding the efficacy of corticosteroid therapy for treating acute interstitial nephritis linked to non-ICI-related causes.261,262

NCCN Recommendations

Elevated serum creatinine could indicate a developing renal irAE. Signs of acute renal failure may include azotemia, creatinine elevation, and ability

to maintain acid/base or electrolyte balance, and changes in urine output.Mild renal irAEs(G1) are categorized by serum creatinine levels 1.5 to 2 times above baseline or an increase in $\geq$ 0.3 mg/dL. Creatinine levels of 2 to 3 times above baseline are considered moderate renal irAEs(G2).With severe irAEs(G3), creatinine levels may be in excess of 3 times above baseline, or >4.0 mg/dL. Creatinine levels > 6 times above baseline indicate life-threatening renal issues (G4) and necessitate dialysis.

Upon development of signs of acute renal damage, the panel recommends conducting a medication review and limiting/discontinuing any nephrotoxic medications(eg, NSAIDS). Dose adjust remaining medications to creatinine clearance. Evaluate for and rule out other potential alternative etiologies for abnormal findings, testing as indicated for potential prerenal and postrenal causes(eg, contrast-enhanced imaging). Distinguish cell infiltrate from immune-complex-mediated injury.Possible considerations should include cardiomyopathy, heart failure,pulmonary hypertension, kidney stones/obstruction, hypovolemia due to a primary Gl issue, diuretics, and infection. Protein-to-creatinine ratio in spot urine samples can be used to assess proteinuria, with follow-up testing for findings of proteinuria above 3 g/24-hour(ie, ANA, RF, ANCA,anti-dsDNA, serum C3 and C4, CH50).

For mild to moderate renal irAEs(G1), follow creatinine and urine protein every 3 to 7 days. Consider holding immunotherapy for G1 renal dysfunction, and hold immunotherapy dose in the setting of moderate renal irAEs(G2). If other causes are ruled out, administer prednisone 0.5-1 mg/kg/day. Increase dose to 1-2 mg/kg/day of methylprednisone/prednisone/prednisone for persistent G2 issues beyond 1 week.After G1/2 irAEs, once symptoms resolve to $\leq$ G1, consider resuming immunotherapy concomitant with corticosteroid.

Permanently discontinue immunotherapy if severe/life-threatening renal irAEs occur. Consider inpatient care, consult nephrology and consider

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renal biopsy, and initiate methylprednisone/prednisolone at 1-2 mg/kg/day. For persistent findings above G2 after 1 week of steroid therapy, consider adding one of the following agents: azathioprine,monthly cyclophosphamide,cyclosporine,inflixab,or mycophenolate.

When corticosteroid therapy is used to manage renal irAEs, continue until improvement to ≤ G1, then taper over 4 to 6 weeks.

Ocular Toxicity

Ophthalmic irAEs are categorized by the affected area of the eye, into ocular inflammation (eg, uveitis, episcleritis, bleharitis, peripheral ulcerative keratitis), orbital inflammation/orbitopathy (eg, idiopathic or thyroid-induced orbitopathy), retinal/choroidal disease (eg, retinopathy or choroidal neovascularization), and optic neuropathy.263-265 Dry eye and uveitis have been the most commonly reported ocular ICI-associated events, with a reported incidence between 1% and 24%.265-267 Based on case series and reports, mild ophthalmic irAEs have generally been managed successfully using a topical steroid, whereas more severe conditions have required systemic corticosteroid therapy and discontinuation of ICI therapy.264,265,268,269 Close cooperation with ophthalmologic specialists is critical for prompt diagnosis and optimal treatment.264,267

NCCN Recommendations

Signs or symptoms such as blurred/distorted vision, changes in color vision,blind spots,ophobia,eye pain,eyelid swelling, and proptosis may indicate the development of an ocular irAE such as uveitis,episcleritis, or blepharitis. Episcleritis can be associated with red/purple discoloration of the eye, and uveitis may present with eye redness.

Grading for uveitis is broken out by mild uveitis(G1), anterior uveitis(G2),posterior or panuveitis(G3), and uveitis causing vision of 20/200 or worse(G4). Episcleritis is graded as mild(G1), associated with vision of 20/40 or

better(G2), associated with vision of 20/40 or worse(G3), or associated with vision of 20/200 or worse(G4).

For mild uveitis, episcleritis, or blearritis, continue immunotherapy,provide artificial tears, and refer to ophthalmology. Avoid eye irritants such as contact lenses and cosmetics. Hold immunotherapy for G2 ocular irAEs and seek urgent ophthalmology consultation. Permanently discontinue immunotherapy for any G3 or G4 ocular irAEs and obtain emergent ophthalmology consultation. Treatment for moderate to severe irAEs should be guided by ophthalmology and will likely include ophthalmic and systemic prednisone/methylprednisone. For ophthalmic conditions refractory to high-dose systemic corticosteroid, consider adding infliximab or an antimetabolic agent(eg, methotrexate).

Corticosteroid treatment should be continued until resolution to $\leq G1$ ,followed by dose taper over 4 to 6 weeks. For G2 ocular irAEs, the panel suggests consideration of resuming immunotherapy in consultation with ophthalmology upon resolution of the irAE to $\leq$ G1. Rechallenge is contraindicated after high-grade irAEs.

Nervous System Toxicity

ICI-mediated neurologic toxicity spans a broad spectrum of conditions related to autoimmunity within the central and/or peripheral nervous systems. Some neurologic irAEs can be quite challenging to diagnose due to nonspecific symptoms, variability in presentation, and the wide range of differential diagnoses to consider.154,156,270 Documented cases of neurologic irAEs include numerous conditions such as myasthenia gravis,GBS-like syndrome, central and/or peripheral neuropathy, aseptic meningitis, encephalitis, and transverse myelitis. With some exceptions(eg, peripheral neuropathies), irAEs of the nervous system are higher grade events by default. Fatalities have been reported in patients receiving encephalitis, myasthenia gravis/myasthenic syndromes, and acute

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immune demyelating polyneuropathy.154,155,270-274 The neurologic irAEs that most commonly resulted in fatality were encephalitis and myasthenia gravis.101

A systematic review of the literature examined data on neurologic AEs from case reports and prospective ICI trials(59 trials, n=9208).275 The overall incidence of neurologic irAEs was 3.8% for CTLA-4 inhibitors, 6%with PD-1 inhibitors, and 12% for combination therapy. Headache,encephalopathy, and meningitis were the most commonly reported events;the majority of events were lower grade.275 Generally, reviews report a≤1% incidence of high-grade neurologic irAEs across various ICI regimens.156,273,275 Another study probed a pharmaceutical Global Pharmacovigilance and Epidemiology database for neurologic irAEs reported in patients with advanced melanoma receiving nivolumab with or without ipilimumab(12 trials, n= 3763).156 Out of 3763 patients, 35(0.93%) experienced 43 serious neurologic irAEs over an 8-year period,with neuropathy being the most commonly reported event. Resolution of irAE(s) was documented in 75% of patients (26 of 35).

leading to partial or full recovery. 154,156,272 However, for several reported cases of myasthenic syndrome, encephalitis, or demyelinating polyneuropathy, irAEs proved fatal despite treatment with multiple lines of immunosuppressant(including plasmapheresis, IVIG, tacrolimus, and/or MMF).154,155 At present, there are no definitive outcomes data to guide decisions regarding immune-modulating treatments, and clinicians have relied on data from neurologic irAE case reports, management of other autoimmune neurologic disorders, and individual patient characteristics(ie, the presence of irAEs affecting other organ systems).154

NCCN Recommendations

Myasthenia Gravis

If myasthenia gravis is suspected, obtain neurology consultation.Alssment should include pulmonary function testing, electromyography(EMG) and nerve conduction study, as well as consideration of brain and/or spine MRI if symptoms are suggestive of malignant CNS involvement.Laboratory testing should include acetylcholine receptor and muscle-specific tyrosine kinase antibodies, erythrocyte sedimentation rate(ESR),C-reactive protein(CRP), creatinine phosphokinase, and aldolase for possible superimposed myositis. If the patient has respiratory insufficiency or elevated CPK, perform cardiac examination to include ECG, troponin, and transthoracic echocardiogram for possible concomitant myocarditis.

Literature and database reviews generally report a median time to onset of neurologic ir AEs of about 6 weeks.154,156,275 Corticosteroid therapy is usually employed as the first line of treatment for neurologic irAEs;high-dose IV corticosteroids and ICI discontinuation was employed in the setting of higher-grade events.154,156 Prompt treatment is critical for reducing long-term morbidity and mortality.123,154,156,270,273 Median time to irAE resolution has been reported at just under 8 weeks.156 Of note, unlike canonical cases of GBS, ICI-mediated development of GBS-like syndrome has been successfully managed using corticosteroid therapy.275

Hold immunotherapy for moderate symptoms(G2) with some interference in ADLs. Administer pyridostigmine and gradually increase to a maximum of 120 mg orally four times/day as tolerated and based on symptoms.Consider low-dose oral prednisone at 20 mg daily and gradually increase agents based on symptom improvement. Consider resuming immunotherapy based on steroid responsiveness. Severe cases(G3/4)warrant permanent discontinuation of immunotherapy, hospitalization, and

Additional lines of immunosuppressive therapy are often required for cases of rapidly progressive or steroid-refractory neurologic irAEs.Autoimmune encephalitis and other neurologic irAEs have been managed with agents such as IVIG, plasmapheresis, rituximab,and cyclosporine,

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neurology consultation with daily neurologic evaluation and frequent pulmonary function testing. Start methylprednisolone 1-2 mg/kg/day. For patients with refractory, severe, or worsening symptoms, initiate plasmapheres or IVIG. Medications that can worsen this condition, such as beta-blockers, ciprofloxacin, and IV magnesium, should be avoided.

<EndOfPara>presentation may be fulminant with profound ileus. Early institution of high-dose steroids in concert with multidisciplinary management is recommended.

In the setting of peripheral neuropathy, obtain neuraxial imaging as recommended by neurology. For mild cases, consider holding immunotherapy and continue to monitor symptoms for any new interference with ADLs due to pain, weakness, difficulty walking, ataxia, or autonomic changes. Hold immunotherapy for moderate cases(G2) and observe closely. If symptoms progress, initiate methylprednisone/prednisone at 0.5-1 mg/kg/day and administer gabapentin, pregabalin, or duloxetine for pain. Increase dose to 2 to 4 mg/kg/day if further progression. Severe peripheral neuropathy (G3/4) is not necessarily GBS, but management can be similar. Gabapentin,pregabalin, or duloxetine can be administered for neuropathic pain.

Guillain-Barré Syndrome (GBS)

Inpatient care with access to intensive care-level monitoring is recommended; consult neurology. Recommended testing includes spinal MRI, lumbar puncture, serum antibody testing for GBS variants, and pulmonary function testing. Permanently discontinue immunotherapy for all cases of GBS and provide inpatient care with capability for rapid transfer to ICU-level monitoring. Initiate IVIG or plasmapheresis in addition to pulse dose methylhypelisnotel (1 g/d for 5 days). Conduct frequent neurologic examinations and pulmonary function testing. Monitor for concurrent autonomic dysfunction and provide non-opiod analgesic for management of neuropathic pain.

Aseptic Meningitis

Unlike classical GBS, in immune-mediated GBS, cerebrospinal fluid (CSF)findings often include elevated protein and WBC count. Although corticosteroid is not typically indicated in idiopathic GBS, a trial is reasonable if the suspected cause is ICI therapy. Slow steroid taper is recommended once symptoms resolve. Immunotherapy rechallenge is not recommended.

When assessing immunotherapy patients for meningitis, exclude potential infectious causes and consider neurology consultation. The panel recommends brain MRI (with and without contrast) to include the pituitary gland, ACTH and AM cortisol can be used to rule out adrenal insufficiency.Lumbar puncture may be helpful in making a differential diagnosis.Relevant measures include opening pressure,CSF cell counts, protein glucose, gram stain, and culture for infectious organisms. Findings may include elevated WBC count with normal glucose, culture, and gram stain.Reactive lymphocytes or histiocytes may be observed on cytology. Based on these results, conduct polymerase chain reaction(PCR) for herpes simplex virus or other suspected viral infections.

Peripheral Neuropathy

Evaluate for other potential causes when assessing mild to moderate peripheral neuropathy. Potential factors include medication, infection,metabolic or endocrine disorders, vascular or autoimmune disease, and trauma, among other potential causes. Any cranial nerve involvement should be treated as a G2 irAE. Gastrointestinal tract paresis due to myenteric neuritis is a rare toxicity associated with ICI therapy.276 The

If severity is mild to moderate, hold immunotherapy. If severe(G3/4),provide inpatient care and permanently discontinue immunotherapy. IV acyclovir can be considered until PCR results are obtained. Once infectious etiology has been ruled out, closely monitor or initiate

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Management of Immune Checkpoint Inhibitor-Related Toxicities

corticosteroid therapy at 0.5-1 mg/kg/day. Provide methylprednisolone dose of 1-2 mg/kg/day for moderate to severe symptoms. Taper corticosteroid rapidly once symptoms resolve. Consider resuming immunotherapy following mild to moderate aseptic meningitis only if symptoms have completely resolved.

bands, cytology, and ononecural antibodies, and conduct viral PCRs as indicated. Laboratory studies include B12 levels, HIV testing, rapid plasma reagin(RPR), ANA, anti-Ro/La antibodies, TSH, and aquaporin-4 IgG and paraneoplastic panel. Inpatient care is recommended. Discontinue immunotherapy. Provide pulse-dose methylprednisolone(1 g/day for 3-5 days) and strongly consider IVIG or plasmapheresis.

Encephalitis

Cardiovascular Toxicity

Infectious causes of encephalitis should be excluded. Consult neurology and perform brain MRI (with and without contrast), lumbar puncture, and electroencephalography (EEG) to rule out seizure activity. Laboratory testing should include CMP, complete blood count (CBC), thyroid panel including thyroid peroxidase (TPO) and thyroglobulin, as well as autoimmune and paraneoplastic panels. Also test ESR, CRP, and antineutrophil cytoplasmic antibody if vasculitis process is suspected. MRI may reveal T2/FLAIR changes typical of what is seen in autoimmune encephalopathies or limbic encephalitis. CSF may have elevated WBCs with lymphocytic predominance and/or elevated protein.

Cardiac irAEs are potentially fatal ICI-associated toxicities that have been associated with ipilimumab, pembrolizumab, and nivolumab. Case series reveal a variety of potential manifestations of cardiovascular irAEs,including myocarditis, cardiomyopathy, cardiac fibrosis, heart failure, and cardiac arrest.76,277,278 Efforts to characterize cardiac irAEs associated with ICI therapy have begun to provide a better understanding of ICI-associated myocarditis. Data collected over 4 years from 8 sites revealed 35 cases of ICI-mediated myocarditis, which were compared to a sample of patients on ICI therapy without myocarditis.278 Prevalence was 1.14% in this patient population with a median onset of 34 days from initiation of treatment. However, recent evidence suggests that ICI-associated cardiovascular toxicity, myocarditis in particular, is more common than initially thought.101,278-280

Hold immunotherapy for mild cases(G1), but permanently discontinue if moderate or severe (G2/3/4) encephalitis occurs. Severe encephalitis warrants inpatient care. A trial of acyclovir can be initiated until CSF PCR results are obtained. Also consider a trial of methylprednisolone 1-2 mg/kg/day. If symptoms are severe/progressive, or if oligoclonal bands are present on CSF, consider pulse-dose corticosteroid (1 g/day for 3-5 days)in addition to IVIG. Consider rituximab if limited or no improvement is seen after 1 to 2 weeks and test results are indicative of autoimmune encephalopathy.

Recent analysis of the WHO database revealed 101 individual case safety reports of severe myocarditis following initiation of ICI therapy.280 Of these cases, 57% had received anti PD-1 monotherapy, and 27% received combination PD-1/PD-L1 plus CTLA-4 inhibitor. For cases with available dosing information(n= 59), 64%(n= 38) had received only 1 or 2 ICI doses at the time of toxicity onset. Concurrent severe irAEs, most commonly myositis and myasthenia gravis, were reported for 42%. Data on cardiovascular comorbidities were not available, but only 25% were on a cardiovascular or diabetes medication regimen.280

Transverse Myelitis

Consult with neurology. Recommended assessment includes MRI of the brain and spine, lumbar puncture, and evaluation for urinary retention or constipation.Examine CSF for cell counts, protein, glucose, oligoclonal

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National PLEASE NOTE: NCCN Guidelines Version 1:2026 Comprehensive Management of Immune Checkpoint Inhibitor-Related

Management of Immune Checkpoint Inhibitor-Related Toxicities

Based on multicenter registry data, myocarditis was observed more often in patients receiving combination ICI therapy and in patients with diabetes.278 Approximately half of the patients diagnosed with myocarditis experienced major adverse cardiac events(MACE), which were defined as“the composite of cardiovascular death, cardiogenic shock, cardiac arrest, and hemodynamically significant complete heart block.278 Troponin levels of≥1.5 ng/mL were associated with a 4-fold increased risk of MACE(HR, 4.0; 95% CI, 1.5-10.9; P=.003). Corticosteroid was administered in 89% of cases, with high-dose steroids resulting in better treatment response. Elevated troponin and higher rates of MACE were observed more commonly among patients who were treated with lower-dose corticosteroid.278

Pre-existing cardiovascular pathology was identified in the majority of patients(5/8) in one case series.277 Co-occurrence with non-cardiac irAEs was also observed in over 50% of patients. Corticosteroids and/or supportive care measures were helpful to improve symptoms in most cases, although permanent cardiotoxicity and fatalities also occurred despite intervention.277 Myositis and myocarditis were observed to co-occur in a recent study of ICI-related fatalities. Notably, myasthenia gravis also co-occurred in 10% of fatal myocarditis cases. 101 Case reports of ICI-related myocarditis have reported irAE flare during steroid taper or ICI rechallenge.281,282 IVIG was successfully used in a case report of smoldering ICI-related myocarditis that initially responded to corticosteroid but flared upon taper.281

NCCN Recommendations

Immediate cardiology consultation and inpatient care is recommended.Assessment should include telemetry monitoring, ECG, and cardiac MRI.Recommended laboratory testing includes cardiac biomarkers(creatinine kinase and troponin) and inflammatory biomarkers(ESR, CRP, and WBC

count). Seek to rule out other potential causes via viral titers,echocardiogram, or biopsy in the case of severe symptoms.

In the setting of severe (G3) cardiac irAE, arrhythmia may be accompanied by significant echocardiogram findings without hypotension,and cardiac biomarkers above the ULN. Life-threatening (G4) cardiac irAEs are denoted by arrhythmia, hemodynamic instability, and cardiac biomarkers more than 3 times the ULN. Permanently discontinue immunotherapy for any G3 or G4 cardiovascular irAEs. The panel recommends methylprednisolone pulse dosing (1 g/day for 3-5 days).Treat until cardiac function returns to baseline, then dose taper over 4 to 6 weeks. For life-threatening cases (G4), if no improvement is noted within 24 hours, consider adding inflixim or anti-thymocyte globulin(ATG).

Musculoskeletal Toxicity

Musculoskeletal and rheumatic irAEs include IA, myositis, and myalgias.Myositis is characterized by inflammation involving the skeletal muscles,and myalgia involves marked discomfort originating from a muscle or group of muscles. IA is typically identified as a result of joint pain(arthralgia) and/or swelling and stiffness after inactivity. Although rare,severe myositis can be fatal and has been documented more commonly in patients receiving PD-1/PD-L1 inhibitor. ${ }^{283}$

A recent systematic review of the literature examined rheumatic and musculoskeletal irAEs associated with ICI therapy. Data from 33 clinical trials, 3 observational studies, and 16 case reports/series were included.283 Arthralgia and myalgia were the most commonly reported irAEs, with a widely ranging incidence of 1% to 43%. Five of 33 clinical trials reported cases of arthritis development, and case reports have described IA,vasculitis, myositis, and lupus nephritis. Prospective cohort studies and retrospective reviews report the incidence of IA or other rheumatologic irAEs among patients receiving ICls to be between 1% and 7%.122,283-285

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Among a prospective cohort of 524 patients receiving ICLs, 35(6.6%) were referred to rheumatology. ${ }^{122}$ Twenty patients had IA that presented similar to rheumatoid arthritis (n=7), polymyalgia rheumaticaica (n=11), or porsiatic arthritis (n=2), while the remaining 15 patients were diagnosed with noninflammatory musculoskeletal conditions. Nineteen patients with IA required low to moderate doses of corticosteroid, and methotrexate was administered in 2 patients. Notably, ICI therapy was not discontinued in these cases.

One case series initially reported on 13 patients (5 receiving nivolumab or ipilimumab monotherapy, 8 receiving combination ICI) who developed new rheumatologic symptoms while receiving an ICI at an academic medical center between 2012 and 2016.286 Clinical presentation varied, with involvement in both large and small joints of the upper and lower extremities. All patients were treated with corticosteroid therapy,demonstrating variable response. The authors later published their findings on the distinct clinical presentation of IA within a cumulative series of 30 patients who received various ICI regimens.287 Patients who received PD-1/PD-L1 inhibitor monotherapy tended to have small joint IA as their sole irAE, whereas patients on a combination regimen (PD-1/CTLA-4 blockade) were more likely to present with knee arthritis, higher levels of CRP, and prior irAE of another type, and display a reactive arthritis-like phenotype. Ten of 30 patients required additional lines of immunosuppressive therapy beyond corticosteroid (ie, methotrexate or TNF blockers).287

Reported cases of IA or other rheumatologic irAEs have generally been responsive to immunosuppressive therapy, with approximately one-quarter to one-third of patients requiring additional lines of therapy beyond corticosteroid.122,287,288

NCCN Recommendations

Inflammatory Arthritis (IA)

When assessing for IA, note the number of joints involved, perform a functional assessment, and obtain imaging as appropriate(eg, x-ray, joint ultrasound, joint MRI). Continue immunotherapy if arthritis is mild and administer NSAIDS or low-dose corticosteroid for refractory symptoms.Intraarticular steroids can be considered depending on joint location and the number of involved joints. For moderately severe arthritis, consider holding immunotherapy and administer prednisone 0.5 mg/kg/day for 4 to 6 weeks. If no improvement is seen within a month, treat per the algorithm for severe IA and seek rheumatology consultation. For severe arthritis that limits instrumental ADLs(with or without irreversible joint damage), hold immunotherapy and prescribe methylprednisone/prednisone 1 mg/kg/day. If no improvement by week 2, consult rheumatology for consideration of additional disease modifying anti-rheumatic drugs depending on the clinical phenotype of inflammatory arthritis. Consider the co-existence of other irAEs in which choice of immunosuppression may be relevant; options may include infliximab, methotrexate, tocilizumab,sulfasalazine, aziophine, leftfunomide, and IVIG. Continued lack of improvement warrants rheumatology consultation for consideration of additional disease-modifying anti-rheumatic agents such as sulfasalazine,methotrexate, or leflunomide.

Continue to treat IA with corticosteroid until symptoms improve to a mild level, then taper the dose over 4 to 6 weeks. Perform serial rheumatologic examinations to monitor the patient's condition; if levels were initially elevated, ESR and CRP testing can also be used to monitor treatment response. After an immunotherapy hold, clinicians can consider resuming therapy upon stabilization or adequate management of symptoms.However, severe IA that impairs ADLs and quality of life may require permanent discontinuation of immunotherapy.

Myositis/Myalgia (Muscle Weakness)

Order a CMP and check creatine kinase and aldolase levels during

workup for myositis or myalgia. Immunotherapy can continue

uninterrupted in the setting of mild pain. Continue serial creatine

kinase/aldolase monitoring and treat pain as indicated. For moderate,

severe, or life-threatening (ie, myositis only, urgent intervention required) irAEs, obtain muscle MRI and EMG. Administer prednisone 1–2

mg/kg/day and treat pain as appropriate. Hold immunotherapy if creatine kinase/aldolase levels are elevated. Muscle biopsy can be considered for severe or refractory cases. Creatine kinase/aldolase serial monitoring

should continue until symptoms resolve or corticosteroid has been

discontinued. Corticosteroid treatment should continue until symptoms are ≤ G1, followed by dose taper over 4 to 6 weeks. Consult rheumatology for follow-up as well as neurology for myositis.

Hematologic Toxicity

This section is under development.

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NCCN Guide/delines Version:2025 National Coefficient Inhibitor-Related

Management of Immune Checkpoint Inhibitor-Related Toxicities

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NCCN Guidelines Version 1.2026 Management of Immune Checkpoint Inhibitor-Related Toxicities

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NCCN Guidelines Version 1.2026 Management of Immune Checkpoint Inhibitor-Related Toxicities

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NCCN Guidelines Version 1.2026 Management of Immune Checkpoint Inhibitor-Related Toxicities

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表 1
Pre-Therapy Assessment	Monitoring Frequencyb	Evaluation for Abnormal Findings/Symptoms
Clinical ●Physical examination ●Patient and relevant family history of any autoimmune/ frequency/consistency) organ-specific disease,indocrinopathy, or infectious disease (ID)	Clinical examination at each visit frequency/consistency) ID screening(human immunodeficiency virus [HIV]; hepatitis A,B, C) as indicated	Follow-up testing based on findings, symptoms
Imaging ●Cross-sectional imaging ●Brain MRI if indicated	Periodic imaging as indicated	Follow-up testing as indicated based on imaging findings
General blood work ●Complete blood count (CBC) (with differential if indicated) ●Comprehensive metabolic panel (CMP)	Repeat prior to each treatment or every 4 weeks during immunotherapy, then in 6-12 weeks or as indicated	HbA1c for elevated glucose
Dermatologic (ICI_DERM-1) ●Examination of skin and mucosa if history of immune-related skin disorder	Conduct/repeat as needed based on symptoms	Consider dermatology referral. Monitor affected skin and lesion type; photographic documentation. Skin biopsy if indicated.
Pancreatic (ICI_ENDO-1) ●Baseline testing is not required	No routine monitoring needed if asymptomatic	Amylase, lipase, and consider abdominal CT with contrast or MRCP for suspected pancreatitis
Thyroid (ICI_ENDO-2) ●Thyroid-stimulating hormone (TSH), free thyroxine (FT4)	Every 4-6 weeks during immunotherapy, then follow-up every 12 weeks as indicated	ICI_ENDO-2
Pituitary/Adrenal (ICI_ENDO-3) ●Consider serum cortisol(morning preferred) and thyroid function as above	Consider repeating every 4-6 weeks during immunotherapy (immuno-oncology [IO]-only regimens], then follow-up every	Morning serum cortisol, adrenocorticotropic hormone (ACTH),TSH,FT4, luteinizing hormone (LH),follice- stimulating hormone (IO)-only premenopausal individuals), and cosytropin stimulation test only as indicated
Fertility
●Advise on family planning and refer to fertility preservation specialists if desired
Pulmonary (ICI_PULM-1) ●Oxygen saturation(resting and with ambulation) ●Consider pulmonary function tests(PFTs) with diffusion capacity for patients who are high risk(eg, interstitul lung disease[ILD] on imaging, chronic obstructive pulmonary disease[COPD], previous suspected treatment-related lung toxicity)	Repeat oxygen saturation tests	Chest CT with contrast to evaluate for pneumonitis, biopsy, or bronchoscopy with bronchoalveolar lavage (BAL) if needed to exclude other causes
●In the absence of prior imaging, consider a chest x-ray
Cardiovascular (ICI_CARD201-1) ●Consider baseline electrocardiogram(ECG) ●Consider high-sensitivity troponin and N-terminal prohomorne B-type natriuretic peptide (NT-proBNP) ●Individualized assessment in consultation with cardiology as indicated	Consider periodic testing for those with abnormal baseline or symptoms	Individualized follow-up in consultation with cardiology as indicated
Musculoskeletal (ICI_MS-1) ● Joint examination/functional assessment as needed for patients with pre-existing disease	No routine monitoring needed if asymptomatic	Consider rheumatology referral. Depending on clinical situation, consider C-reactive protein(CRP), erythrocyte sedimentation rate (ESR), or creatinine kinase (CK)

表 3
CONDITIONS	SIGNS AND SYMPTOMS (MAY INCLUDE ONE OR MORE)
CARDIO: Myocarditis	Chest pain, dyspnea, fatigue, palpitations (arrhythmia: heart block or ventricular ectopic beats), syncope, generalized weakness. This AE may occur in conjunction with myositis and/or myasthenia gravis; these entities must be ruled out.
DERM: Bullous dermatitis	Inflammation of the skin and the presence of bullae, which are filled with fluid. The most common immune-related bullous dermatitis is bullous pemphigoid. May be intense or widespread; intermittent; skin changes from scratching(eg, edema, excoriations, lichenification, oozing/crusts); limiting instrumental activities of daily living (iADLs).
DERM: Maculopapular rash (morbilliform rash)	Macules (flat) and papules (elevated)
DERM: Pruritus	Itching sensation, with or without rash
DERM: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)	SJS, overlapping SJS/TEN, and TEN are characterized by separation of the dermis involving <10%, 10%-30%, and >30% body surface area (BSA), respectively.
DERM: Lichen planus	Violaceous (dark red/purple) papules and plaques without scale over the trunk and extremities, significant pruritus. Erosions and striae (white lines intersecting) in the oral and vulvar mucosa.
DERM: Psoriasis and psoriasis disease	Thick red scaly plaques, accentuated on extensor surfaces,scalp,umbilicus,postauricular surfaces
DERM: Oral mucosa inflammation	Irritated dogs and/or oropharynx, red/white lesions and/or ulcers, lichen planus, mucositis
DERM: Dry mouth (Sicca syndrome)	Dry mouth (may cause difficulty with speaking, eating, swallowing, and/or staying asleep),oral sensitivity, dysarthria, dysphagia, dysgeusia, dental caries/erosion with prolonged salivary hypofunction, dry eye, lack of lubrication
DERM: Oral dyesthesia	Pain most often described as "burning" in the absence of, or disproportionate to, skin changes, oral sensitivity, dysgeusia, phantomgeus, or other altered sensation with normal clinical findings
ENDO: Hyperglycemia-related diabetic ketoacidosis (DKA)	Excessive thirst,frequent urination,general weakness, vomiting,confusion,abdominal pain, dry skin, dry mouth, increased heart rate, fruity odor on the breath
ENDO: Hypothyroidism	Fatigue, lethargy, sensation of being cold, possible constipation, bradycardia. Patient may be asymptomatic or exhibit minimal symptoms
ENDO: Thyrotoxicosis due to thyroiditis	Most patients with thyrotoxicosis due to thyroiditis have minimal, if any symptoms. If symptoms do arise, may include(uncommonly) tachycardia, tremor,anxiety, enlarged and tender thyroid gland(rarely).
ENDO: Hypophysitis	Acute onset headache, photophobia, nausea/emesis, fatigue, muscle weakness; may have low blood pressure
ENDO: Primary adrenal insufficiency	High ACTH with low morning cortisol, abnormal cosytropin stimulation test. This is a rare diagnosis not usually associated with checkpoint immunotherapy.
ENDO: Central hypothyroidism	Symptoms of overt hypothyroidism(fatigue, bradycardia, lethargy, sensation of being cold, possible constipation) plus symptoms of central adrenal insufficiency (nausea/emesis, not feeling well, generalized malaise)
Gl: Esophagitis/Gastritis/ Duodenitis	Nausea, vomiting,dyspepsia, abdominal pain, anorexia
Gl: Diarrhea/Colitis	Watery diarrhea, cramping, urgency, abdominal pain, blood and mucus in the stool, fever, nocturnal bowel movements. Blood in the stool and/or fever should prompt a more thorough workup for infection and for other causes of gastrointestinal (GI) bleeding, including peptic ulcer disease (PUD) and malignant bleeding.
Gl: Transaminitis	Elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
Gl: Cholestasis	Elevated alkaline phosphatase (predominant) with or without bilirubin/AST/ALT elevation
Gl: Pancreatitis	Acute pancreatitis: epigastric pain, nausea, possible vomiting Chronic pancreatitis: chronic abdominal pain, deficiency in pancreatic enzyme production with possible malabsorption
HEM: Hemolytic anemia	Ashthenia, pallor, dark-colored urine, jaundice
HEM: Aplastic anemia	Symptoms secondary to anemia, thrombocytopenia, neutropenia, and infection (dyspnea, fatigue, tachycardia, echymosis, pallor, fever)
HEM: Hemophagocytic lymphohistosictosis (HLH)- like syndrome	Unexplained fever, hepatosplenomegaly, sequelae of low counts, hypofibrinogenemia, elevated ferritin, transaminitis
MUSCULO: Inflammatory arthritis	Joint pain, joint swelling; inflammatory symptoms: stiffness after inactivity, improvement with activity
MUSCULO: Myositis	Myositis is characterized by inflammation and/or weakness involving the skeletal muscles. This adverse AE may occur in conjunction with myocarditis and/or myasthenia gravis; these entities must be ruled out. Common presenting symptoms may include muscle weakness, elevated CK, elevated transaminases, and myalgias.
MUSCULO: Polymyalgia rheumatica (PMR)	PMR symptoms: stiffness with inactivity, fatigue and/or muscle and joint pain typically in shoulders and hips
MUSCULO: Giant cell arteritis (GCA)	Visual symptoms, headache, scalp tenderness, jaw claudication
NEURO: Aseptic meningitis	Headache, photophobia, and neck stiffness, often afebrile but may be febrile. There may be nausea/vomiting. Mental status should be normal (distinguishes from encephalitis).
NEURO: Encephalitis	Confusion, altered behavior, headaches, seizures, short-term memory loss, depressed level of consciousness, focal weakness, and speech abnormality
NEURO: Guillain-Barré syndrome (GBS)	Progressive, most often symmetrical, ascending muscle weakness with absent or reduced deep tendon reflexes. May involve extremities, facial, respiratory, and bulbar and oculomotor nerves. May have dysregulation of autonomic nerves. Often starts with pain in lower back and thighs.
NEURO: Myasthenia gravis/myasthenia gravis-like syndrome	Progressive or fluctuating muscle weakness, generally proximal to distal. May have bulbar involvement (ie,ptosis, extraocular movement abnormalities resulting in double vision, dysphagia, facial muscle weakness, and/or respiratory muscle weakness, May occur with myostitis and myocarditis, which must be ruled out. Respiratory symptoms may require evaluation to rule out pneumonitis. Miller Fisher variant of GBS has overlapping symptoms (ophthalmoplegia and ascending weakness).
NEURO: Peripheral neuropathy	Asymmetric or symmetric sensory-motor deficit. Sensory deficit may be painful or painless paresthesias or potentially life-threatening autonomic(eg),myenteric plexus) dysfunction. Hypo- or areflexia. Isolated sensory deficit or sensory plus lower motor neuron deficit. Gl tract paresis due to myenteric neuritis is a rare toxicity associated with immune checkpoint inhibitor (ICI) therapy.The presentation may be fulminant with profound ileus.
NEURO: ADEM(acute demyelinating encephalomyelitis)	Headache, confusion, seizures, depressed level of consciousness, speech abnormality, focal weakness, sensory change (numbness or tingling), ataxia/loss of balance, or vision loss.
NEURO: Optic neuritis	Vision loss, eye pain, decreased visual acuity, visual field loss, dyschromatopsia, relative afferent pupillary defect, optic disc edema.
NEURO: Transverse myelitis	Acute or subacute weakness or sensory changes bilaterally, often with bowel/bladder changes and spinal level to pinprick, hyperreflexia, positive Babinski.
OCULAR: Vision changes	Blurred/distorted vision, new floaters, itchy eyes, blind spots, change in color vision, diplopia, photophobia, tenderness/pain, eyelid swelling, and proptosis. Scleritis can cause a reddish purple discoloration of the eye. Uveitis can be associated with
PULM: Pneumonitis	Dry cough, shortness of breath, fever, chest pain
RENAL: Acute kidney injury (AKI)	Elevation of creatinine/blood urea nitrogen (BUN), inability to maintain acid/base or electrolyte balance, and urine output change (usually decreased)

表 6
CARDIOVASCULAR SYMPTOMS/SIGNS ADVERSE EVENT(S)	ASSESSMENT/GRADING	MANAGEMENTf
	●Immediate cardiology consultation(preferably cardio-oncology) ● ECG (compare to baseline for any suspected cardiovascular AE)	●Management is tailored to response and acuity of presentation ●High-dose steroids such as IV methylprednisolone 1 g/day for 3-5 days If responding and stable,switch to oral prednisone (1 mg/kg/day), then taper slowly over 6-12 weeks based on clinical response and improvement of biomarkers
Suspected myocarditis/ Pericarditis/ Large vessel vasculitisa	●Ventricular arrhythmias/ Tachycardia ● Conduction abnormalities/heart block ● Heart failure ● Cardiogenic shock ● Pericardial effusion ● Differential Myocardial infarction/ acute coronary syndrome ● Pulmonary embolism (PE); malignant involvement (PE); malignant involvement	Myocarditis → ● If no improvement within 24-48 hours on steroids, initiate additional immunosuppression (listed in alphabetical order): Abatacept Alemtuzumab h Antithymocyte globulin (ATG) Infliximah (use with extreme caution in patients with reduced LV ejection fraction [LVEF]) Intravenous immunoglobulin (lg)(IVig) Methotrexate Mycophenolate Methotrexate ● Mycophenolate mofetii ● Plasmapheresis ●Abatacept with ruxolitinib has been used in concomitant myositis and myocarditisk ● Intensive care unit (ICU)-level monitoring ●Temporary or permanent pacing as required

表 7
DERMATOLOGIC ADVERSE EVENT(S)	ASSESSMENT/GRADING	MANAGEMENTf · Consider holding immunotherapyh ·High-potency topical steroids9 to affected areas
Bullous dermatitis,o	Urgent dermatology consultation: if unavailable, consider skin biopsy q and/or serum testing'	Mild (G1)s	● Hold immunotherapy until G1h ● Prednisone/IV methylprednisolone 0.5-1 mg/kg/day ● If no improvement after 3 days, urgent consultation to dermatology
Bullous dermatitis1,o	Urgent dermatology consultation: if unavailable, consider skin biopsy q and/or serum testing'	Moderate (G2)t	● If no improvement after 3 days, urgent consultation to dermatology
	Severe (G3)u OR Life-threatening (G4)v	● If no access to dermatology, consider inpatient care with dermatology access ● If diagnosis of bullous pemphigoid is confirmed by biopsy or serology, consider rituximabW or dupilumabW

表 8
		Severe (G2)t	Moderate (G2)t
Bullous dermatitis,o	OD	Rege (G3)u OR Life-threatening (G4)v	●Discontinue immunotherapyh 0

表 9
	Stevens-Johnson syndrome(SJS)P	Urgent dermatology consultation:
or	or	Unvasible
Notoxic epidermal	with	unavailable,
$$\text{Intoxic epidermal}$$	consider skin biopsy	which

表 10
MUSCULOSKELETAL ADVERSE EVENT(S)	ASSESSMENT/GRADING	MANAGEMENT9
Polymyalgia rheumatica (PMR)4,v	●Assess for bilateral shoulder and hip girdle pain, and morning stiffness Screen for GCA symptoms (see below) ●Screen for GCA symptoms (see below) ● If visual symptoms or loss, see GCA Assessment/Grading and Management below ●ESR and CRP	●Continue immunotherapy If vision changes or loss present, hold immunotherapy until evaluated for GCAh ●Start prednisone 10-20 mg/day with slow taper over 6-8 weeksw If no resolution, consider holding immunotherapyh and increasing prednisone to 30-40 mgx ●If unable to taper prednisone or no improvement in symptoms, consider: ▶dsMARDs such as methotrexate ●IL-6 inhibitors (tocilizumab or sarilumab)p

表 11
Giant cell arteritis (GCA) (visual symptoms, headache, scalp levels, scalp claudication, often associated with fevers, night sweats, and weight loss)	●Screen for GCA symptoms ●If symptoms present, initiate prednisone 1 mg/kg/day with urgent referral to vascular surgery or ophthalmology for temporal artery biopsy± ultrasound due to risk of vision loss ●If available, refer to rheumatology	●Hold immunotherapyh ●If not already started, initiate prednisone 1 mg/kg/day taper over 8-12 weeks,x,y longer taper may be required ●Urgent referral to rheumatology even in mild cases for consideration of IL-6 inhibitors (tocilizumab or sarilumab) p
Giant cell arteritis (GCA) (visual symptoms, headache, scalp claudication, often associated with fevers, night sweats, and weight loss)	●Screen for GCA symptoms ●If symptoms present, initiate	●Hold immunotherapy 0 ●If not already started, initiate prednisone 1 mg/kg/day taper over 8-12 weeks,x,y longer taper may be required ●Urgent referral to rheumatology even in mild cases for consideration of IL-6 inhibitors (tocilizumab or sarilumab) p

表 12
NEROUS ADVERSE EVENT(S)	ASSESSMENT	MANAGEMENT°	●Hold immunotherapyf if mild/moderate ●Consider discontinuing immunotherapy if severe ●Inpatient care (G3-4cc) ●Consider IV acyclovirdd until HSV and varicella zoster virus(VZV) PCR results obtained ●Add bacterial coverage until cultures/panel results are back ●Rule out bacterial and viral infection, then closely monitor off steroids
Aseptic meningitis	if abnormal neurologic exam of extremities, or unable to obtain exam ●Lumbar puncture(to exclude leptomeningeal disease)aa ●Consider neurology consultation	●Add bacterial coverage until cultures/panel results are back ●Rule out bacterial and viral infection, then closely monitor off steroids ●Start prednisone 0.5-1 mg/kg/day. For severe symptoms may start IV methylprednisolone 1-2 mg/kg/dayee	●Start prednisone 0.5-1 mg/kg/day. For severe symptoms may start IV methylprednisolone 1-2 mg/kg/dayee

表 13
	● MRI of the brain with and without contrastbb
	● Consider MRI of the spine with and without contrast, especially if abnormal neurologic exam of extremities, or unable to obtain exam
Encephalitisy	● Lumbar punctureaa
	● Electroencephalogram (EEG) to evaluate for non-convulsive seizure ● ESR, CRP, ANCA (if vasculitic process suspected)

表 14
PulMONARY ADVERSE EVENT(S)	GRADING	MANAGEMENTf · Consider holding immunotherapyg ·Reassess in 1-2 weeks ·History and physical (H&P) ·Pulse oximetry (resting and with ambulation) ·Consider chest CT with contrasth, i ●Consider repeat chest CT in 4-6 weeks or as clinically indicated if patient develops symptoms
Pneumonitis	Mild (G1)b	●Consider chest CT with contrasth, i ●Consider repeat chest CT in 4-6 weeks or as clinically indicated if patient develops symptoms
Pneumonitis	Moderate (G2)c,d	●Hold immunotherapyg ·Consider pulmonary consultation ·Minimally invasive evaluation ·Consider infectious workup: ▶ Nasal swab for potential viral pathogens ∞ Sputum culture (including bacterial, fungal, and acid-fast bacilli [AFB]), blood culture, and urine antigen test (eg, pneumococcus, legionella) ●Chest CT with contrasth, i and repeat chest CT in 3-4 weeks
Pneumonitis	Moderate (G2)c,d	●Invasive evaluation ·Consider early bronchoscopy with BAL (send for institutional immunocompromised panelk) and consider transbronchial lung biopsy if clinically feasible to evaluate for progressive malignancy, fungal infections, or steroid responsive ILD ●Consider empiric broad-spectrum antibiotics (including coverage for atypical pathogens) if infection has not yet been fully excluded ·Prednisone/IV methylprednisolone 1-2 mg/kg/day ·Consider mycophenolate mofetil as a steroid-sparing immunosuppressant for steroid-dependent pneumonitis at the time of steroid taperingm ●Monitor every 3-7 days with n: H&P and pulse oximetry (resting and with ambulation) ●If no improvement after 48-72 hours of steroids,° treat as grade 3
Severe (G3-4)e	ICI_PULM-2

表 15
Cardio- vascular	· Permanent discontinuation is warranted in the setting of grade 2-4 myocarditis.
Endocrine	● Thyroid: No discontinuation required for hypothyroidism. For symptomatic hyperthyroidism resembling Graves-like disease, consider holding immunotherapy and resuming after workup is complete and there is evidence for improvement in symptoms and TFTs. ● Hypophysitis manifested by deficiency of ACTH, TSH, and/or gonad-stimulating hormones, but without symptomatic pituitary swelling: Immunotherapy may continue while replacement endocrine therapy is regulated. ● Hypophysitis accompanied by symptoms of pituitary swelling(eg, headache, vision disturbance, and/or neurologic dysfunction): Hold immunotherapy until resolution of symptoms after steroid therapy and hormone replacement is initiated; consider resumption of immunotherapy after symptoms related to mass effect are resolved.
1	• T1DM with DKA: Consider resuming once DKA has been corrected and glucose level has stabilized. ● Primary adrenal insufficiency: After appropriate replacement endocrine therapy is instituted, immunotherapy may continue.
Eye	● Hold immunotherapy per guideline; consider resumption of immunotherapy in consultation with ophthalmology.

表 16
GI	•After grade 2 colitis, may consider resumption of immunotherapy after symptoms have resolved to ≤ grade 1. For grade 3 colitis, if combination ICI therapy was used previously, consider resumption of monotherapy with anti-PD-1 or anti-PD-L1. The risk of recurrent colitis is dependent on agent and/or combination resumed(ie,CTLA-4+/-PD-1>PD-1+ LAG-3>PD-1). In rare circumstances in which the patient cannot completely taper off steroids, immunotherapy may be resumed while patient is still on≤10 mg predisneol equivalent daily. Consider concurrent vedolizumab on immunotherapy resumption. ●Esophagitis/gastritis/duodentities: Once symptom remission on medical management has been achieved, immunotherapy rechallenge can also be considered with the same strategy as colitis, although high-level evidence is still lacking. ●Discontinue if irAE is serious or life-threatening. Do not make up doses missed due to irAE and/or required steroid treatment.
Hematologic	●Hemolytic anemia,HLH-like syndrome: Consider resumption of immunotherapy in consultation with hematology. ●Aplastic anemia: For severe or very severe, discontinue. For non-severe, consider resumption of immunotherapy in consultation with hematology. ●Thrombocytopenia: Rechallenge upon resolution of platelet count to ≤ grade 1 (or prior baseline), and treatment for thrombocytopenia has been discontinued.
Kidney	●Hold immunotherapy per guidelines; on resolution to ≤ stage 1, consider resumption concomitant with or without steroid if creatine is stable. ●After restarting immunotherapy, monitor creatinine every 2-3 weeks or more frequently as clinically indicated. If creatinine remains stable, consider longer durations between creatinine checks. Gupta S et al. J Immunoher Cancer 2022;10:e005646. ●Consider permanent discontinuation in the setting of severe (grade 3-4) proteinuria(Discussion). ●For resolved stage 2 and/or stage 3 renal irAE, consider permanent discontinuation if possible; may consider re-challenge if clinically indicated, at least after≥2 months of holding ICI therapy. ●If the patient has partial or complete recovery after AKI, consider rechallenge after discussion with nephrology.
Liver	●Transaminitis without synthetic liver dysfunction: Following a grade 2 irAE, may consider resumption of immunotherapy after ALT/AST return to baseline and steroids, if used, have been tapered to≤10 mg prednisone equivalent daily. ●Permanently discontinue immunotherapy in the setting of G4 synthetic liver dysfunction and/or permanent biliary strictures requiring endoscopic retrograde cholangiopreatatography(ERCP).
Lung	●Progressive grade 1 pneumoniais requiring a hold: Consider resumption on radiographic evidence of improvement. ●Grade 2/3: Consider resuming once pneumonitis has resolved to≤ grade 1 and patient is off steroids. ●Permanent discontinuation is warranted in the setting of severe (grade 4) pneumonitis.
Musculo- skeletal	●Inflammatory arthritis,myositis,PMR,GCA(moderate to severe irAE requiring hold):Resume and stabilization,or adequate management of symptoms. Permanent discontinuation may be warranted for severe inflammatory arthritis,PMR,or GCA that significantly impairs ADLs and quality of life. ●Severe or life-threatening myositis (with or without myocarditis): Consider permanent discontinuation in select patients due to high risk of morbidity/mortality.

表 17
Nervous System	●Myasthenia gravis/myasthenia gravis-like syndrome: Permanently discontinue immunotherapy after grade 3-4 AE. ●GBS: Discontinue immunotherapy for severe(grade 3-4) GBS. ●Peripheral neuropathy: Following hold for grade 1-2 AE, consider resuming if symptoms resolve to≤ grade 1 or if patient has well-controlled isolated painful sensory neuropathy. ●Aseptic meningitis: Consider resuming following mild to moderate AE if symptoms resolve to grade 0. ●Encephalitis: Discontinuation is warranted in the setting of severe encephalitis. ●Demyelinating disease: Discontinuation of immunotherapy following any-grade AE.
Oral Mucosa	●Consider rechallenge after symptoms become grade 1, or mild in the case of oral dyesthesia. ●Discuss risks of potential worsening symptoms compared with benefits for patients with moderate to severe Sicca or dyestesthesia symptoms.
Pancreas	●Symptomatic grade≤3 pancreatitis: Consider resumption of immunotherapy if no clinical/radiologic evidence of pancreatitis± improvement in lipase. Consider consultation with relevant pancreatic specialist regarding resumption. ●Permanent discontinuation is warranted for severe(grade 4) pancreatitis and other related complications(eg, abscess, fistula)
Skin	● Maculapopular rash and/or pruritis: Consider resuming after symptoms have resolved to≤ grade 1(ie, once skin condition is mild/localized with only topical intervention indicated). ●Discontinuation of immunotherapy in the setting of severe or life-threatening bullous disease(grade 3-4), including all cases of SJS and TEN. ● Psoriasis and lichen planus: Rechallenge may be considered if symptoms are controlled and extent of BSA is<30%, especially if the patient is on targeted biologic.

表 18
AChR	acetylcholine receptor
ACTH	adrenocorticotropic hormone
ADEM	acute demyelinating encephalomyelitis
ADL	activities of daily living
AE	adverse event
AFB	acid-fast bacilli
AKI	acute kidney injury
ALT	alanine aminotransferase
ANA	antinuclear antibody
ANC	absolute neutrophil count
ANCA	antineutrophil cytoplasmic antibody
AST	aspartate aminotransferase
ATG	antithymocyte globulin
BAL	bronchoalveolar lavage
BNP	b-type natriuretic peptide
BRAT	bananas,rice,apple sauce,toast
BSA	body surface area
BUN	blood urea nitrogen
CAR	chimeric antigen receptor
CBC	complete blood count
CCP	cyclic citrullinated peptide
CGM	continuous glucose monitoring
CK	reatine kinase
CMP	comprehensive metabolic panel
CMV	cytomegalovirus
COPD	chronic obstructive pulmonary disease

表 19
CRS	cytokine release syndrome
csDMARD	conventional synthetic disease-modifying antirheumatic drug
CSF	cerebrospinal fluid
CTLA-4	cytotoxic T-lymphocyte-associated antigen 4
DAT	direct antiglobulin test
DKA	diabetic ketoacidosis
DM	diabetes mellitus
DRESS	drug reaction with eosinophilia and systemic symptoms
dsDNA	double-stranded DNA
ECG	electrocardiogram
EEG	electroencephalogram
EGD	esophagogastroduodenoscopy
EMG	electromyogram
ENT	ear,nose, and throat
ERCP	endoscopic retrograde cholangiopancreatography
ESR	erythrocyte sedimentation rate
FSH	follicle-stimulating hormone
FT4	free thyroxine
G6PD	glucose-6-phosphate dehydrogenase
GBM	glomerular basement membrane
GBS	Guillain-Barré syndrome
GCA	giant cell arteritis
G-CSF	granulocyte colony-stimulating factor
CGV	gamma-glutamyl transferase
GI	gastrointestinal

表 20
GVHD	graft-versus-host disease	ILD	interstitial lung disease
H&P	history and physical	INR	international normalized
HBsAg	hepatitis B surface antigen	IO	immuno-oncology
HBV	hepatitis B virus	IOP	intraocular pressure
HCP	health care provider	irAE	immune-related adverse event
HCT	hematopoietic cell transplant	IVIG	intravenous immunoglobulin
HCV	hepatitis C virus	LDH	lactate dehydrogenase
Hb	hemoglobin	LFT	liver function test
HIV	human immunodeficiency virus	LH	luteinizing hormone
HLA	human leukocyte antigen	LLN	lower limit of normal
HLH	hemophagocytic lymphohistiocytosis	LV	left ventricular
HSV	herpes simplex virus	LVEF	left ventricular ejection fraction
HUS	hemolytic uremic syndrome	MAS	macrophage activation syndrome
iADL	instrumental activities of daily living	MGFA	Myasthenia Gravis Foundation of America
ICI	immune checkpoint inhibitor	MOG	myelin oligodendrocyte glycoprotein
ICI-T1DM	immune checkpoint inhibitor-associated type 1 diabetes mellitus	MRCP	magnetic resonance cholangiopreatography
ICU	intensive care unit	NAAT	nucleic acid amplification test
ID	infectious disease	NCS	nerve conduction study
IEC	immune effector cell	NIF	negative inspiratory force
IEC-HS	immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome	NK	natural killer
IEF	immunofixation electrophoresis	NT-	nonsteroidal anti-inflammatory drug
Ig	immunofixation electrophoresis	proBNP	N-terminal prohormone B-type natriuretic peptide
IgE	immunoglobulin	OCT	optical coherence tomography
IgG	immunoglobulin G	PCP	primary care physician
IL	interleukin	PCR	polymerase chain reaction
Version 1.2026,10/23/2025	©2025 National Comprehensive Cancer Network® (NCCN®),All rights reserved. NCCN	interleukin	Continued

表 21
ABBREVIATIONS
ILD	interstitial lung disease
INR	international normalized ratio
IO	immuno-oncology
IOP	intraocular pressure
iRAE	immune-related adverse event
IVIG	intravenous immunoglobulin
LDH	lactate dehydrogenase
LFT	liver function test
LH	luteinizing hormone
LLN	lower limit of normal
LV	left ventricular
LVEF	left ventricular ejection fraction
MAS	macrophage activation syndrome
MGFA	Myasthenia Gravis Foundation of America
MOG	myelin oligodendrocyte glycoprotein
MRCP	magnetic resonance cholangiopreatography
NAAT	nucleic acid amplification test
NCS	nerve conduction study
NIF	negative inspiratory force
NK	natural killer
NSAID	nonsteroidal anti-inflammatory drug
NT-	N-terminal prohormone B-type natriuretic peptide
OCT	optical coherence tomography
PCP	primary care physician
PCR	polymerase chain reaction
PD-1	programmed cell death protein 1

表 22
NCCN	National Cancer Network®	NCCN Guidelines Version 1:2026	NCCN Guidelines Index Table of Contents Discussion
NCCN	National Cancer Network®	Management of Immune Checkpoint Inhibitor-Related	NCCN Guidelines Index Table of Contents Discussion	Keckpoint Inhibitor-Related

PD-L1	programmed death ligand 1	TPO	thyroid peroxidase
PE	pulmonary embolism	TRAb	TSH receptor antibody
PFT	pulmonary function test	TSH	thyroid-stimulating hormone
PJP	Pneumocystis jirovecii pneumonia	TSI	thyroid-stimulating immunoglobulin
PMR	polymyalgia rheumatic	TTE	transthoracic echocardiogram
PNH	paroxysmal nocturnal hemoglobinuria	TTP	thrombotic thrombocytopenic purpura
PPI	proton pump inhibitor	ULN	upper limit of normal
PT/INR	prothrombin time/international normalized ratio	UPEP	urine protein electrophoresis
PTT	partial thromboplastin time	UTI	urinary tract infection
PUD	peptic ulcer disease	UVB	ultraviolet B
RBC	red blood cell	VC	vital capacity
RF	rheumatoid factor	VEGF	vascular endothelial growth factor
RNFL	retinal nerve fiber layer	VZV	varicella zoster virus
RPR	rapid plasma reagin	WBC	white blood cell
RR	respiratory rate
RRT	renal replacement therapy
RSV	respiratory syncytial virus
sCR	serum creatinine
SJS	serum creatinine
SPEP	serum protein electrophoresis
TB	tuberculosis
TEN	toxic epidermal necrolysis
TFT	thyroid function test
Tg	thyroglobulin
TNF	tumor necrosis factor
TPN	total parenteral nutrition

表 23
NCCN Categories of Evidence and Consensus
Category 1	Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2A	Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2B	Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the intervention is appropriate.
Category 3	Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

图示：原图识别中

图示：NCCN National MENCC Medive NCC Cancer Network®

图示：NCCN

图示：ADVERSE EVENT(S) ASSESSMENT/GRADING Mild transient reaction(G1) Mild transient reaction ●Intervention not indicated ●Consider premedication with acetaminophen, and antihistamines H2) with future infusions ●Treat per institutional guidelines ●Consider holding or slowing the rate of infusion to half rate ●Continue immunotherapy ●Discontinue premedication with acetaminophen and antihistamines (H1 and H2) with future infusions ●Severe (G3-4)^c Moderate (G2)^b ●Treat per institutional guidelines ●Discontinue offending 1898 class ●Continue immunotherapy ●Consider premedication with acetaminophen and antihistamines (H1 and H2) with future infusions ●Consider corticosteroids (steroids) for patients who premedication may be permitted in these situations ●Treat per institutional guidelines ●Discontinue offending immunotherapy; ●consider alternate agents in therapeutic classl ${}^{c}$

图示：DERMATOLOG ADVERSE EVENT(S) ACSESSMENT/GRADING Mild (G1)^c Moderate (G2)^c × × × × × × × Maxmod Maculopapular rashà Conderate (G2)^c Severe (G3)^c •Hold (G3)^c •Hold (G4)^c •Hold (G5)^c •Continue immunotherapy •Topical emollient and moderate potency$steroids g to affected areas Maculopapular rashà •Consider biopsy if unusual features •Eosinophil count, peripheral blood smear, and liver function tests (LFTs)^b •Overdeator (G3)^c •Hold (G4)^c •Continue immunotherapy •Topical emollient and moderate- to high-potency steroidsg is affected areas •Consider trial of oral antihistamine for symptomatic relief of pruritus •Continue immunotherapy •In addition to moderate temperature 4-15 mg/kg dayi$\times$

图示：Maculopapular rashà Consider biopsy if unusual features ●Eosinophil count, peripheral blood smear, and liver function tests (LFTs)b Severe (G3)e ●Hold immunotherapy●Treatment with high-potency topical steroids9 to affected areas ●Prednisone/lV methylprednisolone 0.5-1 mg/kg/day●Urgent dermatology consultation, consider biopsy●Consider inpatient care

图示：DERMATOLOG ADVERSE EVENT(S) ASSESSMENT/GRADING General (G1, G2, or G3) ················ ·························································································· -Real antihistamines G2, or G3) ················································································································ PERturitusjì Mild（G1* Mild (G1* ) cause Lime (G2) ·Assess for history of prior inflammatory ··/Severe (G3) Moderate (G2) ●Hold immunotherapy ·················

图示：Lichen planus and lichenoid diseases bb,cc

图示：DERMATOLOG ADVERSE EVENT(S) ASSESSMENT/GRADING Mild:<10% BSA Moderate: 10%-30%BSA or not responsive sporiasis and psiasiform diseases ggg,hh Consider deater 2022 Consider and dental evaluation Consider skin biopsy dermatology consultation Moderate: 10%-30%BSA or not responsive sporiasiform diseases ggg,hh Histor and dermatology consultation Mmod: 10%-30%BSA or not responsive Mofilast Morayak Sarek Lindical 10% BSA Domining 10%-0% biologica Hold immunotherapy High-potency topical steroids ● High-potency topical steroids ● Consider transitioning to non-steroidal topical therapies Such as tacrolimus 0.1% or calcipotriene 0.005% for long-term management in intertrinous areas or facial locations Sarek 0. High-potency topical steroids ● Consider transitioning to non-steroidal topical therapies Consider transitioning to non-steroidal topical therapies Sovere: >30% BSA Moderate: 10%-30% BSA or not responsive Sarek Optilipriene 0.005% for long-period rissis ● Near-band UVB phototherapy, if available and feasible term management in intertrinous areas or facial locations Sarek Optilipriene 0.1% or calcipotriene 0.005% for long-period rissis ● Consider: Acitrein (if no childbearing potential) Apremilist Stereat: 01% biologica! Acitrein (if no childbearing potential) Apetilologis 2022;87:399-400.

图示：Dry mouth (Sicca syndrome' r) ● Review medication profile and avoid medications that contribute to dry mouth if possible ● Assess hydration status ● Check salivary pooling in floor of mouth ●Assess thickness of saliva ● Evaluate dentition and gum recession ● Anti-SS-A and anti-SS-B ● Probing G3)(2)/severe (G3)

图示：Mild (G1)vv Most of pain ●�endroce (G2)/ Moderate (G2)/ •Abapentin, high-potency topical steroids(gel or rinse)or viscous lidocaine Moderate (G2)/ ●Hold immunotherapy ●Dietary modifications Assess location and character Mild (G1)vv \■of pain ●Topical steroids (gel or rinse)or Discay ousinale ■viscous lidocaine Moderate (G2)/ •Abapanentin, high-potency topical steroids(gel or rinse)or Assess severity of pain and ●Adietary modifications Mdc has been tested in any work, using this article and is provided to be reproduced in any form without the express written permission of NCCN.

图示：ENDOCRINE ADVERSE EVENT(S) ASSESSMENT Endclinical hypothyroidism ·TSH between 4 to <10 ·Normal FT4 ·Patient asymptomatic OR ·Elevated TSH (\>10) ·Normal FT4 ·Elevated TSH (\>10) ●In TSH elevated,proceed based on TSH levels for TSH levels ●Overt hypothyroidism ·Elevated TSH ▲-Overt HSH ●Low FT4 ●Normal or low TSH ●Low FT4 ●Central hypothyroidism Hypophysitis/Central hypothyroidism(ICI_ENDO-3);exclude recovery from thyrotoxicosis and non-thyroidal illness ●Continue immunotherapy if asymptomatic ●Consider endocrine consultation ●Consider endocrine consultation ●Check serum cortisol to exclude coexistent adrenal insufficiency prior to treatment ●In Initiate thyroid hormone supplementation with levothyroxine n'.....Repeat thyroid hormone supplementation with levothyroxine" ● Iuate thyroid hormone supplementation can follow these experiments on other hand, which are highly synthesized and no thypyroidism ●Systolic system's impact of hybrid histology (60.71/30.8)

图示：ENDOCRINE ADVERSE EVENT(S) ASSESSMENT •Cortisol and ACTH (morning preferred),t TSH,FT4,serum Na • Consiser LH,FSH,and sex Hypophysitisj,r • • Resinsin efficiency is not recommended in acute settings •Brain MRI ± contrast with pituitary/ sellar cuts,especially if mass effect symptoms or concern for metastatic disease • • Cosyntropin stimulation testing is not recommended in acute settings N • Brain MRI ± contrast with pituitary/ sellar cuts,especially if mass effect symptoms or concern for metastatic disease • * Early宣鸦 inufficiency (high ACTH with low morning cortisol, abnormal) Physologic steroids in ambulatory patients and stress dosing for acute illness or surgery/procedures • \ - Central hypothyroid (normal or low TSH, low FT4) Thyroid hormone replacement, titrate to FT4 level

图示：#Hypophysitisj,r ADVERSE EVENT(S) ·Evaluate for symptomsr,s -Cortisol and ACTH(morning preferred),t{TSH,FT4,serum Na Consider LH,FSH, and sex hormonesasappropriate systemis is not recommended in acute settingsu,S -· ● Brain MRI± contrast with pituitary/sellar cuts, especially if mass effect symptoms or concern for metastatic diseaser,V

图示：Primary adrenal insufficiency (high ACTH with low morning cortisol, abnormal abnormal constrathery low morning cortisol, cosyntropin stimulation test) ● Reare diagnosis that is not usually associated with checkpoint immunotherapy ● If there is concern for this diagnosis, recommend endocrine consultation

图示：DANGER SETSMBS ADVERSE EVENT(S) ASSESSMENT SUSPECTED DIAGNOSES Myocarditis ICI_CARDIO-1 ICI_ENDO-1 4 3 2024 1.2024 Upsilon NCCN WCCN Control Non-ICI-related Ⅰ Myerglycemia-related DKA ICI_ENDO-1 ICI_ENDO-2 Hypothyroidism/thyrotoxicosis ICI_ENDO-3 Hypophysitis/primary adrenal insufficiency ICI_ENDO-3 Unexplained drop in hemoglobin ICI_HEM-1 Myositis ICI_MS-3 Pneumonitis ICI_PULM-1

图示：● Diarrhea ● Colitis ● Moderate (G2)" ● In our appropriate clinical contacts, consider ova \& parasites; molecular testing for Giardia, Cryptosporidium spp.,G.histolytica, microsporidia, and Cyclospora/isospora spp. ● Fecal calprotectin±lactoferrin° ● Diarrhea ● Diarrhea ● Colitis ● Severe ●ICI GI-4 G3-4 Mild (G1)^k ● Diarrhea ● G(G2)^k ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ● Diarrhea ●

图示：- Diarrhea - Colitisj Moderate (G2)' - Fecal transport of the other 22536. C. difficile - NAATs for Gl pathogens (other bacteria, viruses) - In appropriate clinical context, consider ova \& parasites; molecular testing for Giardia, Cryptosporidium spp.E.,histolytica, microsporidia, and Cyclospora/isospora spp - Fecal calprotectin± lactoferrin - Consider abdominal/pelvic CT with contrast's · Consider GI Consultation Colonoscopy or flexible sigmoidoscopy - EGD with biopsy^{\circ}

图示：#####Elevated ALT/AST $\rightarrow$ $055527444444 G1 $<3\times 0$ upper limit of normal(ULN) $\rightarrow$ G2 $<3\times 0$ upper limit of normal(ULN) $\rightarrow$ G3 >5 to 20 x ULN G4 >20 x ULN IICI GI-6 4 5 2 905 1000 125 195 180 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 195 1

图示：General (G3 or G4) General (G3 or G4) ●Elevated ALT/AST G3 >5 to 20 x ULN G4 >20 x ULN ·Concomitant elevated Gl/hepatology ∞=Reuse ●See Assessment on ICI Gl-5 eva evaluation G3 G4 G3.

图示：EPEDKaline phosphatase (predominant)nn with or without bilirubin/AST/ALT elevation00 Consider fiber infiltration of charge 5-nuclei 2020 G1<2.5 x ULN (or baseline) 允2.5-5 x ULN (or baseline) G2 2.5-5 x ULN (or baseline) OPERUM Iteathline G4 20 >20 3 4 G3 5 -20 x ULN (or baseline) OHR

图示：PANCREATIC ADVERSE EVENT(S) ASSESSMENT/GRADING Mild S3 x ULN lipase Elevation in lipase (asymptomatic) •Assess for signs/symptoms of pancreatitis $^{t}$ If clinical concern for pancreatitis, see $^{I}$ CJI $-9$ ●If isolated elevation of enzymes without evidence of pancreatitis, consider continuing immunotherapy$\text{e} ●Evaluate for pancreatitis ($CI_I$_G-9) If evidence of pancreatitis, manage according to pancreatitis algorithm ($I_C_I$_9) ●Consider other causes for elevated lipase $\text{uu}$

图示：NCCN National ed MEDIVE NCCN National

图示：Acute pancreatitisxx Assess for signs/symptoms of pancreatitis 049 ■ ■ Assess for signs/symptoms 0 Assess for signs/symptoms of pancreatitis 0ncreparitis Abdominal CT with contrast 0nrevisiting{NCCN 0ncreparatitis Assess for signs/symptoms 0 Assess for signals/symptomsments 0 of pancreatitis 0 Assess for signs/symptoms of pancreatitis 0ncreparatitis Abdominal CT with contrast 0nrevisiting ASSESSMENT/GRADING General ·Evaluate for signs/symptoms of pancreatic of pancreatitis 0ncreparitis ●Assess for other causes (ie,alcohol use,biliary) ·Assess for IgG4; If positive, manage as autoimmune pancreatitis Pancreatitis 0ncreparitis ●Assess for signs/symptoms of pancreatitis of pancreatitis 0ncreparitis ●Assess for other causes (ie, alcohol use,biliary) $\bullet$Assess for IgG4; If positive, manage as autoimmune pancreatitis Pancreatitis 0creparitis ●Overstate for signal 25°ppfical 95°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfical 96°ppfic

图示：HEMATOLOGIC ADVERSE EVENT(S) ASSESSMENT anemia such as bleeding (eg, fecal occult blood test) and iron, B12, and folate deficiencies Aplastic anemiad ICI HEM-3 HCIEM-2 Unexplained drop in hemoglobin (Hb)a Unexplained drop in hemoglobin (Hb)a$\_$ $\_$

图示：Unexplained drop in hemoglobin (Hb)a Aplastic anemiad ICI HEM-3 HLH-like syndrome,f ICI HEM-4 Thrombocytopenia ICI HEM-5 Amidor 2023 Bone marrow biopsyb/aspirate Aplastic anemiad ICI HEM-3 HLH-like syndrome,f ICI HEM-4 Thrombocytopenia ICI HEM-5

图示：HEMATOLOGIC ADVERSE EVENT(S) ASSESSMENT GRADING Non-severe: Does not meet does not meet severe or very severe or severity · Hold immunotherapyg · Consider: Red blood cell (RBC) and/or platelet transfusion as per institutional guidelines ·Red blood cell (RBC) and/or platelet transfusion as per institutional guidelines HEMATOLOGIC ADVERSE EVENT(S) · See Assessment on ICI HEM-1 ·Increased CBC monitoring ·Increased CBC moneturnal hemoglobinuria (PNH) ·Very severe Ìr

图示：National NCCN Management Checkpoint Inhibitor-Related HEMATOLOGIC ADVERSE EVENT(S) ASSESSMENT GRADING Grade 1 Grade 2 ·Consider increased CBC monitoring ·Peripheral blood marced Reticulocyte count PT/INR, partial thromboplastin time (PTT), fibrinogen Abdominal ultrasound Infection panel: HIV,hepatitis C virus (HCV), H. plotoria ·Underd 1275,000/mm3 ·Grade 75,000/00m3 Grad 2 ·Continue immunotherapy ·Monitor for signs of bleeding 75,000/mm3 ·Add 2020-1.2024 Grade 2 50,000/mm3 ·Hold Immunotherapy ·Hold immunotherapy ·Considerne bone marrow results are not conclusive or other cell lines affected and aplastic anemia suspected ·Evaluate for and rule out other non-ICI-related etiologies of thrombocytopenia ·Examples include medication-related causes, infection,thrombotic therapy (TTP) rehomotic purpura (TTP), hemolytic uremic syndrome (HUS),and HLH

图示：Guillain-Barré syndrome (GBS)^j\rightarrow abla_{\text {V}}(P_{1},P_{2})=\frac{\text { Inpatient care with access to ICU-level }}{\text { Inuteri level }} \cdot{MRI}\text { of the spine with and without }\\ 2.1333-23.333-24.33\text { contrast (rule out compressive lesion) } \end{array} \begin{aligned}& \text { |Inpatient care with access to ICU-level } \\ \text { CR16 } \end{aligned} \right. \begin{aligned}& \text {. Neurology consultation \\ \\ \end{aligned} \right. \text { - MRI of the spine with and without \\ \end{aligned} $\text { contrast (rule out compressive lesion) } \end{aligned} \t$ $\begin{aligned} \\ \text { CR16 } \end{aligned}$ \begin{aligned} \text {. Neurology consultation \\ \\ \text { CR16 } \end{aligned} \end{aligned} \t$ $\begin{aligned} \text { MRI of the spine with and without \\ \text { contrast (rule out compressive lesion) } \end{aligned} \right.$ $\begin{aligned} \text { CR16 } \end{aligned}$ \begin{aligned} \text {. Neurology consultation \\ \text { CR16 } \end{aligned} \end{aligned} \t$ $\begin{aligned} \text { - } \\ \text { Serum glioside antibody tests for \text { GBS } \text { variants (GQ1b for Miller Fisher } \\ \text { variant associated with ataxia and } \\ \text { ophthalmoplegia) } \end{aligned}$ $\begin{aligned} \text { + } \\ \text { Severe (G3-4)" } \end{aligned} \begin{aligned} \text { Moderate (G2)m } \\ \text { or } \\ \text { Severe (G3-4)" } \end{aligned} \end{aligned} \begin{aligned} \text { "Stance in1M3M}\\ \text { Moderate (G2)m } \\ \text { Severe (G3-4)" } \end{aligned} \end{aligned} \begin{aligned} \text {.1} \text { Inpatient care with capability of rapid transfer \\ \text { to ICU-level monitoring} \\ \text { to ICU-I level monitoring} \\ \text { - Start IVIGh or plasmapheresis in addition to IV} \\ \text { methylprednisolone 1 gram daily for 5 dayso}\\ \text { then taper over 4 weeks } \\ \end{aligned} \end{aligned} </td> <td>●Discontinue immunotherapyf</td> <td>of rapid transfer to ICU-level monitoring</td> <td>●Start IVIGh or plasmapheresis in addition to IV methylprednisolone 1 gram daily for 5 dayso</td> <td>to ICU-Lhgh or plasmapheresis in addition to IV 4 week</td> <td>●Stive IVIGh or plasmapheresis in addition to IV 4 methylprednisolone 1 gram daily for 5 dayso</td> <td>●Stive (G3-4)" </td> <td>then taper over 4 weeks</td> <td>●Frequent neurologic evaluation and pulmonary function monitoring</td> <td>5.2 function monitoring</td> <td>5.2 function monitoring</td> <td>5.2 function monitoring</td> <td>5.2 function monitoring</td> <td>5.2 function monitoring</td> <td>5.2 function monitoring</td> <td>5.2 function monitoring</td> <td>5.2 function monitoring</td> <td>5.2 function monitoring</td> <td>5.2 function monitoring</td> <td>5.2 function monitoring</td> <td>5.2 function monitoring</td> <td>5.2 function monitoring</td> <td>5.2 function monitoring</td> <td>5.2 function monitoring</td> <td>5.2 function monitoring</td> <td>5.2 function monitoring</td> <td>5.2 function monitoring</td> <t

图示：NERVOUS SYSTEM ADVERSE EVENT(S) Mild (G1)^r and Moderate (G2)^s Mild (G2)^s Mild (G1)^r Moderate (G2)^s Severe (G3-4)^t GBS (ICI) Consider B12, HbA1c, serum protein electrophoresis (SPEP) with immunofixation, HIV, and antineutrophil cytoplasmic antibody (ANCA) ●Consider have3609.05 ·B12, HbA1c, SPEP with immunofixation, HIV, and ANCA ●Consider EMG/NCS ●Consider EMG/NCS ●Consider neurology consultation ·For progress, a result by using a general model by using the following potential to investigate using E2004.0 Merg (G2)^t Peripheral neuropathyp,q Moderate (G2)^s Merg (G1)^r 01, H12, HbA1c, SPEP with immunofixation, HIV, and ANCA ●Neuraxial imaging as per neurology ●Consider EMG/NCS ●Consider neurology consultation ●Gabapentin, pregabalin, or duloxetine for pain Severe (G3-4)^t GBS (ICI) I1, NCCN ●Consider interference with ADLs, symptoms concerning to the patient (ie, pain but no weakness or gait limitation). S Some interference with ADLs, symptoms concerning to the patient (ie, pain but no weakness or gait limitation). The limiting self-care and aids warranted, weakness limiting walking or respiratory problems (ie, leg weakness, foot drop, rapidly ascending sensory changes). The is a low threshold to hold ICls in mild cases of peripheral neuropathy. Sereve peripheral neuropathy and sensory ganglionopathy are not necessarily GBS but the management can be similar. There is a low threshold to hold ICls in mild cases of peripheral neuropathy. Sereve echnology (CI I) NEURO-2) I1, NCCN ●Consider interference with E2004.0 M M O Sour (CI I) NEURO-2) 1, NCCN ●Consider interference with E2004.0 ·B12, HbA1c, SPEP with immunofixation, HIV, and ANCA ●Initial observation or initiate prednisone 0.5-1 mg/kg orally (if progressing from mild) ·If progression, initiate IV methylprednisolone 2-4 mg/kg/day " and see GBS (ICI NEURO-2) ·Gabapentin, pregabalin, or duloxetine for pain

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图示：OULAR ADVERSE EVENT(S) ACERSE EVENT(S) Ophthalmology evaluation and management essential with vision testing to include:Visual acuity in each eye Color vision Pupil size, shape,and reactivity Vision or ocular ocular layer (RNFL) AsSESSMENT/GRADING Vueitis Posterior or panuveitis (G3) 20/200 or worse vision Pupil size, shape,and reactivity Vision or ocularly in intracularular pressure (IOP)Retinal nerve fiber layer (RNFL) Macula optical coherence (OCT) no tomography (OCT) Dilated and visco evaluation:Visual acuity in each eye Color vision Pupil size, including color and reactivity and reactivity Vision or ocular ocular changes a,b Macula optical coherence (OCT) Episcleritis Mild (G1) ·Moderate decrease (worse than than 20/20 but better than 20/20 or 3 lines decreased vision from baseline) (G2) Meadate decrease (worse than 20/40, or≤3 lines decreased 20/40 or >3 lines of decreased vision from baseline, up to 20/200) or worse vision (G4) EDI CLOUC-2 for sclritis, or sinrular and reactivity Vuneitis ·Hold immunotherapy ·Amperular or panveitis (G3) ·Posterior or panveitis (G4) Vuneitis ●Hold immunotherapy ·Treatment guided by ophthalmology ·Holdimmotherapy ·Treatment guided by ophthalmology ·Treatment guided by ophthalmology ·Treatment guided by ophthalmology ·Treatment guided by ophthalmology Maldone decrease (worse than 20/20 but better than 20/40, or 3 lines decreased 20/40 or >3 lines of decreased vision from baseline, up to 20/200) or worse vision (G4)

图示：OULAR ADVERSE EVENT(S) ASSESSMENT/GRADING Scleritis \varnothing - Mild (G1) Oral NSAIDs (eg, flurbiprofen, indomethacin) ● Moderate decrease (worse than 20/20 but better than 20/40, or $\le3$ lines Decreased decrease (worse than 20/40 -20/GHER - Maxed decrease (worse than 20/40 or>3 lines of decreased vision from baseline baseline, baseline, up to 20/200 (G3) 20/200 or worse vision - Continue immunotherapy ●Artificial tears Pupil size, shape, and reactivity Visual field RNFL OIP Dilated容易 with vision eq examination Slit lamp examination ovate for other common causes (HLA-B27),including IDC IDC Mild (G1) Moderate decrease (worse than 20/20 - Not better than 20/40 but better than 20/40, or $\le3$ lines permost and lower vision Marked decrease (worse than 20/40 -20/GHER or>3 lines of decreased vision from baseline AIl Oop LIP RNFL OIP -Marked decrease (worse than 20/40 or>3 lines of decreased vision from baseline Plypl size, shape, and reactivity Mudery field RNFL OIP Moderate decrease (worse than 20/20 but better than 20/40 or>3 lines decreased vision from baseline) 20/200 or worse vision Hold (G1) Mild (G1) ● Moderate decrease (worse than 20/20 but better than 20/40, or $\le3$ lines per most and decreased vision from baseline) Mild\r or>3 lines of decreased vision from baseline, up to 20/200) (G3) Note: All recommendations are category 2A unless otherwise indicated.

图示：OULAR ADVERSE EVENT(S) ASSESSMENT Build(G1) Moderate decrease ( worse than 20/20 but better than 20/40, or $\simeq 3$ lines decreased vision from baseline) (G2) Vision or ocular changes a,b Ocular ADVERSE EVENT(S) Ophthalmology evaluation and management essential with vision testing to include: Visual acuity in each eye Color vision Pupil size, shape,and reactivity Vision field IOP RNFL Macula OCT Dilated NCCN Medical decrease (worse than 20/40 endroly like eye disease/cranial or >3 lines of decreased vision from baseline) (G3) 20/200 or worse vision (G4) Irbital Mild (G1) Moderate decrease (worse than 20/20 but better than 20/40, or $\simeq 3$ lines decreased vision from baseline) (G2) Stilt lamp examination Evaluate for other common causes (HLA-B27), including ID°C Optic neuritis/neuropathy Mild (G1) Moderate decrease (worse than 20/20 or 3 lines of decreased vision from baseline) (G3) Mild (G1) Moderate decrease (worse than 20/40 but better than 20/200 or worse vision (G4) | Hold (G1) Mild (G1) Moderate decrease (worse than 20/20 or 3 lines of decreased vision from baseline) (G3) T - Ad 00/200 (G3) Mild (G1) Moderate decrease (worse than 20/20 but better than 20/40 or 3 lines of decreased vision from baseline) (G4) Vision or ocular changes in or $ Vision or ocular changes in or 49 53 67 18 19 20 Mild (G1) Mild (G1) Moderate decrease (worse than 20/20 but better than 20/40 or worse vision from baseline) (G4) V 20 20/200 or worse vision (G4) estortable (G1) Mild (G1) Moderate decrease (worse than 20/20 but better than 20/40 or 20/200 or worse vision (G4) NccN (G1) Moderate decrease (worse than 20/20 but better than 20/40 or 20/200 or worse vision (G4) NccN (G1) Mild (G1) Moderate decrease (worse than 20/20 but better than 20/40 or 20/200 or worse vision (G4) NccN (G1) Hold immunotherapy) Treatment guided by ophthalmology to include systemic prednisone/ IV methylprednisolonef

图示：NCCN National NCCN Control SSESSMENT GRADING National Comprehensive Not i 2026 NCCN National RENAL ADVERSE EVENT(S) ASSESSMENT General:1 Stage 1, 2, 1 A|K ACK 2 A DERSE EVENT(S) Check BUN, spot urine protein/creatinine ratio, urine microalbumin/creatinine ratio, urine electrolytes (sodium, creatinine),b and urinalysis(c) = 1 $NCCN Guiding Stage 1 A|K I^{-} $ Considering immunotherapy Concluding immunotherapy? $ NCCN High $NCCN High $NCCN High $NCCN High $NCCN High $NCCN High $NCCN High $NCCN High $NCCN High $NCCN High $NCCN High $NCCN High $NCCN High $NCCN High $NCCN High $NCCN High $NCCN High $NCCN High $NCCN High $NCCN High $NCCN High $NCCN High $NCCN

图示：#####Elevated serum serum recine and aruruline rule, rule out acute glomerulonephritise 2018 General:Stage 1,2, and 3AKI Management Humpoire-Related GRADING General:Stage 1,1,2, and 3 AKI Limit/discontinue nephrotoxic medications and dose adjust to creatinine clearance Avoid PPIs; use H2 blockers for Gl prophylaxis if initiating corticosteroids ●Consider increased oral/IV hydration and reassess ●Check sCR every 3-7 days ●End my methodapyj ●Consider holding immunotherapyy ●Consider nephrology consult is still sustained elevations in creatinine ●Hold immunotherapyj ●Hold immunotherapyj ●Consider nephrology consult is in a study of computer 2018/1.066777 Methalprynodisone 1-2 mg/kg/day Stage 2 AKI$| ●Hold immunotherapyj ●Consider inpatient care ●Nephrology consultation ●Prednisone/IV methyl prednisolone 1-2 mg/kg/day Stage 3 AKI$| ●Renal biopsyl tive ●Prednisone/IV methyl prednisolone 1-2 mg/kg/day Stage 3 AKI$| ●Based on biopsy results, consider adding one of the following if kidney injury remains> stage 2 after 4-6 weeks of steroids or if creatinine increases during steroid taper (or once off steroids) (in alphabetical order)m: #######Aethioprine Infliximab Mycophenolate mofetil Rituximab #####Note: All recommendations are category 2A unless otherwise indicated.

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引用 / 出处

（2026.V1）NCCN临床实践指南：免疫检查点抑制剂相关毒性的管理. 2026.