A Practical Guide to Managing Common Immune-

Related Adverse Events

Jeffrey S. Weber, MD, PhD

Deputy Director
Laura and Isaac Perlmutter Cancer Center
NYU Langone Health
Professor of Medicine
NYU Grossman School of Medicine
New York, New York

This program is supported by educational grants from Bristol-Myers Squibb and

Merck Sharp & Dohme Corp.
About These Slides
 Please feel free to use, update, and share some or all of these slides in
your noncommercial presentations to colleagues or patients
 When using our slides, please retain the source attribution:

Slide credit: clinicaloptions.com

 These slides may not be published, posted online, or used in

commercial presentations without permission. Please contact
permissions@clinicaloptions.com for details
Faculty Disclosures
Jeffrey S. Weber, MD, PhD, has disclosed that he has received consulting
fees from AstraZeneca, Bristol-Myers Squibb, Genentech,
GlaxoSmithKline, Merck, Moderna, Novartis, and Pfizer.
 Immune-Related AEs Endocrine
Ocular
Uveitis
Conjunctivitis

Throughout the Body Hyper or hyperthyroidism

Hypophysitis
Adrenal insufficiency
Scleritis, episcleritis
Blepharitis
Retinitis
Diabetes
 Are there unique AEs associated with Respiratory
immune checkpoint inhibitor therapy? Liver Pneumonitis
Hepatitis Pleuritis
Sarcoid-like granulomatosis
‒ Yes: immune-related adverse events Renal
Nephritis Cardiovascular
 These represent a new spectrum of Skin
Myocarditis
Pericarditis
AEs that differ in important ways from Rash Vasculitis

those associated with chemotherapy Pruritus

Vitiligo Gastrointestinal
and targeted agents DRESS
Stevens-Johnson
Colitis/diarrhea
Ileitis
Pancreatitis
‒ Immune-related AEs occur through Blood Gastritis
Hemolytic anemia
an imbalance of tolerance and drug- Thrombocytopenia Neurologic
induced immunity Neutropenia
Hemophilia
Neuropathy
Guillain-Barré
Myelopathy
Musculoskeletal Meningitis
Encephalitis
Arthritis
Myasthenia
Dermatomyositis

Champiat. Ann Oncol. 2016;27:559. Slide credit: clinicaloptions.com

 ICI Treatment and irAEs: Basic Issues
 Most but not all irAEs occur during the first 12 wks of therapy (ie, during
induction therapy)
 Steroids can be used to manage almost all irAEs
 Prolonged steroid tapers are usually required
 irAEs can wax and wane, particularly colitis or hepatitis
 Late irAEs can occur: 1 episode reported at Month 47 during maintenance
ipilimumab
 Each irAE has different kinetics of onset:
‒ Skin first, then colitis, then hypophysitis, and finally hepatitis

Davies. Immunotargets Ther. 2017;6:51. Puzanov. J Immunother Cancer. 2017;5:95. Martins. Nat Rev Clin Oncol. 2019;16:563. Slide credit: clinicaloptions.com
 Meta-analysis: Anti–PD-1 Antibody Toxicity
 N = 5353 patients in 9 randomized trials (melanoma, NSCLC, and RCC)
 Absolute risk of treatment-related death: 0.25%
 Discontinuation due to TRAE: 4.7% to 7.7%
 Absolute risk
‒ Any-grade pancreatitis: 0%
‒ Any-grade pneumonitis: 2.65%
‒ Grade 3/4 diarrhea: ~ 1%
 Median time to resolution of grade 3/4 diarrhea: 1-2 wks
Costa. Oncotarget. 2017;8:8910. Slide credit: clinicaloptions.com
 Select Nivolumab-Related AEs:
Kinetics of Onset and Resolution
Skin  Most irAEs are reversible with
35
GI
Endocrine steroids or other immune
30 suppressants
Hepatic
Pulmonary
25 Renal  Early recognition and
(%)(%)

treatment will reduce risk of

Patients

20
complications
Patients

15
 Consultation with an available
10 team of specialists is critical

5
 Little evidence that type of
irAE varies across histologies,
0 except pneumonitis in lung
0 10 20 30 40
Median Time (Wks)
cancer, vitiligo in melanoma
Beginning and end of a curve indicates median time to onset and median time to
Weber. JCO. 2017;35:785. resolution, respectively. Peak indicates incidence of AE. Slide credit: clinicaloptions.com
 Onset of Grade 3/4 Immune-Related AEs With
Nivolumab + Ipilimumab vs Nivolumab
5.6 (0.1-55.0)
Skin (n = 18)
19.4 (1.3-50.9)
Skin (n = 5)
7.4 (1.0-48.9)
Gastrointestinal (n = 46)
26.3 (13.1-57.0)
Gastrointestinal (n = 7)
12.1 (2.9-17.0)
Endocrine (n = 15)
28.6 (19.1-38.1)
Endocrine (n = 2)
7.4 (2.1-48.0)
Hepatic (n = 60)
14.1 (1.9-25.1) Nivolumab + ipilimumab
Hepatic (n = 8)
3.7 (3.7-9.4) Nivolumab
Pulmonary (n = 3)
Pulmonary (n = 1) 6.7 (6.7-6.7)
11.3 (3.3-23.7)
Renal (n = 6) 50.9 (50.9-50.9)
Renal (n = 1)
0 10 20 30 40 50 60
Wks, Median (Range)
Haanen. Ann Oncol. 2017;28(suppl 4);iv119. Larkin. Eur J Cancer. 2015;51(suppl 3):S664. Slide credit: clinicaloptions.com
 Immune-Related AEs with Combination Immunotherapy
 More grade 3/4 irAEs with ipilimumab 3 mg/kg +  The partner with PD-1 blockade will determine the
nivolumab 1 mg/kg (55%)[1]; less with ipilimumab pattern of irAEs
1 mg/kg + pembrolizumab 2 mg/kg (27%)[2] or
ipilimumab 1 mg/kg + nivolumab 3 mg/kg (31%)[3]  Types of irAEs with PD-1/PD-L1 blockade (alone or
in combinations) are similar to those with
 With concurrent or sequential ipilimumab/ ipilimumab but because therapy is longer, the
nivolumab, irAEs are more frequent, more serious, chronic pattern and kinetics are a bit different
and last longer than with PD-1 blockade alone
 Most irAEs resolve except for endocrine and skin
events
AE With Median Time to Resolution, Wks Resolved, Overall, n/N (%) Resolved, Treated With
Nivolumab + Ipilimumab[4] (95% CI) Immunotherapy, n/N (%)
Skin 3.9 (2.1-6.1) 27/33 (81.8) 23/29 (79.3)
GI 3.6 (2.0-4.3) 69/73 (94.5) 62/65 (95.4)
Hepatic 4.3 (3.1-5.6) 74/76 (97.4) 52/52 (100)
Endocrine 15.1 (4.6-NA) 13/21 (61.9) 9/16 (56.3)
Pulmonary 4.5 (0.3-10.1) 6/6 (100) 5/5 (100)
Renal 1.9 (0.4-3.6) 7/7 (100) 4/4/ (100)

1. Larkin. NEJM. 2015;373:23. 2. Long. Lancet Oncol. 2017;18:1202. 3. Hellman. NEJM. 2018;378:2098. 4. Sznol. JCO. 2017;35:3815. Slide credit: clinicaloptions.com
 General Management of irAEs Associated With
Immune Checkpoint Inhibitors
Grade Steroids Treatment Persistent/Recurring

1  Treat symptomatically;  Can continue

no systemic steroids

 Systemic steroids
2  Steroids for selected irAEs and  Continue
for recurrent irAEs  Hold for selected irAEs  Consider withholding;
discontinue if ≥ 12 wks

3  Systemic steroids, prolonged  Systemic steroids and

tapers  Withhold or discontinue* discontinue

4  High-grade systemic steroids,  Discontinue (unless endocrine  Add other immune suppressants
prolonged tapers irAE)
*Discontinue for grade 3 irAEs renal toxicity, pneumonitis, and infusion reactions; question for grade 3 hepatotoxicity.

Selected AEs: colitis, pneumonitis, liver/renal toxicity, hypophysitis, neurologic

Systemic steroids (PO or IV): 1-2 mg/kg/day prednisone or equivalent
 Slow taper over ≥ 4 wks recommended
 Several courses may be necessary if symptoms worsen when dose decreased
Trinh. Asia Pac J Oncol Nurs. 2019;6:154. Brahmer. JCO. 2018;36:1714.
NCCN Guidelines for Management of Immunotherapy-Related Toxicities. v1.2021. Slide credit: clinicaloptions.com
 Risk Factors for Development of irAEs
 Patients with a history of autoimmune disease or who are being
actively treated for an autoimmune disease are at risk for worsening of
their autoimmune disease while on immune checkpoint blockade[1]
 Patients who receive ipilimumab after a PD-1 inhibitor are at greater
risk of developing irAEs, per retrospective studies[2]
‒ A higher rate of grade 3/4 toxicity (up to 35%)
‒ Patients with grade 3/4 toxicity on ipilimumab followed by PD-1 antibody
developed grade 3/4 irAEs in > 20% of cases[1]

1. Menzies. Ann Oncol. 2017;28:368. 2. Bowyer. Br J Cancer. 2016;114:1084. Slide credit: clinicaloptions.com
Questions: Immune-Related Toxicities in
Immuno-Oncology
 At what point and for how long should a patient be treated with
steroids for ICI toxicity? When to use infliximab or mycophenolic acid?
 Can patients with a grade 3/4 immune-related AE ever be retreated
with an ICI?
 For which patients are there absolute contraindications for the use of
ICIs? Allograft transplant? Preexisting autoimmune disease?

Slide credit: clinicaloptions.com

 Dermatitis With Immune Checkpoint Inhibition
 Low-grade rashes common Management
‒ Reticular erythema  Photos to document and follow
‒ Papules to plaques  Consult Dermatology to obtain
 Rare: Stevens-Johnson biopsy
syndrome/toxic epidermal  Low grade: symptomatic
necrolysis, palmar–plantar treatment (eg, antihistamines)
dysesthesia (hand–foot syndrome)
 High grade: topical or oral steroids
 Skin AEs with PD-1 blockade if more severe symptoms
associated with response and
survival in melanoma! ‒ Hold ICIs (grade 3), permanently
discontinue (grade 4)
Weber. Oncologist. 2016;21:1230. Haanen. Ann Oncol. 2017;28(suppl_4):iv119.
Sanlorenzo. JAMA Dermatol. 2015;151:1206. Freeman-Keller. Clin Cancer Res. 2016;22:886. Slide credit: clinicaloptions.com
 Steroid-Refractory Psoriasiform Dermatitis Treated With
an Anti–IL-17α Antibody (Secukinumab)

Secukinumab

Images courtesy of Jeffrey S. Weber, MD, PhD. Slide credit: clinicaloptions.com

 Colitis and Enteritis With Immune Checkpoint Inhibitors
 Diarrhea is a common irAE with General Management[2,4]
ipilimumab (any grade: 31% to 49%; grade
3/4: 10%); less common with  Most cases respond to symptomatic
PD-1 blockade[1] treatment or high-dose steroids with a
long taper (> 1 mo)
‒ Colonoscopy or sigmoidoscopy shows
diffusely erythematous, friable, and  If steroid refractory (48-72 hrs):
occasionally ulcerated mucosa[2] add infliximab
‒ Colon biopsy usually demonstrates
inflammatory colitis with CD4+ >
CD8+ T-cell infiltrate in interstitium[3]
 Can rarely lead to gastrointestinal
perforation (1%), profound ileus, or toxic
megacolon requiring surgery[2]
1. Som. World J Clin Cases. 2019;7:405. 2. Powell. Lancet Gastroenterol Hepatol. 2020;5:679.
3. Ibraheim. Rheumatology (Oxford). 2019;58 (suppl 7):viii17. 4. Kennedy. J Oncol Pract. 2020;16:464. Slide credit: clinicaloptions.com
 Colitis and Enteritis With ICIs: Grades 1/2
 Inflammation can occur anywhere in GI tract Management of Grades 1/2
(eg, mucositis, gastritis, enteritis, colitis)
 Treat symptomatically
 Diarrhea requires attention, especially if:
 Rule out other causes (eg, C difficile,
‒ New and watery
parasites)
‒ Increased frequency > 50% from baseline
 No systemic steroids unless persistent/
‒ Increased duration grade 2
‒ Bloody  Follow closely for resolution
 Grade 1: 1-2 diarrhea episodes above  Grade 2: hold ICIs
baseline in 24 hrs
 Grade 2: 3-6 diarrhea episodes above
baseline in 24 hrs
Gong. JCO Oncol Pract. 2020;16:453. Powell. Lancet Gastroenterol Hepatol. 2020;5:679.
Haanen. Ann Oncol. 2017;28(suppl_4):iv119. Weber. Oncologist. 2016;21:1230. Slide credit: clinicaloptions.com
 Colitis and Enteritis With ICIs: Grades 3/4
 Grade 3: ≥ 7 diarrhea episodes above baseline Management of Grades 3/4
in 24 hrs
 Discontinue ICIs
 Grade 4: life-threatening, perforation
 Ulceration associated with early need for
 Duration, magnitude, and symptoms infliximab to manage steroid refractoriness
determine need for hospitalization
 High-dose steroids and oral budesonide
 Endoscopy often useful, even for prolonged (for enteritis)
grade 2 or grade 3/4 diarrhea
‒ 125-500 mg methylprednisolone IV daily to
start
‒ Slow taper over 1 mo or longer

 If persistent (eg, 48-72 hrs): Consider

infliximab 5 mg/kg (TNF-α blocking antibody)

Gong. JCO Oncol Pract. 2020;16:453. Powell. Lancet Gastroenterol Hepatol. 2020;5:679.
Haanen. Ann Oncol. 2017;28(suppl_4):iv119. Weber. Oncologist. 2016;21:1230. Slide credit: clinicaloptions.com
 ICI-Related Colitis: Radiologic Images
Diffuse thickening of ascending and descending colon,
cecum, and sigmoid colon after first dose of ipilimumab

Images courtesy of Dr. Adi Diab. Slide credit: clinicaloptions.com

 Hepatitis With Immune Checkpoint Inhibition
 LFTs for transaminases and bilirubin required prior to each dose of
anti–PD-1/PD-L1 antibodies ± ipilimumab
 LFT elevations may be associated with hepatotoxicity (jaundice, right upper
quadrant pain, vomiting) or may be completely asymptomatic
‒ Many patients have other nonspecific symptoms (fever, malaise)
 Elevated LFTs often of long duration
 All subjects must meet LFT criteria before each dose of ipilimumab
‒ With no liver mets: < 3 x ULN for AST, ALT
‒ With liver mets/HCC: < 5 x ULN for AST and ALT, < 3 x ULN for total bilirubin

Haanen. Ann Oncol. 2017;28(suppl_4):iv119. Dougan. Gastroenterology. 2020;[Epub]. Ipilimumab PI. Slide credit: clinicaloptions.com
 Managing Grade 3/4 Immune-Related Hepatitis
 Grade 3: LFTs > 5 to 20 x ULN or total bilirubin
> 3 to 10 x ULN
 Grade 4: LFTs > 20 x ULN, total bilirubin > 10 x ULN,
or hepatic decompensation (eg, ascites)
Haanen. Ann Oncol. 2017;28(suppl_4):iv119. Dougan. Gastroenterology. 2020;[Epub].
Management
 Permanently discontinue ICIs
 Consult with a hepatologist; consider liver biopsy
 Intensified monitoring; LFTs every 1-3 days until
begin to resolve
 High-dose steroids (eg, methylprednisolone
1-2 mg/kg/day); if LFTs decrease, convert to oral
steroids
 If no improvement after 72 hrs or rebound:
add mycophenolate 1 g PO BID
 If no improvement in 5-7 days: add tacrolimus
0.1-0.15 mg/kg/day IV (trough level 5-20 ng/mL)
or antithymocyte globulin; infliximab is not
recommended
Slide credit: clinicaloptions.com
 Managing Immune-Related Endocrine Toxicity
 Symptoms will resolve with treatment Management
‒ Slow return of some endocrine function  If moderate/severe symptoms: hold ICIs
‒ Most patients require lifelong hydrocortisone,  If severe headache: methylprednisolone
possibly even thyroid supplement 1 mg/kg/day IV, taper ≥ 4 wks
 Obtain endocrine consultation if hormone
replacement indicated
 Replace deficient hormones
‒ Replace hydrocortisone before thyroid hormone
supplement for hypophysitis

 Use stress-dose hydrocortisone in perioperative

period and critical illness
‒ Educate about stress-dose steroid, emergency
hydrocortisone injection, medical alert bracelet
Postow. Am Soc Clin Oncol Educ Book. 2015;76. Fecher. Oncologist. 2013;18:733.
Haanen. Ann Oncol. 2017;28(suppl 4):iv119. Lewis. Br J Anaesth. 2020;124:251. Slide credit: clinicaloptions.com
 ICI-Related Endocrinopathy
 Prospective study of patients with metastatic melanoma who received ipilimumab (n = 15),
nivolumab or pembrolizumab (n = 103), or ipilimumab + (nivolumab or pembrolizumab) (n = 59)
 n = 31 (18%) developed an endocrine immune-related AE: thyroid dysfunction, 14.0%; hypophysitis,
6.0%; autoimmune diabetes, 0.6%
 Increased risk of endocrinopathy with addition of anti–PD-1 antibodies to ipilimumab
‒ Single or multiple endocrinopathy more likely with ipilimumab + anti–PD-1 antibodies than with anti–PD-1
antibody monotherapy (27% vs 9% and 7% vs 0%, respectively; P < .01)
‒ Endocrinopathies occurred at median of 8 wks from start of treatment (range: 12-225 days) but
significantly earlier onset with combination immunotherapy (median: 30 vs 76 days with ipilimumab
alone; P = .046)
 Most endocrinopathies were asymptomatic, identified with lab (hormonal) screening
 Investigators suggest regular biochemical profiling to identify early endocrinopathy

Scott. Eur J Endocrinol. 2018;178:173. Slide credit: clinicaloptions.com

 ICI-Mediated Endocrinopathy: Type 1 Diabetes Mellitus
 Rare (< 1%), more common with anti–PD-1/PD-L1 Management
antibodies
 Monitor serum glucose at baseline and prior to
 May occur with rapid onset anytime during therapy each cycle of ICI
 Obtain endocrine consult
‒ C-peptide and diabetes-related autoantibodies
(GAD-65, IA-2, IAAA)

 Generally, lifelong insulin therapy is required

 Role of high-dose steroid unclear
‒ Exacerbate hyperglycemia

‒ No data to suggest high-dose steroid can prevent

total β-cell loss

 Resume ICIs once blood sugar well controlled

NCCN Guidelines for Management of Immunotherapy-Related Toxicities v1.2021. Slide credit: clinicaloptions.com
 Anti–PD-1 Antibodies: Managing Pneumonitis
 Pneumonitis has been associated with ICIs but is
uncommon (all grades, ≤ 5%; high grade, ~ 1%)
 Uncommon with anti–PD-L1 antibodies; higher
rates with ipilimumab + nivolumab
 CT findings lag behind patient’s symptoms
 Most cases will resolve with immunosuppressants
 It remains unclear if ICI-associated pneumonitis will
worsen COVID-19 outcomes
NCCN Guidelines for Management of Immunotherapy-Related Toxicities v1.2021.
Haanen. Ann Oncol. 2017;28(suppl 4):iv119. Naidoo. J Immunother Cancer. 2020;8:e000984.
Management
 Routinely check pulse oximetry in all patients
 Obtain chest x-ray in any patient receiving anti–
PD-1 with SOB, chronic cough, increased sputum
‒ Have a low threshold for obtaining a CT scan of the
chest and pulmonary consultation!
 High-dose steroids starting at 1-2 mg/kg/day are
required, then taper over 45-60 days
 May need to retaper steroids if symptoms return
 No relief in 72-96 hrs: use infliximab at 5 mg/kg
 Infectious workup: include a nasal swab for
potential viral pathogens, including COVID-19
Slide credit: clinicaloptions.com
 Immune-Related Pneumonitis: Radiologic Images

6 Wks Post
Treatment
 Hospitalization

 IV steroids
(2 mg/kg/day)

 Pulmonary
consult

Images courtesy of Dr. Adi Diab. Slide credit: clinicaloptions.com

 Go Online for More CCO
Coverage of Immune-Related Adverse Events!
MedicalMinutes on the most important considerations for multidisciplinary healthcare
providers when monitoring for, assessing, and managing irAEs
Downloadable slides with key data from live presentations on this topic
CME/CPE/CE-certified Webcast of a live CCO Webinar featuring
expert perspectives on this topic from a medical oncologist and
oncology nurse practitioner

clinicaloptions.com/oncology
clinicaloptions.com/immuneAEtool